Acute Pain Management From Clinical Evidence to
Clinical Practice
BERNARD LEE MKBERNARD LEE MKDIRECTOR CHRONIC AND INTERVENTIONAL
PAIN MANAGEMENT SERVICECONSULTANT PAIN SPECIALIST
FPM ANZCA (Australia)CONSULTANT ANAESTHESIOLOGIST
M MED (ANAESTHESIOLOGY) (Singapore)MEDICAL ACUPUNCTURIST
AMAC (Australia)
Protective
Noxious stimulusPinchpinprickIntense heatcoldAcute trauma
PNS and CNSlesionsPHNPDNSCI
Neuropathic Pain
Pathological
Post-operative painPost-traumaArthritis Inflammatory
Healingrepairor pathological
Nociceptive Pain Functional Pain
Fibromyalgia
Pathological
TYPES OF PAIN
CNS=Central nervous system IBS=Irritable bowel syndrome PDN=Painful diabetic neuropathy PHN=Post-herpetic neuralgia PNS=Peripheral nervous system SCI=Spinal cord injury
Woolf et al Ann Intern Med 2004140(6)441-51
Nociceptive pain
Neuropathic pain
Functional pain(non-inflammatorynon-neuropathic)
Peripheral nerve damage
No known tissue or nerve damage Abnormal central processing
Multiple mechanisms
Noxious stimuli
Inflammation
3
Multiple Types of Pain
Woolf Ann Intern Med 2004140(6)441-51 Chong et al J Pain Symptom Manage 200325(55)S4-S11
4
Pain and Inflammation Overview
bull Osteoarthritis (OA)bull Rheumatoid Arthritis (RA)bull Ankylosing spondylitis (AS)bull Acute pain
ndash Postoperative painndash Acute ankle sprainndash Acute shoulder tendonitisbursitisndash Acute low back pain
5References 1
European Bone and Joint Health Strategies Project European Action Toward Better Musculoskeletal Health 2005 2
European Opinion Research Group EEIG Health food and alcohol and safety Special Eurobarometer 186 2003
Epidemiology of osteoarthritis (OA) and rheumatoid arthritis (RA)
bull OA and RA are leading causes of severe long-term pain and physical disability1
bull Approximately 1 in 4 Europeans has some form of arthritisrheumatism 1 in 5 is under long-term treatment12
bull OA is the most common joint disorder and accounts for more disability among elderly patients than any other condition1
bull In developed countries 1 in 10 of the population gt60 y has significant clinical problems attributed to OA1
bull RA is the most common form of inflammatory joint disease and affects 03 to 10 of the general population in Europe1
Mem
bran
e Po
tent
ial (
mV)
Mem
bran
e Po
tent
ial (
mV)
60
40
20
0
-20
-40
-60
50 100 15050 100 150
Time (ms)Time (ms)
60
40
20
0
-20
-40
-60
50 100 15050 100 150
Time (ms)Time (ms)
30 seconds after application of 1 mM PGE2
No PGE2
PGE2 increases excitability of neurones
England et al J Physiol 1996495429-440
COX-2 and Peripheral Sensitisation
EP EP receptorreceptor PKAPKA
PKCPKCεε
IncreasedIncreasedneuronal neuronal
membrane membrane excitabilityexcitability
PGEPGE22
SNSPN3SNSPN3
TTx resistantTTx resistantsodium sodium channelchannel
Neurone Neurone firing thresholdfiring threshold
decreasesdecreases
Tissue InjuryTissue Injury
COXCOX--2 expressed2 expressed
P
COXCOX--2 and Central 2 and Central SensitisationSensitisation
Interleukin-1szlig-mediated induction of COX-2 in the CNS contributes to inflammatory pain hypersensitivityTAREK A SAMAD KIMBERLY A MOORE ADAM SAPIRSTEINdagger SARA BILLET ANDREW ALLCHORNEDagger STEPHEN POOLEsect JOSEPH V BONVENTRE amp CLIFFORD J WOOLFDagger
Neural Plasticity Research Group Department of Anesthesia amp Critical Care Department of Anesthesia amp Critical Care and Department of Medicine Massachusetts General Hospital and Harvard Medical School Charlestown Massachusetts 02129 USA
Dagger
Department of Anatomy University College London London WC1E 6BT UK
sect National Institute for Biological Standards and Control Blanche Lane South Mimms Hertfordshire EN6 3QG UK
Nature 2001410471 ndash 475
Convergence at WDR Neurone
Central Sensitisation
tissue or nerve injury
release of EAAsand neuropeptides
increased depolarizationat the NMDA receptor
expanded receptive fieldsand hyperexcitability
Increased Pain
excitotoxicity
loss of inhibition
adapted from Dubner
CNS
Central Sensitization May Have Contributed to OA Pain and Neuropathic
Pain Symptoms1
bull Focus group transcripts from participants with knee OA (N=80) were analyzed to determine the use of unprompted NP descriptors to characterize their pain (including burning tingling pins and needles and numbness) to determine whether people with chronic symptomatic knee OA use pain descriptors suggestive of underlying NP
bull The proportion of participants who used NP descriptors to characterize their pain was 34 (95 CI 24 to 45)
bull Participants using NP descriptors were younger than those who did not (mean age plusmn SD age 648 plusmn 97 years vs 720 plusmn 100 years respectively P=0003)
bull Characteristics that did not statistically distinguish participants who used NP descriptors from those who did included duration of OA pain intensity OA severity and gender
OA = osteoarthritis NP = neuropathic pain CI = confidence interval SD = standard deviation
1 Hochman JR et al Arthritis Care Res (Hoboken) 2010621019ndash1023
Central Sensitization in OA Expansion of Symptoms Beyond the
Joint
bull Quantitative sensory testing of PPTs in patients with knee OA pain (n=48) and matched controls without knee pain (n=24) revealed that subjects with OA pain exhibited sensitization in both OA-affected and unaffected areasndash Increasing pain intensity in
the OA-affected (knee) joint was associated with lower PPT in OA-unaffected areas (eg arm)1
PPT at arm (OA-unaffected area)
R = -032 Plt005
VAS at OA-affected Knee Joint
1500
1000
500
0 1 2 3 4 5 6 7 8 9 10PP
T k
Pa
Arendt-Nielsen L et al Pain 2010149573ndash581
OA = osteoarthritis PPT = pressure pain threshold VAS = visual analog scale
OA = osteoarthritis PPT = pressure pain threshold VAS = visual analog scale WOMAC = Western Ontario and McMaster Universities SF-36 = short form-36 health survey
Central Sensitization in OA Increased Pain Severity and Worse Pain-Associated
OutcomesImamura M et al Arthritis Rheum 2008591424ndash1431
Measure Spearmanrsquos rank correlation coefficient r P Value
VASPatellar tendon Sacral 2 subcutaneous dermatome levelAdductor longus muscle
-0545 -0546 -0561
lt0001 lt0001 lt0001
WOMAC painPatellar tendon Sacral 2 subcutaneous dermatome levelAdductor longus muscle
-0589-0601 -0540
lt0001 lt0001lt0001
WOMAC physical activityLumbar 2 subcutaneous dermatome level Sacral 2 subcutaneous dermatome level Peroneus longus muscle
-0550 -0509 -0571
lt0001lt0001 lt0001
SF-36 bodily painLumbar 1ndashLumbar 2 supraspinous ligamentLumbar 2 subcutaneous dermatome level Adductor longus muscle
0534 0606 0569
lt0001 lt0001 lt0001
A cross-sectional study that assessed hyperalgesia in patients with refractory OA-associated pain (n=62) reported significant correlations between PPT values at each listed site and VAS WOMAC pain and physical activity subscales and SF-36 bodily pain score
SKIN
SPINAL CORD
Dorsal horn
PRIMARY AFFERENT NERVE
Dorsal root ganglion
POSTSYNAPTIC PROCESSPRESYNAPTIC PROCESS
NMDA receptor
Ca2+ Second messengers
kinases (eg PKC) diacylglycerol cAMP
Gene transcription
P
CELL NUCLEUS
Long term changes
(receptor function transmitter production)
Glutamate release
C-fosoncogene
Cortical Reorganisation
I will show that my client is welltolerated amp effectivehelliphellip
I will showthat my clientis well tolerated and effective
bull For chronic pain most measures of treatment response involve patient- reported outcomes for which the patient is the most important judge of whether changes are important or meaningful12
ndash Determinations of statistical significance must be supplemented by consideration of the clinical importance of changes in outcome measures1
bull The IMMPACT consensus meeting proposed provisional benchmarks for identifying clinically important changes in the specific outcome measures for chronic pain clinical trials1
Using NNT Analyses in the Treatment of Pain IMMPACT Consensus Meeting Recommendations
NNT = number needed to treat IMMPACT = Initiative on Methods Measurement and Pain Assessment in Clinical Trials1 Dworkin RH et al J Pain 20089105ndash121 2 Acquadro C et al Value Health 20036522ndash531
10ndash20Reduction in pain intensity
ge50Reduction in pain intensity
ge30Reduction in pain intensity
Minimally Important Improvement
Moderately Important Improvement
Substantial Improvement
132
253
353638
4244
55788
1718
0 4 8 12 16 20
Oxycodone 5Codeine 60Tramadol 50Propoxyphene 65APAP 325Oxycodone 5ASA 650Codeine 60Tramadol 100APAP 650Propox 100APAP 1000APAP 600Cod 60Morphine 10APAP 1000Oxyc 10Ibuprofen 400Oxycodone 15
McQuay H BMJ 1997
Patients with 50 reduction Patients with 50 reduction in pain vs placeboin pain vs placebo
NNT
USE OF PARACETAMOL IN TREATMENT OF OA PAIN
22
How effective was paracetamol
How effective was paracetamol compared with NSAIDs
F Wolfe S Zhao N Lane Preference for nonsteroidal antiinflammatory drugs over acetaminophen by rheumatic disease patients Arthritis amp Rheumatism 2000 43 378-385
2007 League table of NNT for at least 50 pain relief over 4-6 hrs in patients with moderate to severe pain
(all oral analgesics except IM morphine )
[httpwwwmedicineoxacukbandolierboothpainpagacutrevanalgesicsleagtabhtml
ETORICOXIB IN ACUTE PAIN
bull Etoricoxib 120 mg has been approved for treating acute pain which includes post-operative pain and other acute pain such as primary dysmenorrhea and acute gouty arthritis
bull Efficacy of etoricoxib in the post-operative setting as evaluated by NNT bull COCHRANE REVIEW Five randomized placebo-controlled studies
with a total number of 880 patients were included -- Four studies on patients with dental pain following extraction of at least one impacted third molar
--One study on patients with pain following uncomplicated orthopaedic surgery
bull NNT were calculated to measure at least 50 pain relief over 4-6 hrs (substantial pain relief) based on TOPAR scores
Results 120 mg etoricoxib with a NNT of 19 for acute post-operative pain
1 Chang DJ Desjardins PJ King TR Erb T Geba GP The analgesic efficacy of etoricoxib compared with oxycodoneacetaminophen in an acute postoperative pain model a randomized double-blind clinical trial Anesthesia and Analgesia 200499(3)807ndash15
2 Malmstrom K Sapre A Couglin H Agrawal NG Mazenko RS Fricke JR Jr Etoricoxib in acute pain associated with dental surgery a randomized double-blind placebo- and active comparator-controlled dose-ranging study Clinical Therapeutics 200426(5)667ndash79
3 Malmstrom K Kotey P Coughlin H Desjardins PJ A randomized double-blind parallel-group study comparing the analgesic effect of etoricoxib to placebo naproxen sodium and acetaminophen with codeine using the dental impaction pain model Clinical Journal of Pain 200420(3)147ndash 55
4 Malmstrom K Ang J Fricke JR Shingo S Reicin A The analgesic effect of etoricoxib relative to that of cetaminophen analgesics a randomized controlled single-dose study in acute dental impaction pain Current Medical Research and Opinion 200521(1)141ndash9 Rasmussen 2005 published data only
5 Rasmussen GL Malmstrom K Bourne MH Jove M Rhondeau SM Kotey P Etoricoxib provides analgesic efficacy to patients after knee or hip replacement surgery a randomized double-blind placebo-controlled study Anaesthesia and Analgesia 2005101(4) 1104ndash11
Etoricoxib in acute pain bull Indirect comparisons of NNTs for at least 50 pain
relief over 4 to 6 hours in reviews of other analgesics using identical methods indicate that etoricoxib 120 mg
-- has slightly better efficacy than rofecoxib 50 mg (22 (19 to 24) Barden 2005)
-- is significantly better than lumiracoxib 400mg (27 (22 to 35) Roy 2007) or-- celecoxib 400 mg (25 (22 to 29) Derry 2008)
-- better than the non-selective NSAIDs ibuprofen 400 mg (27 (25 to 30) Collins 1999) naproxen 500 mg (27 (23 to 32 Derry 2009a) and diclofenac 50mg (24 (18 to 33Derry 2009b)
Placebo
Paracetamol 10007
Paracetamolcodeine 1000606
Ibuprofen 4005
Celecoxib 4004
Naproxen 5005503
Rofecoxib 502
Etoricoxib 1201
0 4 8 12 16 20 24Median remedication time (hr)
Each bar is from a Cochrane review
Acute pain Time for patients to Re-medication
The weighted median time to re-medication with ARCOXIA 120mg is about 24hrs
vs placebo at 18hrs
1 Clarke R et al Cochrane Database Syst Rev 2009 Apr 15(2)CD004309 2 Bulley S et al Cochrane Database Syst Rev 2009 Oct 7(4)CD0046043 Derry C et al Cochrane Database Syst Rev 2009 Jan 21(1)CD004234 4 Derry S Cochrane Database Syst Rev 2008 Oct 8(4)CD0042335 Derry C et al Cochrane Database Syst Rev 2009 Jul 8(3)CD0015486 Toms L et al Cochrane Database Syst Rev 2009 Jan 21(1)CD0015477 Toms L et al Cochrane Database Syst Rev 2008 Oct 8(4)CD004602
Placebo (n=56)
Etoricoxib 60 mg (n=224)
Naproxen 1000 mgc
(n=221)
a0-
to 100-mm VAS (0 = none to 100 = extreme)
b0-
to 100-mm VAS (0 = very well to 100 = very poor) c500 mg twice dailyPlt0001 vs placebo for both etoricoxib and naproxen P = NS etoricoxib vs naproxen
Leung AT et al Curr Med Res Opin 200218(2)49ndash58
LS M
ean
Cha
nge
plusmnSE
Weeks Postrandomization
Osteoarthritis Etoricoxib 60 mg vs Naproxen
Results Etoricoxib relieved pain and improved mobility and disease statuEtoricoxib relieved pain and improved mobility and disease statuss
ndash35
ndash25
ndash5
5
ndash15
WOMAC Pain Subscalea
S R 4 82 12
WOMAC Physical Function Subscalea PGADSb
ndash35
ndash25
ndash5
5
ndash15
S R 4 82 12ndash35
ndash25
ndash5
5
ndash15
S R 4 82 12Weeks Postrandomization Weeks Postrandomization
Adverse effects of NSAIDsAdverse effects of NSAIDs
BNF March 2002
Dose-dependent toxicityIntolerability dyspepsiaGI bleedingUlcers ndash bleeds perforations
Upper-GI
Renal
Contributes to blood loss
Fluid retention oedema hypertensionRenal dysfunction failure ndash acute chronicHeart failure
Anti-platelet effects
Angioedema bronchospasmHypersensitivity
No Short-Term Adverse GI Effects -
The Big Mistake
bull Study designed to evaluate short-term GI effects in elderly
bull Study planned to enrol 160 patientsbull Study terminated by investigator at 17 subjects
ndash 8 patients had ulcersndash 4 of 4 in ketorolac group
lsquo hellip because of the unexpectedly high incidence of gastroduodenal ulcers observedhelliprsquo
Harris et al ClinTher 2001231422
Class Effect of All NSAIDs
httpwwwfdagovcderdruginfopageCOX2NSAIDdecisionMemopdf
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
33
Cardiovascular Safetybull Arthritis patients often have concomitant CV
disease1
bull Pain is an important predictor of CV risk23
bull Randomized controlled trials and observational data demonstrate that CV risk of etoricoxib appears similar to that of traditional NSAIDs4-6
bull Recent data suggest that differential CV effects of NSAIDs (selective and nonselective) may be independent of COX-2 inhibition78
References 1 Singh G et al Am J Manag Care 20028(suppl)S383-S391 2
Sokka T Pincus T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 3
Pincus T Sokka T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 4
httpwwwfdagovohrmsdocketsac05slides2005-4090S1_06_01_Pfizer-celecoxibppt (accessed 14 February 2006) 5
White WB et al Am J Cardiol 200289425ndash430 6
Graham DJ et al Lancet 2005365475ndash481 7 Yang HM et al Circulation 2004110301ndash308 8 Steffel J et al Circulation 20051111685ndash1689
Events per 100 patient years
Coxib Coxib Placebo Coxib NSAID Percent naproxen
Rofecoxib 17 19 11 08 73
Celecoxib 13 15 11 11 20
Valdecoxib 13 12 13 20 about 50
Etoricoxib 13 12 12 08 67
Lumiracoxib 09 08 52
34
APTC endpoint (cardiovascular haemorrhagic and unknown death and nonfatal myocardial infarction and stroke)
1
MR Weir et al Selective COX-2 inhibition and cardiovascular effects a review of the rofecoxib development program American heart Journal 2003 146 591-604
2
WB White et al Cardiovascular thrombotic events in arthritis trials of the cyclooxygenase-2 inhibitor celecoxib American Journal of cardiology 2003 92 411-418
3
WB White et al Effects of the cyclooxygenase-2 specific inhibitor valdecoxib versus nonsteroidal anti-inflammatory agents and placebo on cardiovascular thrombotic events in patients with arthritis American Journal of Therapeutics 2004 11 244-250
4
S Curtis et al Cardiovascular safety summary associated with the etoricoxib development programme Arthritis amp Rheumatism 2003 48 Suppl S616
5
ME Farkouh et al Comparison of lumiracoxib with naproxen and ibuprofen in the therapeutic arthritis research and gastrointestinal event trial (TARGET) cardiovascular outcomes randomised controlled trial Lancet 2004 364 675-684
RECOMMENDATIONS
NSAIDs COXIBs
bull Use lowest effective dose shortest duration
bull Not for patients who have recently undergone coronary artery bypass graft (CABG) surgery and revascularisation procedures
bull Coxibs should not be prescribed for patients with established ischaemic heart disease stroke or congestive heart failure
bull Caution for Coxibs for patients who have hypertension hyperlipidaemia diabetes and smoking as well as peripheral arterial disease
bull Etoricoxib should not be prescribed for patients with hypertension whose blood pressure has not been adequately controlled
The EU Summit is supported by Pfizer
Tricyclic Agents
bull best documented analgesics here (NNT 22)bull amitriptyline best investigatedbull desipraminenortriptyline less AEs
bull start on low doses increases compliancebullOften adverse effects (NNH 28)bull effect needs timebull SSRIs not as effective (NNT 67)
bull noradrenergic effect necessarybull venlafaxine another option
Antidepressants Compared with Placebo
Condition Number of trials
Antidepressant improvedtotal
Placebo improvedtotal
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 13 180260 73205 19 (16 to
24)30 (24 to 40)
Postherpetic neuralgia 3 4377 868 48 (24 to
94)23 (17 to 33)
Atypical facial pain 2 6288 3085 20 (15 to
28)28 (20 to 47)
Central pain 1 1015 115 10 (15 to 69)
17 (11 to 30)
Bandolier
Anticonvulsants as Membrane Stabilisers
bull pregabalinbull gabapentin bull carbamazepinebull clonazepam pooled NNT 27bull valproatebull lamotriginebull baclofen
Anticonvulsants Compared with Placebo
Condition Number of trials
Anticonvulsant improvedtotal
Placebo improvedtot
al
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 3 5668 2668 19 (14 to 27) 25 (18
to 40)
Trigeminal neuralgia 3 178315 41224 31 (23 to 41) 26 (22
to 33)
Migraine prophylaxis 2 6374 1777 37 (24 to 59) 16 (13
to 20)
Other pain syndromes 1 514 115 54 (07 to 40)
not calculat ed
Bandolier
Relative Activity on Serotonin and Norepinephrine Reuptake Among
Antidepressants
CitalopramFluvoxamineSertralineParoxetineFluoxetine
VenlafaxineDuloxetine
MaprotilineDesipramineNortriptylineReboxetine
AmitriptylineMilnacipranImipramine
Serotonin Mixed Norepinephrine
Antidepressant Analgesic Antidepressant
Fishbain et al Pain Med 20001310-316
Opioidsbull In principle opioids are effective in nociceptive
and some neuropathic pain however not always and not necessarily completely for dynamic pain
bull Possibly preferable opioids here arendash tramadol
bull noradrenergic and serotoninergic effectndash morphine
bull Mu receptor anatagonistmonaminergic effect
ndash oxycodonebull kappa receptor effect
Opioids
bull lsquoLack of analgesic effect of opioids on neuropathic hellip painrsquo Pain 19883311
bull lsquohellip intravenous hellip morphine reduce the pain of Osteoarthritisrsquo Neurology
1991411024bull lsquoA call for more science not more
rhetoric regarding opioids and arthritic painrsquo Pain 2001471
bull lsquoEfficacy of oxycodone in neuropathic painhelliprsquo Neurology 1998501837
OPIOIDS FOR OA PAINbull Osteoarthritis guidelines provide limited guidance on opioid use bull The 1995 ACR guidelines for hip OA suggest opioids be avoided for
long term use but short term use may be helpful without reference to primary data15
bull The 1995 ACR knee OA guidelines do not discuss opioids directly16 bull The 1998 UK guidelines on degenerative arthritis suggest that if
relief is inadequate with 24 grams of ibuprofen and 40 grams of paracetamol a day other antiinflammatories or opioids may be considered18
bull The 2000 update of the ACR OA guidelines suggests that opioids might be used as a medication of last resort17
bull Opioids are effective in OA hip and knee pain and have predictable side effects
bull It would be unwise were physicians to discount an entire class of medications over unfounded fears and incomplete knowledge of their benefits44
USE OF ULTRACET IN OA KNEESbull The efficacy of tramadolacetaminophen combination tablets (Ultracetreg) as add-
on and maintenance therapy in knee osteoarthritis pain inadequately controlled by nonsteroidal anti-inflammatory drug (NSAID)
Park KS Choi JJ Kim WU Min JK Park SH Cho CS
bull TramadolAPAP add-on significantly improved knee OA pain which had been inadequately controlled by NSAIDs In those subjects who showed favorable response to tramadolAPAP and NSAID combination therapy both tramadolAPAP and NSAIDs were effective at maintaining the pain-reduced state and there was no significant difference in efficacy between tramadolAPAP and NSAIDs
Clinical Rheumatology 2011 3 Aug
Opioid Sparing Regimes
bull Multimodal analgesia (Kehlet et al 1999)
bull NSAIDs and COX-2 (Romsing Moiniche 2004)
bull Paracetamol (Romsing 2002)
bull Ketamine (Elia Tramer 2005)
bull Gabapentin and Pregabalin (Dahl et al 2004)
bull Gabapentin and Rofecoxib (Gilron et al 2005)
Opioid reduction 20 ndash 40 Reduction of PONV 30
Clinical effects
Single-modality treatment of a Multi- modality problem is
futile
ldquoTherersquos no pain thatrsquos so easy to bear than that of
someone elserdquo
ndashLeriche
Van Gogh ldquoOld Man in Sorrowrdquo
Protective
Noxious stimulusPinchpinprickIntense heatcoldAcute trauma
PNS and CNSlesionsPHNPDNSCI
Neuropathic Pain
Pathological
Post-operative painPost-traumaArthritis Inflammatory
Healingrepairor pathological
Nociceptive Pain Functional Pain
Fibromyalgia
Pathological
TYPES OF PAIN
CNS=Central nervous system IBS=Irritable bowel syndrome PDN=Painful diabetic neuropathy PHN=Post-herpetic neuralgia PNS=Peripheral nervous system SCI=Spinal cord injury
Woolf et al Ann Intern Med 2004140(6)441-51
Nociceptive pain
Neuropathic pain
Functional pain(non-inflammatorynon-neuropathic)
Peripheral nerve damage
No known tissue or nerve damage Abnormal central processing
Multiple mechanisms
Noxious stimuli
Inflammation
3
Multiple Types of Pain
Woolf Ann Intern Med 2004140(6)441-51 Chong et al J Pain Symptom Manage 200325(55)S4-S11
4
Pain and Inflammation Overview
bull Osteoarthritis (OA)bull Rheumatoid Arthritis (RA)bull Ankylosing spondylitis (AS)bull Acute pain
ndash Postoperative painndash Acute ankle sprainndash Acute shoulder tendonitisbursitisndash Acute low back pain
5References 1
European Bone and Joint Health Strategies Project European Action Toward Better Musculoskeletal Health 2005 2
European Opinion Research Group EEIG Health food and alcohol and safety Special Eurobarometer 186 2003
Epidemiology of osteoarthritis (OA) and rheumatoid arthritis (RA)
bull OA and RA are leading causes of severe long-term pain and physical disability1
bull Approximately 1 in 4 Europeans has some form of arthritisrheumatism 1 in 5 is under long-term treatment12
bull OA is the most common joint disorder and accounts for more disability among elderly patients than any other condition1
bull In developed countries 1 in 10 of the population gt60 y has significant clinical problems attributed to OA1
bull RA is the most common form of inflammatory joint disease and affects 03 to 10 of the general population in Europe1
Mem
bran
e Po
tent
ial (
mV)
Mem
bran
e Po
tent
ial (
mV)
60
40
20
0
-20
-40
-60
50 100 15050 100 150
Time (ms)Time (ms)
60
40
20
0
-20
-40
-60
50 100 15050 100 150
Time (ms)Time (ms)
30 seconds after application of 1 mM PGE2
No PGE2
PGE2 increases excitability of neurones
England et al J Physiol 1996495429-440
COX-2 and Peripheral Sensitisation
EP EP receptorreceptor PKAPKA
PKCPKCεε
IncreasedIncreasedneuronal neuronal
membrane membrane excitabilityexcitability
PGEPGE22
SNSPN3SNSPN3
TTx resistantTTx resistantsodium sodium channelchannel
Neurone Neurone firing thresholdfiring threshold
decreasesdecreases
Tissue InjuryTissue Injury
COXCOX--2 expressed2 expressed
P
COXCOX--2 and Central 2 and Central SensitisationSensitisation
Interleukin-1szlig-mediated induction of COX-2 in the CNS contributes to inflammatory pain hypersensitivityTAREK A SAMAD KIMBERLY A MOORE ADAM SAPIRSTEINdagger SARA BILLET ANDREW ALLCHORNEDagger STEPHEN POOLEsect JOSEPH V BONVENTRE amp CLIFFORD J WOOLFDagger
Neural Plasticity Research Group Department of Anesthesia amp Critical Care Department of Anesthesia amp Critical Care and Department of Medicine Massachusetts General Hospital and Harvard Medical School Charlestown Massachusetts 02129 USA
Dagger
Department of Anatomy University College London London WC1E 6BT UK
sect National Institute for Biological Standards and Control Blanche Lane South Mimms Hertfordshire EN6 3QG UK
Nature 2001410471 ndash 475
Convergence at WDR Neurone
Central Sensitisation
tissue or nerve injury
release of EAAsand neuropeptides
increased depolarizationat the NMDA receptor
expanded receptive fieldsand hyperexcitability
Increased Pain
excitotoxicity
loss of inhibition
adapted from Dubner
CNS
Central Sensitization May Have Contributed to OA Pain and Neuropathic
Pain Symptoms1
bull Focus group transcripts from participants with knee OA (N=80) were analyzed to determine the use of unprompted NP descriptors to characterize their pain (including burning tingling pins and needles and numbness) to determine whether people with chronic symptomatic knee OA use pain descriptors suggestive of underlying NP
bull The proportion of participants who used NP descriptors to characterize their pain was 34 (95 CI 24 to 45)
bull Participants using NP descriptors were younger than those who did not (mean age plusmn SD age 648 plusmn 97 years vs 720 plusmn 100 years respectively P=0003)
bull Characteristics that did not statistically distinguish participants who used NP descriptors from those who did included duration of OA pain intensity OA severity and gender
OA = osteoarthritis NP = neuropathic pain CI = confidence interval SD = standard deviation
1 Hochman JR et al Arthritis Care Res (Hoboken) 2010621019ndash1023
Central Sensitization in OA Expansion of Symptoms Beyond the
Joint
bull Quantitative sensory testing of PPTs in patients with knee OA pain (n=48) and matched controls without knee pain (n=24) revealed that subjects with OA pain exhibited sensitization in both OA-affected and unaffected areasndash Increasing pain intensity in
the OA-affected (knee) joint was associated with lower PPT in OA-unaffected areas (eg arm)1
PPT at arm (OA-unaffected area)
R = -032 Plt005
VAS at OA-affected Knee Joint
1500
1000
500
0 1 2 3 4 5 6 7 8 9 10PP
T k
Pa
Arendt-Nielsen L et al Pain 2010149573ndash581
OA = osteoarthritis PPT = pressure pain threshold VAS = visual analog scale
OA = osteoarthritis PPT = pressure pain threshold VAS = visual analog scale WOMAC = Western Ontario and McMaster Universities SF-36 = short form-36 health survey
Central Sensitization in OA Increased Pain Severity and Worse Pain-Associated
OutcomesImamura M et al Arthritis Rheum 2008591424ndash1431
Measure Spearmanrsquos rank correlation coefficient r P Value
VASPatellar tendon Sacral 2 subcutaneous dermatome levelAdductor longus muscle
-0545 -0546 -0561
lt0001 lt0001 lt0001
WOMAC painPatellar tendon Sacral 2 subcutaneous dermatome levelAdductor longus muscle
-0589-0601 -0540
lt0001 lt0001lt0001
WOMAC physical activityLumbar 2 subcutaneous dermatome level Sacral 2 subcutaneous dermatome level Peroneus longus muscle
-0550 -0509 -0571
lt0001lt0001 lt0001
SF-36 bodily painLumbar 1ndashLumbar 2 supraspinous ligamentLumbar 2 subcutaneous dermatome level Adductor longus muscle
0534 0606 0569
lt0001 lt0001 lt0001
A cross-sectional study that assessed hyperalgesia in patients with refractory OA-associated pain (n=62) reported significant correlations between PPT values at each listed site and VAS WOMAC pain and physical activity subscales and SF-36 bodily pain score
SKIN
SPINAL CORD
Dorsal horn
PRIMARY AFFERENT NERVE
Dorsal root ganglion
POSTSYNAPTIC PROCESSPRESYNAPTIC PROCESS
NMDA receptor
Ca2+ Second messengers
kinases (eg PKC) diacylglycerol cAMP
Gene transcription
P
CELL NUCLEUS
Long term changes
(receptor function transmitter production)
Glutamate release
C-fosoncogene
Cortical Reorganisation
I will show that my client is welltolerated amp effectivehelliphellip
I will showthat my clientis well tolerated and effective
bull For chronic pain most measures of treatment response involve patient- reported outcomes for which the patient is the most important judge of whether changes are important or meaningful12
ndash Determinations of statistical significance must be supplemented by consideration of the clinical importance of changes in outcome measures1
bull The IMMPACT consensus meeting proposed provisional benchmarks for identifying clinically important changes in the specific outcome measures for chronic pain clinical trials1
Using NNT Analyses in the Treatment of Pain IMMPACT Consensus Meeting Recommendations
NNT = number needed to treat IMMPACT = Initiative on Methods Measurement and Pain Assessment in Clinical Trials1 Dworkin RH et al J Pain 20089105ndash121 2 Acquadro C et al Value Health 20036522ndash531
10ndash20Reduction in pain intensity
ge50Reduction in pain intensity
ge30Reduction in pain intensity
Minimally Important Improvement
Moderately Important Improvement
Substantial Improvement
132
253
353638
4244
55788
1718
0 4 8 12 16 20
Oxycodone 5Codeine 60Tramadol 50Propoxyphene 65APAP 325Oxycodone 5ASA 650Codeine 60Tramadol 100APAP 650Propox 100APAP 1000APAP 600Cod 60Morphine 10APAP 1000Oxyc 10Ibuprofen 400Oxycodone 15
McQuay H BMJ 1997
Patients with 50 reduction Patients with 50 reduction in pain vs placeboin pain vs placebo
NNT
USE OF PARACETAMOL IN TREATMENT OF OA PAIN
22
How effective was paracetamol
How effective was paracetamol compared with NSAIDs
F Wolfe S Zhao N Lane Preference for nonsteroidal antiinflammatory drugs over acetaminophen by rheumatic disease patients Arthritis amp Rheumatism 2000 43 378-385
2007 League table of NNT for at least 50 pain relief over 4-6 hrs in patients with moderate to severe pain
(all oral analgesics except IM morphine )
[httpwwwmedicineoxacukbandolierboothpainpagacutrevanalgesicsleagtabhtml
ETORICOXIB IN ACUTE PAIN
bull Etoricoxib 120 mg has been approved for treating acute pain which includes post-operative pain and other acute pain such as primary dysmenorrhea and acute gouty arthritis
bull Efficacy of etoricoxib in the post-operative setting as evaluated by NNT bull COCHRANE REVIEW Five randomized placebo-controlled studies
with a total number of 880 patients were included -- Four studies on patients with dental pain following extraction of at least one impacted third molar
--One study on patients with pain following uncomplicated orthopaedic surgery
bull NNT were calculated to measure at least 50 pain relief over 4-6 hrs (substantial pain relief) based on TOPAR scores
Results 120 mg etoricoxib with a NNT of 19 for acute post-operative pain
1 Chang DJ Desjardins PJ King TR Erb T Geba GP The analgesic efficacy of etoricoxib compared with oxycodoneacetaminophen in an acute postoperative pain model a randomized double-blind clinical trial Anesthesia and Analgesia 200499(3)807ndash15
2 Malmstrom K Sapre A Couglin H Agrawal NG Mazenko RS Fricke JR Jr Etoricoxib in acute pain associated with dental surgery a randomized double-blind placebo- and active comparator-controlled dose-ranging study Clinical Therapeutics 200426(5)667ndash79
3 Malmstrom K Kotey P Coughlin H Desjardins PJ A randomized double-blind parallel-group study comparing the analgesic effect of etoricoxib to placebo naproxen sodium and acetaminophen with codeine using the dental impaction pain model Clinical Journal of Pain 200420(3)147ndash 55
4 Malmstrom K Ang J Fricke JR Shingo S Reicin A The analgesic effect of etoricoxib relative to that of cetaminophen analgesics a randomized controlled single-dose study in acute dental impaction pain Current Medical Research and Opinion 200521(1)141ndash9 Rasmussen 2005 published data only
5 Rasmussen GL Malmstrom K Bourne MH Jove M Rhondeau SM Kotey P Etoricoxib provides analgesic efficacy to patients after knee or hip replacement surgery a randomized double-blind placebo-controlled study Anaesthesia and Analgesia 2005101(4) 1104ndash11
Etoricoxib in acute pain bull Indirect comparisons of NNTs for at least 50 pain
relief over 4 to 6 hours in reviews of other analgesics using identical methods indicate that etoricoxib 120 mg
-- has slightly better efficacy than rofecoxib 50 mg (22 (19 to 24) Barden 2005)
-- is significantly better than lumiracoxib 400mg (27 (22 to 35) Roy 2007) or-- celecoxib 400 mg (25 (22 to 29) Derry 2008)
-- better than the non-selective NSAIDs ibuprofen 400 mg (27 (25 to 30) Collins 1999) naproxen 500 mg (27 (23 to 32 Derry 2009a) and diclofenac 50mg (24 (18 to 33Derry 2009b)
Placebo
Paracetamol 10007
Paracetamolcodeine 1000606
Ibuprofen 4005
Celecoxib 4004
Naproxen 5005503
Rofecoxib 502
Etoricoxib 1201
0 4 8 12 16 20 24Median remedication time (hr)
Each bar is from a Cochrane review
Acute pain Time for patients to Re-medication
The weighted median time to re-medication with ARCOXIA 120mg is about 24hrs
vs placebo at 18hrs
1 Clarke R et al Cochrane Database Syst Rev 2009 Apr 15(2)CD004309 2 Bulley S et al Cochrane Database Syst Rev 2009 Oct 7(4)CD0046043 Derry C et al Cochrane Database Syst Rev 2009 Jan 21(1)CD004234 4 Derry S Cochrane Database Syst Rev 2008 Oct 8(4)CD0042335 Derry C et al Cochrane Database Syst Rev 2009 Jul 8(3)CD0015486 Toms L et al Cochrane Database Syst Rev 2009 Jan 21(1)CD0015477 Toms L et al Cochrane Database Syst Rev 2008 Oct 8(4)CD004602
Placebo (n=56)
Etoricoxib 60 mg (n=224)
Naproxen 1000 mgc
(n=221)
a0-
to 100-mm VAS (0 = none to 100 = extreme)
b0-
to 100-mm VAS (0 = very well to 100 = very poor) c500 mg twice dailyPlt0001 vs placebo for both etoricoxib and naproxen P = NS etoricoxib vs naproxen
Leung AT et al Curr Med Res Opin 200218(2)49ndash58
LS M
ean
Cha
nge
plusmnSE
Weeks Postrandomization
Osteoarthritis Etoricoxib 60 mg vs Naproxen
Results Etoricoxib relieved pain and improved mobility and disease statuEtoricoxib relieved pain and improved mobility and disease statuss
ndash35
ndash25
ndash5
5
ndash15
WOMAC Pain Subscalea
S R 4 82 12
WOMAC Physical Function Subscalea PGADSb
ndash35
ndash25
ndash5
5
ndash15
S R 4 82 12ndash35
ndash25
ndash5
5
ndash15
S R 4 82 12Weeks Postrandomization Weeks Postrandomization
Adverse effects of NSAIDsAdverse effects of NSAIDs
BNF March 2002
Dose-dependent toxicityIntolerability dyspepsiaGI bleedingUlcers ndash bleeds perforations
Upper-GI
Renal
Contributes to blood loss
Fluid retention oedema hypertensionRenal dysfunction failure ndash acute chronicHeart failure
Anti-platelet effects
Angioedema bronchospasmHypersensitivity
No Short-Term Adverse GI Effects -
The Big Mistake
bull Study designed to evaluate short-term GI effects in elderly
bull Study planned to enrol 160 patientsbull Study terminated by investigator at 17 subjects
ndash 8 patients had ulcersndash 4 of 4 in ketorolac group
lsquo hellip because of the unexpectedly high incidence of gastroduodenal ulcers observedhelliprsquo
Harris et al ClinTher 2001231422
Class Effect of All NSAIDs
httpwwwfdagovcderdruginfopageCOX2NSAIDdecisionMemopdf
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
33
Cardiovascular Safetybull Arthritis patients often have concomitant CV
disease1
bull Pain is an important predictor of CV risk23
bull Randomized controlled trials and observational data demonstrate that CV risk of etoricoxib appears similar to that of traditional NSAIDs4-6
bull Recent data suggest that differential CV effects of NSAIDs (selective and nonselective) may be independent of COX-2 inhibition78
References 1 Singh G et al Am J Manag Care 20028(suppl)S383-S391 2
Sokka T Pincus T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 3
Pincus T Sokka T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 4
httpwwwfdagovohrmsdocketsac05slides2005-4090S1_06_01_Pfizer-celecoxibppt (accessed 14 February 2006) 5
White WB et al Am J Cardiol 200289425ndash430 6
Graham DJ et al Lancet 2005365475ndash481 7 Yang HM et al Circulation 2004110301ndash308 8 Steffel J et al Circulation 20051111685ndash1689
Events per 100 patient years
Coxib Coxib Placebo Coxib NSAID Percent naproxen
Rofecoxib 17 19 11 08 73
Celecoxib 13 15 11 11 20
Valdecoxib 13 12 13 20 about 50
Etoricoxib 13 12 12 08 67
Lumiracoxib 09 08 52
34
APTC endpoint (cardiovascular haemorrhagic and unknown death and nonfatal myocardial infarction and stroke)
1
MR Weir et al Selective COX-2 inhibition and cardiovascular effects a review of the rofecoxib development program American heart Journal 2003 146 591-604
2
WB White et al Cardiovascular thrombotic events in arthritis trials of the cyclooxygenase-2 inhibitor celecoxib American Journal of cardiology 2003 92 411-418
3
WB White et al Effects of the cyclooxygenase-2 specific inhibitor valdecoxib versus nonsteroidal anti-inflammatory agents and placebo on cardiovascular thrombotic events in patients with arthritis American Journal of Therapeutics 2004 11 244-250
4
S Curtis et al Cardiovascular safety summary associated with the etoricoxib development programme Arthritis amp Rheumatism 2003 48 Suppl S616
5
ME Farkouh et al Comparison of lumiracoxib with naproxen and ibuprofen in the therapeutic arthritis research and gastrointestinal event trial (TARGET) cardiovascular outcomes randomised controlled trial Lancet 2004 364 675-684
RECOMMENDATIONS
NSAIDs COXIBs
bull Use lowest effective dose shortest duration
bull Not for patients who have recently undergone coronary artery bypass graft (CABG) surgery and revascularisation procedures
bull Coxibs should not be prescribed for patients with established ischaemic heart disease stroke or congestive heart failure
bull Caution for Coxibs for patients who have hypertension hyperlipidaemia diabetes and smoking as well as peripheral arterial disease
bull Etoricoxib should not be prescribed for patients with hypertension whose blood pressure has not been adequately controlled
The EU Summit is supported by Pfizer
Tricyclic Agents
bull best documented analgesics here (NNT 22)bull amitriptyline best investigatedbull desipraminenortriptyline less AEs
bull start on low doses increases compliancebullOften adverse effects (NNH 28)bull effect needs timebull SSRIs not as effective (NNT 67)
bull noradrenergic effect necessarybull venlafaxine another option
Antidepressants Compared with Placebo
Condition Number of trials
Antidepressant improvedtotal
Placebo improvedtotal
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 13 180260 73205 19 (16 to
24)30 (24 to 40)
Postherpetic neuralgia 3 4377 868 48 (24 to
94)23 (17 to 33)
Atypical facial pain 2 6288 3085 20 (15 to
28)28 (20 to 47)
Central pain 1 1015 115 10 (15 to 69)
17 (11 to 30)
Bandolier
Anticonvulsants as Membrane Stabilisers
bull pregabalinbull gabapentin bull carbamazepinebull clonazepam pooled NNT 27bull valproatebull lamotriginebull baclofen
Anticonvulsants Compared with Placebo
Condition Number of trials
Anticonvulsant improvedtotal
Placebo improvedtot
al
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 3 5668 2668 19 (14 to 27) 25 (18
to 40)
Trigeminal neuralgia 3 178315 41224 31 (23 to 41) 26 (22
to 33)
Migraine prophylaxis 2 6374 1777 37 (24 to 59) 16 (13
to 20)
Other pain syndromes 1 514 115 54 (07 to 40)
not calculat ed
Bandolier
Relative Activity on Serotonin and Norepinephrine Reuptake Among
Antidepressants
CitalopramFluvoxamineSertralineParoxetineFluoxetine
VenlafaxineDuloxetine
MaprotilineDesipramineNortriptylineReboxetine
AmitriptylineMilnacipranImipramine
Serotonin Mixed Norepinephrine
Antidepressant Analgesic Antidepressant
Fishbain et al Pain Med 20001310-316
Opioidsbull In principle opioids are effective in nociceptive
and some neuropathic pain however not always and not necessarily completely for dynamic pain
bull Possibly preferable opioids here arendash tramadol
bull noradrenergic and serotoninergic effectndash morphine
bull Mu receptor anatagonistmonaminergic effect
ndash oxycodonebull kappa receptor effect
Opioids
bull lsquoLack of analgesic effect of opioids on neuropathic hellip painrsquo Pain 19883311
bull lsquohellip intravenous hellip morphine reduce the pain of Osteoarthritisrsquo Neurology
1991411024bull lsquoA call for more science not more
rhetoric regarding opioids and arthritic painrsquo Pain 2001471
bull lsquoEfficacy of oxycodone in neuropathic painhelliprsquo Neurology 1998501837
OPIOIDS FOR OA PAINbull Osteoarthritis guidelines provide limited guidance on opioid use bull The 1995 ACR guidelines for hip OA suggest opioids be avoided for
long term use but short term use may be helpful without reference to primary data15
bull The 1995 ACR knee OA guidelines do not discuss opioids directly16 bull The 1998 UK guidelines on degenerative arthritis suggest that if
relief is inadequate with 24 grams of ibuprofen and 40 grams of paracetamol a day other antiinflammatories or opioids may be considered18
bull The 2000 update of the ACR OA guidelines suggests that opioids might be used as a medication of last resort17
bull Opioids are effective in OA hip and knee pain and have predictable side effects
bull It would be unwise were physicians to discount an entire class of medications over unfounded fears and incomplete knowledge of their benefits44
USE OF ULTRACET IN OA KNEESbull The efficacy of tramadolacetaminophen combination tablets (Ultracetreg) as add-
on and maintenance therapy in knee osteoarthritis pain inadequately controlled by nonsteroidal anti-inflammatory drug (NSAID)
Park KS Choi JJ Kim WU Min JK Park SH Cho CS
bull TramadolAPAP add-on significantly improved knee OA pain which had been inadequately controlled by NSAIDs In those subjects who showed favorable response to tramadolAPAP and NSAID combination therapy both tramadolAPAP and NSAIDs were effective at maintaining the pain-reduced state and there was no significant difference in efficacy between tramadolAPAP and NSAIDs
Clinical Rheumatology 2011 3 Aug
Opioid Sparing Regimes
bull Multimodal analgesia (Kehlet et al 1999)
bull NSAIDs and COX-2 (Romsing Moiniche 2004)
bull Paracetamol (Romsing 2002)
bull Ketamine (Elia Tramer 2005)
bull Gabapentin and Pregabalin (Dahl et al 2004)
bull Gabapentin and Rofecoxib (Gilron et al 2005)
Opioid reduction 20 ndash 40 Reduction of PONV 30
Clinical effects
Single-modality treatment of a Multi- modality problem is
futile
ldquoTherersquos no pain thatrsquos so easy to bear than that of
someone elserdquo
ndashLeriche
Van Gogh ldquoOld Man in Sorrowrdquo
Nociceptive pain
Neuropathic pain
Functional pain(non-inflammatorynon-neuropathic)
Peripheral nerve damage
No known tissue or nerve damage Abnormal central processing
Multiple mechanisms
Noxious stimuli
Inflammation
3
Multiple Types of Pain
Woolf Ann Intern Med 2004140(6)441-51 Chong et al J Pain Symptom Manage 200325(55)S4-S11
4
Pain and Inflammation Overview
bull Osteoarthritis (OA)bull Rheumatoid Arthritis (RA)bull Ankylosing spondylitis (AS)bull Acute pain
ndash Postoperative painndash Acute ankle sprainndash Acute shoulder tendonitisbursitisndash Acute low back pain
5References 1
European Bone and Joint Health Strategies Project European Action Toward Better Musculoskeletal Health 2005 2
European Opinion Research Group EEIG Health food and alcohol and safety Special Eurobarometer 186 2003
Epidemiology of osteoarthritis (OA) and rheumatoid arthritis (RA)
bull OA and RA are leading causes of severe long-term pain and physical disability1
bull Approximately 1 in 4 Europeans has some form of arthritisrheumatism 1 in 5 is under long-term treatment12
bull OA is the most common joint disorder and accounts for more disability among elderly patients than any other condition1
bull In developed countries 1 in 10 of the population gt60 y has significant clinical problems attributed to OA1
bull RA is the most common form of inflammatory joint disease and affects 03 to 10 of the general population in Europe1
Mem
bran
e Po
tent
ial (
mV)
Mem
bran
e Po
tent
ial (
mV)
60
40
20
0
-20
-40
-60
50 100 15050 100 150
Time (ms)Time (ms)
60
40
20
0
-20
-40
-60
50 100 15050 100 150
Time (ms)Time (ms)
30 seconds after application of 1 mM PGE2
No PGE2
PGE2 increases excitability of neurones
England et al J Physiol 1996495429-440
COX-2 and Peripheral Sensitisation
EP EP receptorreceptor PKAPKA
PKCPKCεε
IncreasedIncreasedneuronal neuronal
membrane membrane excitabilityexcitability
PGEPGE22
SNSPN3SNSPN3
TTx resistantTTx resistantsodium sodium channelchannel
Neurone Neurone firing thresholdfiring threshold
decreasesdecreases
Tissue InjuryTissue Injury
COXCOX--2 expressed2 expressed
P
COXCOX--2 and Central 2 and Central SensitisationSensitisation
Interleukin-1szlig-mediated induction of COX-2 in the CNS contributes to inflammatory pain hypersensitivityTAREK A SAMAD KIMBERLY A MOORE ADAM SAPIRSTEINdagger SARA BILLET ANDREW ALLCHORNEDagger STEPHEN POOLEsect JOSEPH V BONVENTRE amp CLIFFORD J WOOLFDagger
Neural Plasticity Research Group Department of Anesthesia amp Critical Care Department of Anesthesia amp Critical Care and Department of Medicine Massachusetts General Hospital and Harvard Medical School Charlestown Massachusetts 02129 USA
Dagger
Department of Anatomy University College London London WC1E 6BT UK
sect National Institute for Biological Standards and Control Blanche Lane South Mimms Hertfordshire EN6 3QG UK
Nature 2001410471 ndash 475
Convergence at WDR Neurone
Central Sensitisation
tissue or nerve injury
release of EAAsand neuropeptides
increased depolarizationat the NMDA receptor
expanded receptive fieldsand hyperexcitability
Increased Pain
excitotoxicity
loss of inhibition
adapted from Dubner
CNS
Central Sensitization May Have Contributed to OA Pain and Neuropathic
Pain Symptoms1
bull Focus group transcripts from participants with knee OA (N=80) were analyzed to determine the use of unprompted NP descriptors to characterize their pain (including burning tingling pins and needles and numbness) to determine whether people with chronic symptomatic knee OA use pain descriptors suggestive of underlying NP
bull The proportion of participants who used NP descriptors to characterize their pain was 34 (95 CI 24 to 45)
bull Participants using NP descriptors were younger than those who did not (mean age plusmn SD age 648 plusmn 97 years vs 720 plusmn 100 years respectively P=0003)
bull Characteristics that did not statistically distinguish participants who used NP descriptors from those who did included duration of OA pain intensity OA severity and gender
OA = osteoarthritis NP = neuropathic pain CI = confidence interval SD = standard deviation
1 Hochman JR et al Arthritis Care Res (Hoboken) 2010621019ndash1023
Central Sensitization in OA Expansion of Symptoms Beyond the
Joint
bull Quantitative sensory testing of PPTs in patients with knee OA pain (n=48) and matched controls without knee pain (n=24) revealed that subjects with OA pain exhibited sensitization in both OA-affected and unaffected areasndash Increasing pain intensity in
the OA-affected (knee) joint was associated with lower PPT in OA-unaffected areas (eg arm)1
PPT at arm (OA-unaffected area)
R = -032 Plt005
VAS at OA-affected Knee Joint
1500
1000
500
0 1 2 3 4 5 6 7 8 9 10PP
T k
Pa
Arendt-Nielsen L et al Pain 2010149573ndash581
OA = osteoarthritis PPT = pressure pain threshold VAS = visual analog scale
OA = osteoarthritis PPT = pressure pain threshold VAS = visual analog scale WOMAC = Western Ontario and McMaster Universities SF-36 = short form-36 health survey
Central Sensitization in OA Increased Pain Severity and Worse Pain-Associated
OutcomesImamura M et al Arthritis Rheum 2008591424ndash1431
Measure Spearmanrsquos rank correlation coefficient r P Value
VASPatellar tendon Sacral 2 subcutaneous dermatome levelAdductor longus muscle
-0545 -0546 -0561
lt0001 lt0001 lt0001
WOMAC painPatellar tendon Sacral 2 subcutaneous dermatome levelAdductor longus muscle
-0589-0601 -0540
lt0001 lt0001lt0001
WOMAC physical activityLumbar 2 subcutaneous dermatome level Sacral 2 subcutaneous dermatome level Peroneus longus muscle
-0550 -0509 -0571
lt0001lt0001 lt0001
SF-36 bodily painLumbar 1ndashLumbar 2 supraspinous ligamentLumbar 2 subcutaneous dermatome level Adductor longus muscle
0534 0606 0569
lt0001 lt0001 lt0001
A cross-sectional study that assessed hyperalgesia in patients with refractory OA-associated pain (n=62) reported significant correlations between PPT values at each listed site and VAS WOMAC pain and physical activity subscales and SF-36 bodily pain score
SKIN
SPINAL CORD
Dorsal horn
PRIMARY AFFERENT NERVE
Dorsal root ganglion
POSTSYNAPTIC PROCESSPRESYNAPTIC PROCESS
NMDA receptor
Ca2+ Second messengers
kinases (eg PKC) diacylglycerol cAMP
Gene transcription
P
CELL NUCLEUS
Long term changes
(receptor function transmitter production)
Glutamate release
C-fosoncogene
Cortical Reorganisation
I will show that my client is welltolerated amp effectivehelliphellip
I will showthat my clientis well tolerated and effective
bull For chronic pain most measures of treatment response involve patient- reported outcomes for which the patient is the most important judge of whether changes are important or meaningful12
ndash Determinations of statistical significance must be supplemented by consideration of the clinical importance of changes in outcome measures1
bull The IMMPACT consensus meeting proposed provisional benchmarks for identifying clinically important changes in the specific outcome measures for chronic pain clinical trials1
Using NNT Analyses in the Treatment of Pain IMMPACT Consensus Meeting Recommendations
NNT = number needed to treat IMMPACT = Initiative on Methods Measurement and Pain Assessment in Clinical Trials1 Dworkin RH et al J Pain 20089105ndash121 2 Acquadro C et al Value Health 20036522ndash531
10ndash20Reduction in pain intensity
ge50Reduction in pain intensity
ge30Reduction in pain intensity
Minimally Important Improvement
Moderately Important Improvement
Substantial Improvement
132
253
353638
4244
55788
1718
0 4 8 12 16 20
Oxycodone 5Codeine 60Tramadol 50Propoxyphene 65APAP 325Oxycodone 5ASA 650Codeine 60Tramadol 100APAP 650Propox 100APAP 1000APAP 600Cod 60Morphine 10APAP 1000Oxyc 10Ibuprofen 400Oxycodone 15
McQuay H BMJ 1997
Patients with 50 reduction Patients with 50 reduction in pain vs placeboin pain vs placebo
NNT
USE OF PARACETAMOL IN TREATMENT OF OA PAIN
22
How effective was paracetamol
How effective was paracetamol compared with NSAIDs
F Wolfe S Zhao N Lane Preference for nonsteroidal antiinflammatory drugs over acetaminophen by rheumatic disease patients Arthritis amp Rheumatism 2000 43 378-385
2007 League table of NNT for at least 50 pain relief over 4-6 hrs in patients with moderate to severe pain
(all oral analgesics except IM morphine )
[httpwwwmedicineoxacukbandolierboothpainpagacutrevanalgesicsleagtabhtml
ETORICOXIB IN ACUTE PAIN
bull Etoricoxib 120 mg has been approved for treating acute pain which includes post-operative pain and other acute pain such as primary dysmenorrhea and acute gouty arthritis
bull Efficacy of etoricoxib in the post-operative setting as evaluated by NNT bull COCHRANE REVIEW Five randomized placebo-controlled studies
with a total number of 880 patients were included -- Four studies on patients with dental pain following extraction of at least one impacted third molar
--One study on patients with pain following uncomplicated orthopaedic surgery
bull NNT were calculated to measure at least 50 pain relief over 4-6 hrs (substantial pain relief) based on TOPAR scores
Results 120 mg etoricoxib with a NNT of 19 for acute post-operative pain
1 Chang DJ Desjardins PJ King TR Erb T Geba GP The analgesic efficacy of etoricoxib compared with oxycodoneacetaminophen in an acute postoperative pain model a randomized double-blind clinical trial Anesthesia and Analgesia 200499(3)807ndash15
2 Malmstrom K Sapre A Couglin H Agrawal NG Mazenko RS Fricke JR Jr Etoricoxib in acute pain associated with dental surgery a randomized double-blind placebo- and active comparator-controlled dose-ranging study Clinical Therapeutics 200426(5)667ndash79
3 Malmstrom K Kotey P Coughlin H Desjardins PJ A randomized double-blind parallel-group study comparing the analgesic effect of etoricoxib to placebo naproxen sodium and acetaminophen with codeine using the dental impaction pain model Clinical Journal of Pain 200420(3)147ndash 55
4 Malmstrom K Ang J Fricke JR Shingo S Reicin A The analgesic effect of etoricoxib relative to that of cetaminophen analgesics a randomized controlled single-dose study in acute dental impaction pain Current Medical Research and Opinion 200521(1)141ndash9 Rasmussen 2005 published data only
5 Rasmussen GL Malmstrom K Bourne MH Jove M Rhondeau SM Kotey P Etoricoxib provides analgesic efficacy to patients after knee or hip replacement surgery a randomized double-blind placebo-controlled study Anaesthesia and Analgesia 2005101(4) 1104ndash11
Etoricoxib in acute pain bull Indirect comparisons of NNTs for at least 50 pain
relief over 4 to 6 hours in reviews of other analgesics using identical methods indicate that etoricoxib 120 mg
-- has slightly better efficacy than rofecoxib 50 mg (22 (19 to 24) Barden 2005)
-- is significantly better than lumiracoxib 400mg (27 (22 to 35) Roy 2007) or-- celecoxib 400 mg (25 (22 to 29) Derry 2008)
-- better than the non-selective NSAIDs ibuprofen 400 mg (27 (25 to 30) Collins 1999) naproxen 500 mg (27 (23 to 32 Derry 2009a) and diclofenac 50mg (24 (18 to 33Derry 2009b)
Placebo
Paracetamol 10007
Paracetamolcodeine 1000606
Ibuprofen 4005
Celecoxib 4004
Naproxen 5005503
Rofecoxib 502
Etoricoxib 1201
0 4 8 12 16 20 24Median remedication time (hr)
Each bar is from a Cochrane review
Acute pain Time for patients to Re-medication
The weighted median time to re-medication with ARCOXIA 120mg is about 24hrs
vs placebo at 18hrs
1 Clarke R et al Cochrane Database Syst Rev 2009 Apr 15(2)CD004309 2 Bulley S et al Cochrane Database Syst Rev 2009 Oct 7(4)CD0046043 Derry C et al Cochrane Database Syst Rev 2009 Jan 21(1)CD004234 4 Derry S Cochrane Database Syst Rev 2008 Oct 8(4)CD0042335 Derry C et al Cochrane Database Syst Rev 2009 Jul 8(3)CD0015486 Toms L et al Cochrane Database Syst Rev 2009 Jan 21(1)CD0015477 Toms L et al Cochrane Database Syst Rev 2008 Oct 8(4)CD004602
Placebo (n=56)
Etoricoxib 60 mg (n=224)
Naproxen 1000 mgc
(n=221)
a0-
to 100-mm VAS (0 = none to 100 = extreme)
b0-
to 100-mm VAS (0 = very well to 100 = very poor) c500 mg twice dailyPlt0001 vs placebo for both etoricoxib and naproxen P = NS etoricoxib vs naproxen
Leung AT et al Curr Med Res Opin 200218(2)49ndash58
LS M
ean
Cha
nge
plusmnSE
Weeks Postrandomization
Osteoarthritis Etoricoxib 60 mg vs Naproxen
Results Etoricoxib relieved pain and improved mobility and disease statuEtoricoxib relieved pain and improved mobility and disease statuss
ndash35
ndash25
ndash5
5
ndash15
WOMAC Pain Subscalea
S R 4 82 12
WOMAC Physical Function Subscalea PGADSb
ndash35
ndash25
ndash5
5
ndash15
S R 4 82 12ndash35
ndash25
ndash5
5
ndash15
S R 4 82 12Weeks Postrandomization Weeks Postrandomization
Adverse effects of NSAIDsAdverse effects of NSAIDs
BNF March 2002
Dose-dependent toxicityIntolerability dyspepsiaGI bleedingUlcers ndash bleeds perforations
Upper-GI
Renal
Contributes to blood loss
Fluid retention oedema hypertensionRenal dysfunction failure ndash acute chronicHeart failure
Anti-platelet effects
Angioedema bronchospasmHypersensitivity
No Short-Term Adverse GI Effects -
The Big Mistake
bull Study designed to evaluate short-term GI effects in elderly
bull Study planned to enrol 160 patientsbull Study terminated by investigator at 17 subjects
ndash 8 patients had ulcersndash 4 of 4 in ketorolac group
lsquo hellip because of the unexpectedly high incidence of gastroduodenal ulcers observedhelliprsquo
Harris et al ClinTher 2001231422
Class Effect of All NSAIDs
httpwwwfdagovcderdruginfopageCOX2NSAIDdecisionMemopdf
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
33
Cardiovascular Safetybull Arthritis patients often have concomitant CV
disease1
bull Pain is an important predictor of CV risk23
bull Randomized controlled trials and observational data demonstrate that CV risk of etoricoxib appears similar to that of traditional NSAIDs4-6
bull Recent data suggest that differential CV effects of NSAIDs (selective and nonselective) may be independent of COX-2 inhibition78
References 1 Singh G et al Am J Manag Care 20028(suppl)S383-S391 2
Sokka T Pincus T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 3
Pincus T Sokka T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 4
httpwwwfdagovohrmsdocketsac05slides2005-4090S1_06_01_Pfizer-celecoxibppt (accessed 14 February 2006) 5
White WB et al Am J Cardiol 200289425ndash430 6
Graham DJ et al Lancet 2005365475ndash481 7 Yang HM et al Circulation 2004110301ndash308 8 Steffel J et al Circulation 20051111685ndash1689
Events per 100 patient years
Coxib Coxib Placebo Coxib NSAID Percent naproxen
Rofecoxib 17 19 11 08 73
Celecoxib 13 15 11 11 20
Valdecoxib 13 12 13 20 about 50
Etoricoxib 13 12 12 08 67
Lumiracoxib 09 08 52
34
APTC endpoint (cardiovascular haemorrhagic and unknown death and nonfatal myocardial infarction and stroke)
1
MR Weir et al Selective COX-2 inhibition and cardiovascular effects a review of the rofecoxib development program American heart Journal 2003 146 591-604
2
WB White et al Cardiovascular thrombotic events in arthritis trials of the cyclooxygenase-2 inhibitor celecoxib American Journal of cardiology 2003 92 411-418
3
WB White et al Effects of the cyclooxygenase-2 specific inhibitor valdecoxib versus nonsteroidal anti-inflammatory agents and placebo on cardiovascular thrombotic events in patients with arthritis American Journal of Therapeutics 2004 11 244-250
4
S Curtis et al Cardiovascular safety summary associated with the etoricoxib development programme Arthritis amp Rheumatism 2003 48 Suppl S616
5
ME Farkouh et al Comparison of lumiracoxib with naproxen and ibuprofen in the therapeutic arthritis research and gastrointestinal event trial (TARGET) cardiovascular outcomes randomised controlled trial Lancet 2004 364 675-684
RECOMMENDATIONS
NSAIDs COXIBs
bull Use lowest effective dose shortest duration
bull Not for patients who have recently undergone coronary artery bypass graft (CABG) surgery and revascularisation procedures
bull Coxibs should not be prescribed for patients with established ischaemic heart disease stroke or congestive heart failure
bull Caution for Coxibs for patients who have hypertension hyperlipidaemia diabetes and smoking as well as peripheral arterial disease
bull Etoricoxib should not be prescribed for patients with hypertension whose blood pressure has not been adequately controlled
The EU Summit is supported by Pfizer
Tricyclic Agents
bull best documented analgesics here (NNT 22)bull amitriptyline best investigatedbull desipraminenortriptyline less AEs
bull start on low doses increases compliancebullOften adverse effects (NNH 28)bull effect needs timebull SSRIs not as effective (NNT 67)
bull noradrenergic effect necessarybull venlafaxine another option
Antidepressants Compared with Placebo
Condition Number of trials
Antidepressant improvedtotal
Placebo improvedtotal
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 13 180260 73205 19 (16 to
24)30 (24 to 40)
Postherpetic neuralgia 3 4377 868 48 (24 to
94)23 (17 to 33)
Atypical facial pain 2 6288 3085 20 (15 to
28)28 (20 to 47)
Central pain 1 1015 115 10 (15 to 69)
17 (11 to 30)
Bandolier
Anticonvulsants as Membrane Stabilisers
bull pregabalinbull gabapentin bull carbamazepinebull clonazepam pooled NNT 27bull valproatebull lamotriginebull baclofen
Anticonvulsants Compared with Placebo
Condition Number of trials
Anticonvulsant improvedtotal
Placebo improvedtot
al
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 3 5668 2668 19 (14 to 27) 25 (18
to 40)
Trigeminal neuralgia 3 178315 41224 31 (23 to 41) 26 (22
to 33)
Migraine prophylaxis 2 6374 1777 37 (24 to 59) 16 (13
to 20)
Other pain syndromes 1 514 115 54 (07 to 40)
not calculat ed
Bandolier
Relative Activity on Serotonin and Norepinephrine Reuptake Among
Antidepressants
CitalopramFluvoxamineSertralineParoxetineFluoxetine
VenlafaxineDuloxetine
MaprotilineDesipramineNortriptylineReboxetine
AmitriptylineMilnacipranImipramine
Serotonin Mixed Norepinephrine
Antidepressant Analgesic Antidepressant
Fishbain et al Pain Med 20001310-316
Opioidsbull In principle opioids are effective in nociceptive
and some neuropathic pain however not always and not necessarily completely for dynamic pain
bull Possibly preferable opioids here arendash tramadol
bull noradrenergic and serotoninergic effectndash morphine
bull Mu receptor anatagonistmonaminergic effect
ndash oxycodonebull kappa receptor effect
Opioids
bull lsquoLack of analgesic effect of opioids on neuropathic hellip painrsquo Pain 19883311
bull lsquohellip intravenous hellip morphine reduce the pain of Osteoarthritisrsquo Neurology
1991411024bull lsquoA call for more science not more
rhetoric regarding opioids and arthritic painrsquo Pain 2001471
bull lsquoEfficacy of oxycodone in neuropathic painhelliprsquo Neurology 1998501837
OPIOIDS FOR OA PAINbull Osteoarthritis guidelines provide limited guidance on opioid use bull The 1995 ACR guidelines for hip OA suggest opioids be avoided for
long term use but short term use may be helpful without reference to primary data15
bull The 1995 ACR knee OA guidelines do not discuss opioids directly16 bull The 1998 UK guidelines on degenerative arthritis suggest that if
relief is inadequate with 24 grams of ibuprofen and 40 grams of paracetamol a day other antiinflammatories or opioids may be considered18
bull The 2000 update of the ACR OA guidelines suggests that opioids might be used as a medication of last resort17
bull Opioids are effective in OA hip and knee pain and have predictable side effects
bull It would be unwise were physicians to discount an entire class of medications over unfounded fears and incomplete knowledge of their benefits44
USE OF ULTRACET IN OA KNEESbull The efficacy of tramadolacetaminophen combination tablets (Ultracetreg) as add-
on and maintenance therapy in knee osteoarthritis pain inadequately controlled by nonsteroidal anti-inflammatory drug (NSAID)
Park KS Choi JJ Kim WU Min JK Park SH Cho CS
bull TramadolAPAP add-on significantly improved knee OA pain which had been inadequately controlled by NSAIDs In those subjects who showed favorable response to tramadolAPAP and NSAID combination therapy both tramadolAPAP and NSAIDs were effective at maintaining the pain-reduced state and there was no significant difference in efficacy between tramadolAPAP and NSAIDs
Clinical Rheumatology 2011 3 Aug
Opioid Sparing Regimes
bull Multimodal analgesia (Kehlet et al 1999)
bull NSAIDs and COX-2 (Romsing Moiniche 2004)
bull Paracetamol (Romsing 2002)
bull Ketamine (Elia Tramer 2005)
bull Gabapentin and Pregabalin (Dahl et al 2004)
bull Gabapentin and Rofecoxib (Gilron et al 2005)
Opioid reduction 20 ndash 40 Reduction of PONV 30
Clinical effects
Single-modality treatment of a Multi- modality problem is
futile
ldquoTherersquos no pain thatrsquos so easy to bear than that of
someone elserdquo
ndashLeriche
Van Gogh ldquoOld Man in Sorrowrdquo
4
Pain and Inflammation Overview
bull Osteoarthritis (OA)bull Rheumatoid Arthritis (RA)bull Ankylosing spondylitis (AS)bull Acute pain
ndash Postoperative painndash Acute ankle sprainndash Acute shoulder tendonitisbursitisndash Acute low back pain
5References 1
European Bone and Joint Health Strategies Project European Action Toward Better Musculoskeletal Health 2005 2
European Opinion Research Group EEIG Health food and alcohol and safety Special Eurobarometer 186 2003
Epidemiology of osteoarthritis (OA) and rheumatoid arthritis (RA)
bull OA and RA are leading causes of severe long-term pain and physical disability1
bull Approximately 1 in 4 Europeans has some form of arthritisrheumatism 1 in 5 is under long-term treatment12
bull OA is the most common joint disorder and accounts for more disability among elderly patients than any other condition1
bull In developed countries 1 in 10 of the population gt60 y has significant clinical problems attributed to OA1
bull RA is the most common form of inflammatory joint disease and affects 03 to 10 of the general population in Europe1
Mem
bran
e Po
tent
ial (
mV)
Mem
bran
e Po
tent
ial (
mV)
60
40
20
0
-20
-40
-60
50 100 15050 100 150
Time (ms)Time (ms)
60
40
20
0
-20
-40
-60
50 100 15050 100 150
Time (ms)Time (ms)
30 seconds after application of 1 mM PGE2
No PGE2
PGE2 increases excitability of neurones
England et al J Physiol 1996495429-440
COX-2 and Peripheral Sensitisation
EP EP receptorreceptor PKAPKA
PKCPKCεε
IncreasedIncreasedneuronal neuronal
membrane membrane excitabilityexcitability
PGEPGE22
SNSPN3SNSPN3
TTx resistantTTx resistantsodium sodium channelchannel
Neurone Neurone firing thresholdfiring threshold
decreasesdecreases
Tissue InjuryTissue Injury
COXCOX--2 expressed2 expressed
P
COXCOX--2 and Central 2 and Central SensitisationSensitisation
Interleukin-1szlig-mediated induction of COX-2 in the CNS contributes to inflammatory pain hypersensitivityTAREK A SAMAD KIMBERLY A MOORE ADAM SAPIRSTEINdagger SARA BILLET ANDREW ALLCHORNEDagger STEPHEN POOLEsect JOSEPH V BONVENTRE amp CLIFFORD J WOOLFDagger
Neural Plasticity Research Group Department of Anesthesia amp Critical Care Department of Anesthesia amp Critical Care and Department of Medicine Massachusetts General Hospital and Harvard Medical School Charlestown Massachusetts 02129 USA
Dagger
Department of Anatomy University College London London WC1E 6BT UK
sect National Institute for Biological Standards and Control Blanche Lane South Mimms Hertfordshire EN6 3QG UK
Nature 2001410471 ndash 475
Convergence at WDR Neurone
Central Sensitisation
tissue or nerve injury
release of EAAsand neuropeptides
increased depolarizationat the NMDA receptor
expanded receptive fieldsand hyperexcitability
Increased Pain
excitotoxicity
loss of inhibition
adapted from Dubner
CNS
Central Sensitization May Have Contributed to OA Pain and Neuropathic
Pain Symptoms1
bull Focus group transcripts from participants with knee OA (N=80) were analyzed to determine the use of unprompted NP descriptors to characterize their pain (including burning tingling pins and needles and numbness) to determine whether people with chronic symptomatic knee OA use pain descriptors suggestive of underlying NP
bull The proportion of participants who used NP descriptors to characterize their pain was 34 (95 CI 24 to 45)
bull Participants using NP descriptors were younger than those who did not (mean age plusmn SD age 648 plusmn 97 years vs 720 plusmn 100 years respectively P=0003)
bull Characteristics that did not statistically distinguish participants who used NP descriptors from those who did included duration of OA pain intensity OA severity and gender
OA = osteoarthritis NP = neuropathic pain CI = confidence interval SD = standard deviation
1 Hochman JR et al Arthritis Care Res (Hoboken) 2010621019ndash1023
Central Sensitization in OA Expansion of Symptoms Beyond the
Joint
bull Quantitative sensory testing of PPTs in patients with knee OA pain (n=48) and matched controls without knee pain (n=24) revealed that subjects with OA pain exhibited sensitization in both OA-affected and unaffected areasndash Increasing pain intensity in
the OA-affected (knee) joint was associated with lower PPT in OA-unaffected areas (eg arm)1
PPT at arm (OA-unaffected area)
R = -032 Plt005
VAS at OA-affected Knee Joint
1500
1000
500
0 1 2 3 4 5 6 7 8 9 10PP
T k
Pa
Arendt-Nielsen L et al Pain 2010149573ndash581
OA = osteoarthritis PPT = pressure pain threshold VAS = visual analog scale
OA = osteoarthritis PPT = pressure pain threshold VAS = visual analog scale WOMAC = Western Ontario and McMaster Universities SF-36 = short form-36 health survey
Central Sensitization in OA Increased Pain Severity and Worse Pain-Associated
OutcomesImamura M et al Arthritis Rheum 2008591424ndash1431
Measure Spearmanrsquos rank correlation coefficient r P Value
VASPatellar tendon Sacral 2 subcutaneous dermatome levelAdductor longus muscle
-0545 -0546 -0561
lt0001 lt0001 lt0001
WOMAC painPatellar tendon Sacral 2 subcutaneous dermatome levelAdductor longus muscle
-0589-0601 -0540
lt0001 lt0001lt0001
WOMAC physical activityLumbar 2 subcutaneous dermatome level Sacral 2 subcutaneous dermatome level Peroneus longus muscle
-0550 -0509 -0571
lt0001lt0001 lt0001
SF-36 bodily painLumbar 1ndashLumbar 2 supraspinous ligamentLumbar 2 subcutaneous dermatome level Adductor longus muscle
0534 0606 0569
lt0001 lt0001 lt0001
A cross-sectional study that assessed hyperalgesia in patients with refractory OA-associated pain (n=62) reported significant correlations between PPT values at each listed site and VAS WOMAC pain and physical activity subscales and SF-36 bodily pain score
SKIN
SPINAL CORD
Dorsal horn
PRIMARY AFFERENT NERVE
Dorsal root ganglion
POSTSYNAPTIC PROCESSPRESYNAPTIC PROCESS
NMDA receptor
Ca2+ Second messengers
kinases (eg PKC) diacylglycerol cAMP
Gene transcription
P
CELL NUCLEUS
Long term changes
(receptor function transmitter production)
Glutamate release
C-fosoncogene
Cortical Reorganisation
I will show that my client is welltolerated amp effectivehelliphellip
I will showthat my clientis well tolerated and effective
bull For chronic pain most measures of treatment response involve patient- reported outcomes for which the patient is the most important judge of whether changes are important or meaningful12
ndash Determinations of statistical significance must be supplemented by consideration of the clinical importance of changes in outcome measures1
bull The IMMPACT consensus meeting proposed provisional benchmarks for identifying clinically important changes in the specific outcome measures for chronic pain clinical trials1
Using NNT Analyses in the Treatment of Pain IMMPACT Consensus Meeting Recommendations
NNT = number needed to treat IMMPACT = Initiative on Methods Measurement and Pain Assessment in Clinical Trials1 Dworkin RH et al J Pain 20089105ndash121 2 Acquadro C et al Value Health 20036522ndash531
10ndash20Reduction in pain intensity
ge50Reduction in pain intensity
ge30Reduction in pain intensity
Minimally Important Improvement
Moderately Important Improvement
Substantial Improvement
132
253
353638
4244
55788
1718
0 4 8 12 16 20
Oxycodone 5Codeine 60Tramadol 50Propoxyphene 65APAP 325Oxycodone 5ASA 650Codeine 60Tramadol 100APAP 650Propox 100APAP 1000APAP 600Cod 60Morphine 10APAP 1000Oxyc 10Ibuprofen 400Oxycodone 15
McQuay H BMJ 1997
Patients with 50 reduction Patients with 50 reduction in pain vs placeboin pain vs placebo
NNT
USE OF PARACETAMOL IN TREATMENT OF OA PAIN
22
How effective was paracetamol
How effective was paracetamol compared with NSAIDs
F Wolfe S Zhao N Lane Preference for nonsteroidal antiinflammatory drugs over acetaminophen by rheumatic disease patients Arthritis amp Rheumatism 2000 43 378-385
2007 League table of NNT for at least 50 pain relief over 4-6 hrs in patients with moderate to severe pain
(all oral analgesics except IM morphine )
[httpwwwmedicineoxacukbandolierboothpainpagacutrevanalgesicsleagtabhtml
ETORICOXIB IN ACUTE PAIN
bull Etoricoxib 120 mg has been approved for treating acute pain which includes post-operative pain and other acute pain such as primary dysmenorrhea and acute gouty arthritis
bull Efficacy of etoricoxib in the post-operative setting as evaluated by NNT bull COCHRANE REVIEW Five randomized placebo-controlled studies
with a total number of 880 patients were included -- Four studies on patients with dental pain following extraction of at least one impacted third molar
--One study on patients with pain following uncomplicated orthopaedic surgery
bull NNT were calculated to measure at least 50 pain relief over 4-6 hrs (substantial pain relief) based on TOPAR scores
Results 120 mg etoricoxib with a NNT of 19 for acute post-operative pain
1 Chang DJ Desjardins PJ King TR Erb T Geba GP The analgesic efficacy of etoricoxib compared with oxycodoneacetaminophen in an acute postoperative pain model a randomized double-blind clinical trial Anesthesia and Analgesia 200499(3)807ndash15
2 Malmstrom K Sapre A Couglin H Agrawal NG Mazenko RS Fricke JR Jr Etoricoxib in acute pain associated with dental surgery a randomized double-blind placebo- and active comparator-controlled dose-ranging study Clinical Therapeutics 200426(5)667ndash79
3 Malmstrom K Kotey P Coughlin H Desjardins PJ A randomized double-blind parallel-group study comparing the analgesic effect of etoricoxib to placebo naproxen sodium and acetaminophen with codeine using the dental impaction pain model Clinical Journal of Pain 200420(3)147ndash 55
4 Malmstrom K Ang J Fricke JR Shingo S Reicin A The analgesic effect of etoricoxib relative to that of cetaminophen analgesics a randomized controlled single-dose study in acute dental impaction pain Current Medical Research and Opinion 200521(1)141ndash9 Rasmussen 2005 published data only
5 Rasmussen GL Malmstrom K Bourne MH Jove M Rhondeau SM Kotey P Etoricoxib provides analgesic efficacy to patients after knee or hip replacement surgery a randomized double-blind placebo-controlled study Anaesthesia and Analgesia 2005101(4) 1104ndash11
Etoricoxib in acute pain bull Indirect comparisons of NNTs for at least 50 pain
relief over 4 to 6 hours in reviews of other analgesics using identical methods indicate that etoricoxib 120 mg
-- has slightly better efficacy than rofecoxib 50 mg (22 (19 to 24) Barden 2005)
-- is significantly better than lumiracoxib 400mg (27 (22 to 35) Roy 2007) or-- celecoxib 400 mg (25 (22 to 29) Derry 2008)
-- better than the non-selective NSAIDs ibuprofen 400 mg (27 (25 to 30) Collins 1999) naproxen 500 mg (27 (23 to 32 Derry 2009a) and diclofenac 50mg (24 (18 to 33Derry 2009b)
Placebo
Paracetamol 10007
Paracetamolcodeine 1000606
Ibuprofen 4005
Celecoxib 4004
Naproxen 5005503
Rofecoxib 502
Etoricoxib 1201
0 4 8 12 16 20 24Median remedication time (hr)
Each bar is from a Cochrane review
Acute pain Time for patients to Re-medication
The weighted median time to re-medication with ARCOXIA 120mg is about 24hrs
vs placebo at 18hrs
1 Clarke R et al Cochrane Database Syst Rev 2009 Apr 15(2)CD004309 2 Bulley S et al Cochrane Database Syst Rev 2009 Oct 7(4)CD0046043 Derry C et al Cochrane Database Syst Rev 2009 Jan 21(1)CD004234 4 Derry S Cochrane Database Syst Rev 2008 Oct 8(4)CD0042335 Derry C et al Cochrane Database Syst Rev 2009 Jul 8(3)CD0015486 Toms L et al Cochrane Database Syst Rev 2009 Jan 21(1)CD0015477 Toms L et al Cochrane Database Syst Rev 2008 Oct 8(4)CD004602
Placebo (n=56)
Etoricoxib 60 mg (n=224)
Naproxen 1000 mgc
(n=221)
a0-
to 100-mm VAS (0 = none to 100 = extreme)
b0-
to 100-mm VAS (0 = very well to 100 = very poor) c500 mg twice dailyPlt0001 vs placebo for both etoricoxib and naproxen P = NS etoricoxib vs naproxen
Leung AT et al Curr Med Res Opin 200218(2)49ndash58
LS M
ean
Cha
nge
plusmnSE
Weeks Postrandomization
Osteoarthritis Etoricoxib 60 mg vs Naproxen
Results Etoricoxib relieved pain and improved mobility and disease statuEtoricoxib relieved pain and improved mobility and disease statuss
ndash35
ndash25
ndash5
5
ndash15
WOMAC Pain Subscalea
S R 4 82 12
WOMAC Physical Function Subscalea PGADSb
ndash35
ndash25
ndash5
5
ndash15
S R 4 82 12ndash35
ndash25
ndash5
5
ndash15
S R 4 82 12Weeks Postrandomization Weeks Postrandomization
Adverse effects of NSAIDsAdverse effects of NSAIDs
BNF March 2002
Dose-dependent toxicityIntolerability dyspepsiaGI bleedingUlcers ndash bleeds perforations
Upper-GI
Renal
Contributes to blood loss
Fluid retention oedema hypertensionRenal dysfunction failure ndash acute chronicHeart failure
Anti-platelet effects
Angioedema bronchospasmHypersensitivity
No Short-Term Adverse GI Effects -
The Big Mistake
bull Study designed to evaluate short-term GI effects in elderly
bull Study planned to enrol 160 patientsbull Study terminated by investigator at 17 subjects
ndash 8 patients had ulcersndash 4 of 4 in ketorolac group
lsquo hellip because of the unexpectedly high incidence of gastroduodenal ulcers observedhelliprsquo
Harris et al ClinTher 2001231422
Class Effect of All NSAIDs
httpwwwfdagovcderdruginfopageCOX2NSAIDdecisionMemopdf
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
33
Cardiovascular Safetybull Arthritis patients often have concomitant CV
disease1
bull Pain is an important predictor of CV risk23
bull Randomized controlled trials and observational data demonstrate that CV risk of etoricoxib appears similar to that of traditional NSAIDs4-6
bull Recent data suggest that differential CV effects of NSAIDs (selective and nonselective) may be independent of COX-2 inhibition78
References 1 Singh G et al Am J Manag Care 20028(suppl)S383-S391 2
Sokka T Pincus T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 3
Pincus T Sokka T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 4
httpwwwfdagovohrmsdocketsac05slides2005-4090S1_06_01_Pfizer-celecoxibppt (accessed 14 February 2006) 5
White WB et al Am J Cardiol 200289425ndash430 6
Graham DJ et al Lancet 2005365475ndash481 7 Yang HM et al Circulation 2004110301ndash308 8 Steffel J et al Circulation 20051111685ndash1689
Events per 100 patient years
Coxib Coxib Placebo Coxib NSAID Percent naproxen
Rofecoxib 17 19 11 08 73
Celecoxib 13 15 11 11 20
Valdecoxib 13 12 13 20 about 50
Etoricoxib 13 12 12 08 67
Lumiracoxib 09 08 52
34
APTC endpoint (cardiovascular haemorrhagic and unknown death and nonfatal myocardial infarction and stroke)
1
MR Weir et al Selective COX-2 inhibition and cardiovascular effects a review of the rofecoxib development program American heart Journal 2003 146 591-604
2
WB White et al Cardiovascular thrombotic events in arthritis trials of the cyclooxygenase-2 inhibitor celecoxib American Journal of cardiology 2003 92 411-418
3
WB White et al Effects of the cyclooxygenase-2 specific inhibitor valdecoxib versus nonsteroidal anti-inflammatory agents and placebo on cardiovascular thrombotic events in patients with arthritis American Journal of Therapeutics 2004 11 244-250
4
S Curtis et al Cardiovascular safety summary associated with the etoricoxib development programme Arthritis amp Rheumatism 2003 48 Suppl S616
5
ME Farkouh et al Comparison of lumiracoxib with naproxen and ibuprofen in the therapeutic arthritis research and gastrointestinal event trial (TARGET) cardiovascular outcomes randomised controlled trial Lancet 2004 364 675-684
RECOMMENDATIONS
NSAIDs COXIBs
bull Use lowest effective dose shortest duration
bull Not for patients who have recently undergone coronary artery bypass graft (CABG) surgery and revascularisation procedures
bull Coxibs should not be prescribed for patients with established ischaemic heart disease stroke or congestive heart failure
bull Caution for Coxibs for patients who have hypertension hyperlipidaemia diabetes and smoking as well as peripheral arterial disease
bull Etoricoxib should not be prescribed for patients with hypertension whose blood pressure has not been adequately controlled
The EU Summit is supported by Pfizer
Tricyclic Agents
bull best documented analgesics here (NNT 22)bull amitriptyline best investigatedbull desipraminenortriptyline less AEs
bull start on low doses increases compliancebullOften adverse effects (NNH 28)bull effect needs timebull SSRIs not as effective (NNT 67)
bull noradrenergic effect necessarybull venlafaxine another option
Antidepressants Compared with Placebo
Condition Number of trials
Antidepressant improvedtotal
Placebo improvedtotal
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 13 180260 73205 19 (16 to
24)30 (24 to 40)
Postherpetic neuralgia 3 4377 868 48 (24 to
94)23 (17 to 33)
Atypical facial pain 2 6288 3085 20 (15 to
28)28 (20 to 47)
Central pain 1 1015 115 10 (15 to 69)
17 (11 to 30)
Bandolier
Anticonvulsants as Membrane Stabilisers
bull pregabalinbull gabapentin bull carbamazepinebull clonazepam pooled NNT 27bull valproatebull lamotriginebull baclofen
Anticonvulsants Compared with Placebo
Condition Number of trials
Anticonvulsant improvedtotal
Placebo improvedtot
al
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 3 5668 2668 19 (14 to 27) 25 (18
to 40)
Trigeminal neuralgia 3 178315 41224 31 (23 to 41) 26 (22
to 33)
Migraine prophylaxis 2 6374 1777 37 (24 to 59) 16 (13
to 20)
Other pain syndromes 1 514 115 54 (07 to 40)
not calculat ed
Bandolier
Relative Activity on Serotonin and Norepinephrine Reuptake Among
Antidepressants
CitalopramFluvoxamineSertralineParoxetineFluoxetine
VenlafaxineDuloxetine
MaprotilineDesipramineNortriptylineReboxetine
AmitriptylineMilnacipranImipramine
Serotonin Mixed Norepinephrine
Antidepressant Analgesic Antidepressant
Fishbain et al Pain Med 20001310-316
Opioidsbull In principle opioids are effective in nociceptive
and some neuropathic pain however not always and not necessarily completely for dynamic pain
bull Possibly preferable opioids here arendash tramadol
bull noradrenergic and serotoninergic effectndash morphine
bull Mu receptor anatagonistmonaminergic effect
ndash oxycodonebull kappa receptor effect
Opioids
bull lsquoLack of analgesic effect of opioids on neuropathic hellip painrsquo Pain 19883311
bull lsquohellip intravenous hellip morphine reduce the pain of Osteoarthritisrsquo Neurology
1991411024bull lsquoA call for more science not more
rhetoric regarding opioids and arthritic painrsquo Pain 2001471
bull lsquoEfficacy of oxycodone in neuropathic painhelliprsquo Neurology 1998501837
OPIOIDS FOR OA PAINbull Osteoarthritis guidelines provide limited guidance on opioid use bull The 1995 ACR guidelines for hip OA suggest opioids be avoided for
long term use but short term use may be helpful without reference to primary data15
bull The 1995 ACR knee OA guidelines do not discuss opioids directly16 bull The 1998 UK guidelines on degenerative arthritis suggest that if
relief is inadequate with 24 grams of ibuprofen and 40 grams of paracetamol a day other antiinflammatories or opioids may be considered18
bull The 2000 update of the ACR OA guidelines suggests that opioids might be used as a medication of last resort17
bull Opioids are effective in OA hip and knee pain and have predictable side effects
bull It would be unwise were physicians to discount an entire class of medications over unfounded fears and incomplete knowledge of their benefits44
USE OF ULTRACET IN OA KNEESbull The efficacy of tramadolacetaminophen combination tablets (Ultracetreg) as add-
on and maintenance therapy in knee osteoarthritis pain inadequately controlled by nonsteroidal anti-inflammatory drug (NSAID)
Park KS Choi JJ Kim WU Min JK Park SH Cho CS
bull TramadolAPAP add-on significantly improved knee OA pain which had been inadequately controlled by NSAIDs In those subjects who showed favorable response to tramadolAPAP and NSAID combination therapy both tramadolAPAP and NSAIDs were effective at maintaining the pain-reduced state and there was no significant difference in efficacy between tramadolAPAP and NSAIDs
Clinical Rheumatology 2011 3 Aug
Opioid Sparing Regimes
bull Multimodal analgesia (Kehlet et al 1999)
bull NSAIDs and COX-2 (Romsing Moiniche 2004)
bull Paracetamol (Romsing 2002)
bull Ketamine (Elia Tramer 2005)
bull Gabapentin and Pregabalin (Dahl et al 2004)
bull Gabapentin and Rofecoxib (Gilron et al 2005)
Opioid reduction 20 ndash 40 Reduction of PONV 30
Clinical effects
Single-modality treatment of a Multi- modality problem is
futile
ldquoTherersquos no pain thatrsquos so easy to bear than that of
someone elserdquo
ndashLeriche
Van Gogh ldquoOld Man in Sorrowrdquo
5References 1
European Bone and Joint Health Strategies Project European Action Toward Better Musculoskeletal Health 2005 2
European Opinion Research Group EEIG Health food and alcohol and safety Special Eurobarometer 186 2003
Epidemiology of osteoarthritis (OA) and rheumatoid arthritis (RA)
bull OA and RA are leading causes of severe long-term pain and physical disability1
bull Approximately 1 in 4 Europeans has some form of arthritisrheumatism 1 in 5 is under long-term treatment12
bull OA is the most common joint disorder and accounts for more disability among elderly patients than any other condition1
bull In developed countries 1 in 10 of the population gt60 y has significant clinical problems attributed to OA1
bull RA is the most common form of inflammatory joint disease and affects 03 to 10 of the general population in Europe1
Mem
bran
e Po
tent
ial (
mV)
Mem
bran
e Po
tent
ial (
mV)
60
40
20
0
-20
-40
-60
50 100 15050 100 150
Time (ms)Time (ms)
60
40
20
0
-20
-40
-60
50 100 15050 100 150
Time (ms)Time (ms)
30 seconds after application of 1 mM PGE2
No PGE2
PGE2 increases excitability of neurones
England et al J Physiol 1996495429-440
COX-2 and Peripheral Sensitisation
EP EP receptorreceptor PKAPKA
PKCPKCεε
IncreasedIncreasedneuronal neuronal
membrane membrane excitabilityexcitability
PGEPGE22
SNSPN3SNSPN3
TTx resistantTTx resistantsodium sodium channelchannel
Neurone Neurone firing thresholdfiring threshold
decreasesdecreases
Tissue InjuryTissue Injury
COXCOX--2 expressed2 expressed
P
COXCOX--2 and Central 2 and Central SensitisationSensitisation
Interleukin-1szlig-mediated induction of COX-2 in the CNS contributes to inflammatory pain hypersensitivityTAREK A SAMAD KIMBERLY A MOORE ADAM SAPIRSTEINdagger SARA BILLET ANDREW ALLCHORNEDagger STEPHEN POOLEsect JOSEPH V BONVENTRE amp CLIFFORD J WOOLFDagger
Neural Plasticity Research Group Department of Anesthesia amp Critical Care Department of Anesthesia amp Critical Care and Department of Medicine Massachusetts General Hospital and Harvard Medical School Charlestown Massachusetts 02129 USA
Dagger
Department of Anatomy University College London London WC1E 6BT UK
sect National Institute for Biological Standards and Control Blanche Lane South Mimms Hertfordshire EN6 3QG UK
Nature 2001410471 ndash 475
Convergence at WDR Neurone
Central Sensitisation
tissue or nerve injury
release of EAAsand neuropeptides
increased depolarizationat the NMDA receptor
expanded receptive fieldsand hyperexcitability
Increased Pain
excitotoxicity
loss of inhibition
adapted from Dubner
CNS
Central Sensitization May Have Contributed to OA Pain and Neuropathic
Pain Symptoms1
bull Focus group transcripts from participants with knee OA (N=80) were analyzed to determine the use of unprompted NP descriptors to characterize their pain (including burning tingling pins and needles and numbness) to determine whether people with chronic symptomatic knee OA use pain descriptors suggestive of underlying NP
bull The proportion of participants who used NP descriptors to characterize their pain was 34 (95 CI 24 to 45)
bull Participants using NP descriptors were younger than those who did not (mean age plusmn SD age 648 plusmn 97 years vs 720 plusmn 100 years respectively P=0003)
bull Characteristics that did not statistically distinguish participants who used NP descriptors from those who did included duration of OA pain intensity OA severity and gender
OA = osteoarthritis NP = neuropathic pain CI = confidence interval SD = standard deviation
1 Hochman JR et al Arthritis Care Res (Hoboken) 2010621019ndash1023
Central Sensitization in OA Expansion of Symptoms Beyond the
Joint
bull Quantitative sensory testing of PPTs in patients with knee OA pain (n=48) and matched controls without knee pain (n=24) revealed that subjects with OA pain exhibited sensitization in both OA-affected and unaffected areasndash Increasing pain intensity in
the OA-affected (knee) joint was associated with lower PPT in OA-unaffected areas (eg arm)1
PPT at arm (OA-unaffected area)
R = -032 Plt005
VAS at OA-affected Knee Joint
1500
1000
500
0 1 2 3 4 5 6 7 8 9 10PP
T k
Pa
Arendt-Nielsen L et al Pain 2010149573ndash581
OA = osteoarthritis PPT = pressure pain threshold VAS = visual analog scale
OA = osteoarthritis PPT = pressure pain threshold VAS = visual analog scale WOMAC = Western Ontario and McMaster Universities SF-36 = short form-36 health survey
Central Sensitization in OA Increased Pain Severity and Worse Pain-Associated
OutcomesImamura M et al Arthritis Rheum 2008591424ndash1431
Measure Spearmanrsquos rank correlation coefficient r P Value
VASPatellar tendon Sacral 2 subcutaneous dermatome levelAdductor longus muscle
-0545 -0546 -0561
lt0001 lt0001 lt0001
WOMAC painPatellar tendon Sacral 2 subcutaneous dermatome levelAdductor longus muscle
-0589-0601 -0540
lt0001 lt0001lt0001
WOMAC physical activityLumbar 2 subcutaneous dermatome level Sacral 2 subcutaneous dermatome level Peroneus longus muscle
-0550 -0509 -0571
lt0001lt0001 lt0001
SF-36 bodily painLumbar 1ndashLumbar 2 supraspinous ligamentLumbar 2 subcutaneous dermatome level Adductor longus muscle
0534 0606 0569
lt0001 lt0001 lt0001
A cross-sectional study that assessed hyperalgesia in patients with refractory OA-associated pain (n=62) reported significant correlations between PPT values at each listed site and VAS WOMAC pain and physical activity subscales and SF-36 bodily pain score
SKIN
SPINAL CORD
Dorsal horn
PRIMARY AFFERENT NERVE
Dorsal root ganglion
POSTSYNAPTIC PROCESSPRESYNAPTIC PROCESS
NMDA receptor
Ca2+ Second messengers
kinases (eg PKC) diacylglycerol cAMP
Gene transcription
P
CELL NUCLEUS
Long term changes
(receptor function transmitter production)
Glutamate release
C-fosoncogene
Cortical Reorganisation
I will show that my client is welltolerated amp effectivehelliphellip
I will showthat my clientis well tolerated and effective
bull For chronic pain most measures of treatment response involve patient- reported outcomes for which the patient is the most important judge of whether changes are important or meaningful12
ndash Determinations of statistical significance must be supplemented by consideration of the clinical importance of changes in outcome measures1
bull The IMMPACT consensus meeting proposed provisional benchmarks for identifying clinically important changes in the specific outcome measures for chronic pain clinical trials1
Using NNT Analyses in the Treatment of Pain IMMPACT Consensus Meeting Recommendations
NNT = number needed to treat IMMPACT = Initiative on Methods Measurement and Pain Assessment in Clinical Trials1 Dworkin RH et al J Pain 20089105ndash121 2 Acquadro C et al Value Health 20036522ndash531
10ndash20Reduction in pain intensity
ge50Reduction in pain intensity
ge30Reduction in pain intensity
Minimally Important Improvement
Moderately Important Improvement
Substantial Improvement
132
253
353638
4244
55788
1718
0 4 8 12 16 20
Oxycodone 5Codeine 60Tramadol 50Propoxyphene 65APAP 325Oxycodone 5ASA 650Codeine 60Tramadol 100APAP 650Propox 100APAP 1000APAP 600Cod 60Morphine 10APAP 1000Oxyc 10Ibuprofen 400Oxycodone 15
McQuay H BMJ 1997
Patients with 50 reduction Patients with 50 reduction in pain vs placeboin pain vs placebo
NNT
USE OF PARACETAMOL IN TREATMENT OF OA PAIN
22
How effective was paracetamol
How effective was paracetamol compared with NSAIDs
F Wolfe S Zhao N Lane Preference for nonsteroidal antiinflammatory drugs over acetaminophen by rheumatic disease patients Arthritis amp Rheumatism 2000 43 378-385
2007 League table of NNT for at least 50 pain relief over 4-6 hrs in patients with moderate to severe pain
(all oral analgesics except IM morphine )
[httpwwwmedicineoxacukbandolierboothpainpagacutrevanalgesicsleagtabhtml
ETORICOXIB IN ACUTE PAIN
bull Etoricoxib 120 mg has been approved for treating acute pain which includes post-operative pain and other acute pain such as primary dysmenorrhea and acute gouty arthritis
bull Efficacy of etoricoxib in the post-operative setting as evaluated by NNT bull COCHRANE REVIEW Five randomized placebo-controlled studies
with a total number of 880 patients were included -- Four studies on patients with dental pain following extraction of at least one impacted third molar
--One study on patients with pain following uncomplicated orthopaedic surgery
bull NNT were calculated to measure at least 50 pain relief over 4-6 hrs (substantial pain relief) based on TOPAR scores
Results 120 mg etoricoxib with a NNT of 19 for acute post-operative pain
1 Chang DJ Desjardins PJ King TR Erb T Geba GP The analgesic efficacy of etoricoxib compared with oxycodoneacetaminophen in an acute postoperative pain model a randomized double-blind clinical trial Anesthesia and Analgesia 200499(3)807ndash15
2 Malmstrom K Sapre A Couglin H Agrawal NG Mazenko RS Fricke JR Jr Etoricoxib in acute pain associated with dental surgery a randomized double-blind placebo- and active comparator-controlled dose-ranging study Clinical Therapeutics 200426(5)667ndash79
3 Malmstrom K Kotey P Coughlin H Desjardins PJ A randomized double-blind parallel-group study comparing the analgesic effect of etoricoxib to placebo naproxen sodium and acetaminophen with codeine using the dental impaction pain model Clinical Journal of Pain 200420(3)147ndash 55
4 Malmstrom K Ang J Fricke JR Shingo S Reicin A The analgesic effect of etoricoxib relative to that of cetaminophen analgesics a randomized controlled single-dose study in acute dental impaction pain Current Medical Research and Opinion 200521(1)141ndash9 Rasmussen 2005 published data only
5 Rasmussen GL Malmstrom K Bourne MH Jove M Rhondeau SM Kotey P Etoricoxib provides analgesic efficacy to patients after knee or hip replacement surgery a randomized double-blind placebo-controlled study Anaesthesia and Analgesia 2005101(4) 1104ndash11
Etoricoxib in acute pain bull Indirect comparisons of NNTs for at least 50 pain
relief over 4 to 6 hours in reviews of other analgesics using identical methods indicate that etoricoxib 120 mg
-- has slightly better efficacy than rofecoxib 50 mg (22 (19 to 24) Barden 2005)
-- is significantly better than lumiracoxib 400mg (27 (22 to 35) Roy 2007) or-- celecoxib 400 mg (25 (22 to 29) Derry 2008)
-- better than the non-selective NSAIDs ibuprofen 400 mg (27 (25 to 30) Collins 1999) naproxen 500 mg (27 (23 to 32 Derry 2009a) and diclofenac 50mg (24 (18 to 33Derry 2009b)
Placebo
Paracetamol 10007
Paracetamolcodeine 1000606
Ibuprofen 4005
Celecoxib 4004
Naproxen 5005503
Rofecoxib 502
Etoricoxib 1201
0 4 8 12 16 20 24Median remedication time (hr)
Each bar is from a Cochrane review
Acute pain Time for patients to Re-medication
The weighted median time to re-medication with ARCOXIA 120mg is about 24hrs
vs placebo at 18hrs
1 Clarke R et al Cochrane Database Syst Rev 2009 Apr 15(2)CD004309 2 Bulley S et al Cochrane Database Syst Rev 2009 Oct 7(4)CD0046043 Derry C et al Cochrane Database Syst Rev 2009 Jan 21(1)CD004234 4 Derry S Cochrane Database Syst Rev 2008 Oct 8(4)CD0042335 Derry C et al Cochrane Database Syst Rev 2009 Jul 8(3)CD0015486 Toms L et al Cochrane Database Syst Rev 2009 Jan 21(1)CD0015477 Toms L et al Cochrane Database Syst Rev 2008 Oct 8(4)CD004602
Placebo (n=56)
Etoricoxib 60 mg (n=224)
Naproxen 1000 mgc
(n=221)
a0-
to 100-mm VAS (0 = none to 100 = extreme)
b0-
to 100-mm VAS (0 = very well to 100 = very poor) c500 mg twice dailyPlt0001 vs placebo for both etoricoxib and naproxen P = NS etoricoxib vs naproxen
Leung AT et al Curr Med Res Opin 200218(2)49ndash58
LS M
ean
Cha
nge
plusmnSE
Weeks Postrandomization
Osteoarthritis Etoricoxib 60 mg vs Naproxen
Results Etoricoxib relieved pain and improved mobility and disease statuEtoricoxib relieved pain and improved mobility and disease statuss
ndash35
ndash25
ndash5
5
ndash15
WOMAC Pain Subscalea
S R 4 82 12
WOMAC Physical Function Subscalea PGADSb
ndash35
ndash25
ndash5
5
ndash15
S R 4 82 12ndash35
ndash25
ndash5
5
ndash15
S R 4 82 12Weeks Postrandomization Weeks Postrandomization
Adverse effects of NSAIDsAdverse effects of NSAIDs
BNF March 2002
Dose-dependent toxicityIntolerability dyspepsiaGI bleedingUlcers ndash bleeds perforations
Upper-GI
Renal
Contributes to blood loss
Fluid retention oedema hypertensionRenal dysfunction failure ndash acute chronicHeart failure
Anti-platelet effects
Angioedema bronchospasmHypersensitivity
No Short-Term Adverse GI Effects -
The Big Mistake
bull Study designed to evaluate short-term GI effects in elderly
bull Study planned to enrol 160 patientsbull Study terminated by investigator at 17 subjects
ndash 8 patients had ulcersndash 4 of 4 in ketorolac group
lsquo hellip because of the unexpectedly high incidence of gastroduodenal ulcers observedhelliprsquo
Harris et al ClinTher 2001231422
Class Effect of All NSAIDs
httpwwwfdagovcderdruginfopageCOX2NSAIDdecisionMemopdf
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
33
Cardiovascular Safetybull Arthritis patients often have concomitant CV
disease1
bull Pain is an important predictor of CV risk23
bull Randomized controlled trials and observational data demonstrate that CV risk of etoricoxib appears similar to that of traditional NSAIDs4-6
bull Recent data suggest that differential CV effects of NSAIDs (selective and nonselective) may be independent of COX-2 inhibition78
References 1 Singh G et al Am J Manag Care 20028(suppl)S383-S391 2
Sokka T Pincus T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 3
Pincus T Sokka T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 4
httpwwwfdagovohrmsdocketsac05slides2005-4090S1_06_01_Pfizer-celecoxibppt (accessed 14 February 2006) 5
White WB et al Am J Cardiol 200289425ndash430 6
Graham DJ et al Lancet 2005365475ndash481 7 Yang HM et al Circulation 2004110301ndash308 8 Steffel J et al Circulation 20051111685ndash1689
Events per 100 patient years
Coxib Coxib Placebo Coxib NSAID Percent naproxen
Rofecoxib 17 19 11 08 73
Celecoxib 13 15 11 11 20
Valdecoxib 13 12 13 20 about 50
Etoricoxib 13 12 12 08 67
Lumiracoxib 09 08 52
34
APTC endpoint (cardiovascular haemorrhagic and unknown death and nonfatal myocardial infarction and stroke)
1
MR Weir et al Selective COX-2 inhibition and cardiovascular effects a review of the rofecoxib development program American heart Journal 2003 146 591-604
2
WB White et al Cardiovascular thrombotic events in arthritis trials of the cyclooxygenase-2 inhibitor celecoxib American Journal of cardiology 2003 92 411-418
3
WB White et al Effects of the cyclooxygenase-2 specific inhibitor valdecoxib versus nonsteroidal anti-inflammatory agents and placebo on cardiovascular thrombotic events in patients with arthritis American Journal of Therapeutics 2004 11 244-250
4
S Curtis et al Cardiovascular safety summary associated with the etoricoxib development programme Arthritis amp Rheumatism 2003 48 Suppl S616
5
ME Farkouh et al Comparison of lumiracoxib with naproxen and ibuprofen in the therapeutic arthritis research and gastrointestinal event trial (TARGET) cardiovascular outcomes randomised controlled trial Lancet 2004 364 675-684
RECOMMENDATIONS
NSAIDs COXIBs
bull Use lowest effective dose shortest duration
bull Not for patients who have recently undergone coronary artery bypass graft (CABG) surgery and revascularisation procedures
bull Coxibs should not be prescribed for patients with established ischaemic heart disease stroke or congestive heart failure
bull Caution for Coxibs for patients who have hypertension hyperlipidaemia diabetes and smoking as well as peripheral arterial disease
bull Etoricoxib should not be prescribed for patients with hypertension whose blood pressure has not been adequately controlled
The EU Summit is supported by Pfizer
Tricyclic Agents
bull best documented analgesics here (NNT 22)bull amitriptyline best investigatedbull desipraminenortriptyline less AEs
bull start on low doses increases compliancebullOften adverse effects (NNH 28)bull effect needs timebull SSRIs not as effective (NNT 67)
bull noradrenergic effect necessarybull venlafaxine another option
Antidepressants Compared with Placebo
Condition Number of trials
Antidepressant improvedtotal
Placebo improvedtotal
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 13 180260 73205 19 (16 to
24)30 (24 to 40)
Postherpetic neuralgia 3 4377 868 48 (24 to
94)23 (17 to 33)
Atypical facial pain 2 6288 3085 20 (15 to
28)28 (20 to 47)
Central pain 1 1015 115 10 (15 to 69)
17 (11 to 30)
Bandolier
Anticonvulsants as Membrane Stabilisers
bull pregabalinbull gabapentin bull carbamazepinebull clonazepam pooled NNT 27bull valproatebull lamotriginebull baclofen
Anticonvulsants Compared with Placebo
Condition Number of trials
Anticonvulsant improvedtotal
Placebo improvedtot
al
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 3 5668 2668 19 (14 to 27) 25 (18
to 40)
Trigeminal neuralgia 3 178315 41224 31 (23 to 41) 26 (22
to 33)
Migraine prophylaxis 2 6374 1777 37 (24 to 59) 16 (13
to 20)
Other pain syndromes 1 514 115 54 (07 to 40)
not calculat ed
Bandolier
Relative Activity on Serotonin and Norepinephrine Reuptake Among
Antidepressants
CitalopramFluvoxamineSertralineParoxetineFluoxetine
VenlafaxineDuloxetine
MaprotilineDesipramineNortriptylineReboxetine
AmitriptylineMilnacipranImipramine
Serotonin Mixed Norepinephrine
Antidepressant Analgesic Antidepressant
Fishbain et al Pain Med 20001310-316
Opioidsbull In principle opioids are effective in nociceptive
and some neuropathic pain however not always and not necessarily completely for dynamic pain
bull Possibly preferable opioids here arendash tramadol
bull noradrenergic and serotoninergic effectndash morphine
bull Mu receptor anatagonistmonaminergic effect
ndash oxycodonebull kappa receptor effect
Opioids
bull lsquoLack of analgesic effect of opioids on neuropathic hellip painrsquo Pain 19883311
bull lsquohellip intravenous hellip morphine reduce the pain of Osteoarthritisrsquo Neurology
1991411024bull lsquoA call for more science not more
rhetoric regarding opioids and arthritic painrsquo Pain 2001471
bull lsquoEfficacy of oxycodone in neuropathic painhelliprsquo Neurology 1998501837
OPIOIDS FOR OA PAINbull Osteoarthritis guidelines provide limited guidance on opioid use bull The 1995 ACR guidelines for hip OA suggest opioids be avoided for
long term use but short term use may be helpful without reference to primary data15
bull The 1995 ACR knee OA guidelines do not discuss opioids directly16 bull The 1998 UK guidelines on degenerative arthritis suggest that if
relief is inadequate with 24 grams of ibuprofen and 40 grams of paracetamol a day other antiinflammatories or opioids may be considered18
bull The 2000 update of the ACR OA guidelines suggests that opioids might be used as a medication of last resort17
bull Opioids are effective in OA hip and knee pain and have predictable side effects
bull It would be unwise were physicians to discount an entire class of medications over unfounded fears and incomplete knowledge of their benefits44
USE OF ULTRACET IN OA KNEESbull The efficacy of tramadolacetaminophen combination tablets (Ultracetreg) as add-
on and maintenance therapy in knee osteoarthritis pain inadequately controlled by nonsteroidal anti-inflammatory drug (NSAID)
Park KS Choi JJ Kim WU Min JK Park SH Cho CS
bull TramadolAPAP add-on significantly improved knee OA pain which had been inadequately controlled by NSAIDs In those subjects who showed favorable response to tramadolAPAP and NSAID combination therapy both tramadolAPAP and NSAIDs were effective at maintaining the pain-reduced state and there was no significant difference in efficacy between tramadolAPAP and NSAIDs
Clinical Rheumatology 2011 3 Aug
Opioid Sparing Regimes
bull Multimodal analgesia (Kehlet et al 1999)
bull NSAIDs and COX-2 (Romsing Moiniche 2004)
bull Paracetamol (Romsing 2002)
bull Ketamine (Elia Tramer 2005)
bull Gabapentin and Pregabalin (Dahl et al 2004)
bull Gabapentin and Rofecoxib (Gilron et al 2005)
Opioid reduction 20 ndash 40 Reduction of PONV 30
Clinical effects
Single-modality treatment of a Multi- modality problem is
futile
ldquoTherersquos no pain thatrsquos so easy to bear than that of
someone elserdquo
ndashLeriche
Van Gogh ldquoOld Man in Sorrowrdquo
Mem
bran
e Po
tent
ial (
mV)
Mem
bran
e Po
tent
ial (
mV)
60
40
20
0
-20
-40
-60
50 100 15050 100 150
Time (ms)Time (ms)
60
40
20
0
-20
-40
-60
50 100 15050 100 150
Time (ms)Time (ms)
30 seconds after application of 1 mM PGE2
No PGE2
PGE2 increases excitability of neurones
England et al J Physiol 1996495429-440
COX-2 and Peripheral Sensitisation
EP EP receptorreceptor PKAPKA
PKCPKCεε
IncreasedIncreasedneuronal neuronal
membrane membrane excitabilityexcitability
PGEPGE22
SNSPN3SNSPN3
TTx resistantTTx resistantsodium sodium channelchannel
Neurone Neurone firing thresholdfiring threshold
decreasesdecreases
Tissue InjuryTissue Injury
COXCOX--2 expressed2 expressed
P
COXCOX--2 and Central 2 and Central SensitisationSensitisation
Interleukin-1szlig-mediated induction of COX-2 in the CNS contributes to inflammatory pain hypersensitivityTAREK A SAMAD KIMBERLY A MOORE ADAM SAPIRSTEINdagger SARA BILLET ANDREW ALLCHORNEDagger STEPHEN POOLEsect JOSEPH V BONVENTRE amp CLIFFORD J WOOLFDagger
Neural Plasticity Research Group Department of Anesthesia amp Critical Care Department of Anesthesia amp Critical Care and Department of Medicine Massachusetts General Hospital and Harvard Medical School Charlestown Massachusetts 02129 USA
Dagger
Department of Anatomy University College London London WC1E 6BT UK
sect National Institute for Biological Standards and Control Blanche Lane South Mimms Hertfordshire EN6 3QG UK
Nature 2001410471 ndash 475
Convergence at WDR Neurone
Central Sensitisation
tissue or nerve injury
release of EAAsand neuropeptides
increased depolarizationat the NMDA receptor
expanded receptive fieldsand hyperexcitability
Increased Pain
excitotoxicity
loss of inhibition
adapted from Dubner
CNS
Central Sensitization May Have Contributed to OA Pain and Neuropathic
Pain Symptoms1
bull Focus group transcripts from participants with knee OA (N=80) were analyzed to determine the use of unprompted NP descriptors to characterize their pain (including burning tingling pins and needles and numbness) to determine whether people with chronic symptomatic knee OA use pain descriptors suggestive of underlying NP
bull The proportion of participants who used NP descriptors to characterize their pain was 34 (95 CI 24 to 45)
bull Participants using NP descriptors were younger than those who did not (mean age plusmn SD age 648 plusmn 97 years vs 720 plusmn 100 years respectively P=0003)
bull Characteristics that did not statistically distinguish participants who used NP descriptors from those who did included duration of OA pain intensity OA severity and gender
OA = osteoarthritis NP = neuropathic pain CI = confidence interval SD = standard deviation
1 Hochman JR et al Arthritis Care Res (Hoboken) 2010621019ndash1023
Central Sensitization in OA Expansion of Symptoms Beyond the
Joint
bull Quantitative sensory testing of PPTs in patients with knee OA pain (n=48) and matched controls without knee pain (n=24) revealed that subjects with OA pain exhibited sensitization in both OA-affected and unaffected areasndash Increasing pain intensity in
the OA-affected (knee) joint was associated with lower PPT in OA-unaffected areas (eg arm)1
PPT at arm (OA-unaffected area)
R = -032 Plt005
VAS at OA-affected Knee Joint
1500
1000
500
0 1 2 3 4 5 6 7 8 9 10PP
T k
Pa
Arendt-Nielsen L et al Pain 2010149573ndash581
OA = osteoarthritis PPT = pressure pain threshold VAS = visual analog scale
OA = osteoarthritis PPT = pressure pain threshold VAS = visual analog scale WOMAC = Western Ontario and McMaster Universities SF-36 = short form-36 health survey
Central Sensitization in OA Increased Pain Severity and Worse Pain-Associated
OutcomesImamura M et al Arthritis Rheum 2008591424ndash1431
Measure Spearmanrsquos rank correlation coefficient r P Value
VASPatellar tendon Sacral 2 subcutaneous dermatome levelAdductor longus muscle
-0545 -0546 -0561
lt0001 lt0001 lt0001
WOMAC painPatellar tendon Sacral 2 subcutaneous dermatome levelAdductor longus muscle
-0589-0601 -0540
lt0001 lt0001lt0001
WOMAC physical activityLumbar 2 subcutaneous dermatome level Sacral 2 subcutaneous dermatome level Peroneus longus muscle
-0550 -0509 -0571
lt0001lt0001 lt0001
SF-36 bodily painLumbar 1ndashLumbar 2 supraspinous ligamentLumbar 2 subcutaneous dermatome level Adductor longus muscle
0534 0606 0569
lt0001 lt0001 lt0001
A cross-sectional study that assessed hyperalgesia in patients with refractory OA-associated pain (n=62) reported significant correlations between PPT values at each listed site and VAS WOMAC pain and physical activity subscales and SF-36 bodily pain score
SKIN
SPINAL CORD
Dorsal horn
PRIMARY AFFERENT NERVE
Dorsal root ganglion
POSTSYNAPTIC PROCESSPRESYNAPTIC PROCESS
NMDA receptor
Ca2+ Second messengers
kinases (eg PKC) diacylglycerol cAMP
Gene transcription
P
CELL NUCLEUS
Long term changes
(receptor function transmitter production)
Glutamate release
C-fosoncogene
Cortical Reorganisation
I will show that my client is welltolerated amp effectivehelliphellip
I will showthat my clientis well tolerated and effective
bull For chronic pain most measures of treatment response involve patient- reported outcomes for which the patient is the most important judge of whether changes are important or meaningful12
ndash Determinations of statistical significance must be supplemented by consideration of the clinical importance of changes in outcome measures1
bull The IMMPACT consensus meeting proposed provisional benchmarks for identifying clinically important changes in the specific outcome measures for chronic pain clinical trials1
Using NNT Analyses in the Treatment of Pain IMMPACT Consensus Meeting Recommendations
NNT = number needed to treat IMMPACT = Initiative on Methods Measurement and Pain Assessment in Clinical Trials1 Dworkin RH et al J Pain 20089105ndash121 2 Acquadro C et al Value Health 20036522ndash531
10ndash20Reduction in pain intensity
ge50Reduction in pain intensity
ge30Reduction in pain intensity
Minimally Important Improvement
Moderately Important Improvement
Substantial Improvement
132
253
353638
4244
55788
1718
0 4 8 12 16 20
Oxycodone 5Codeine 60Tramadol 50Propoxyphene 65APAP 325Oxycodone 5ASA 650Codeine 60Tramadol 100APAP 650Propox 100APAP 1000APAP 600Cod 60Morphine 10APAP 1000Oxyc 10Ibuprofen 400Oxycodone 15
McQuay H BMJ 1997
Patients with 50 reduction Patients with 50 reduction in pain vs placeboin pain vs placebo
NNT
USE OF PARACETAMOL IN TREATMENT OF OA PAIN
22
How effective was paracetamol
How effective was paracetamol compared with NSAIDs
F Wolfe S Zhao N Lane Preference for nonsteroidal antiinflammatory drugs over acetaminophen by rheumatic disease patients Arthritis amp Rheumatism 2000 43 378-385
2007 League table of NNT for at least 50 pain relief over 4-6 hrs in patients with moderate to severe pain
(all oral analgesics except IM morphine )
[httpwwwmedicineoxacukbandolierboothpainpagacutrevanalgesicsleagtabhtml
ETORICOXIB IN ACUTE PAIN
bull Etoricoxib 120 mg has been approved for treating acute pain which includes post-operative pain and other acute pain such as primary dysmenorrhea and acute gouty arthritis
bull Efficacy of etoricoxib in the post-operative setting as evaluated by NNT bull COCHRANE REVIEW Five randomized placebo-controlled studies
with a total number of 880 patients were included -- Four studies on patients with dental pain following extraction of at least one impacted third molar
--One study on patients with pain following uncomplicated orthopaedic surgery
bull NNT were calculated to measure at least 50 pain relief over 4-6 hrs (substantial pain relief) based on TOPAR scores
Results 120 mg etoricoxib with a NNT of 19 for acute post-operative pain
1 Chang DJ Desjardins PJ King TR Erb T Geba GP The analgesic efficacy of etoricoxib compared with oxycodoneacetaminophen in an acute postoperative pain model a randomized double-blind clinical trial Anesthesia and Analgesia 200499(3)807ndash15
2 Malmstrom K Sapre A Couglin H Agrawal NG Mazenko RS Fricke JR Jr Etoricoxib in acute pain associated with dental surgery a randomized double-blind placebo- and active comparator-controlled dose-ranging study Clinical Therapeutics 200426(5)667ndash79
3 Malmstrom K Kotey P Coughlin H Desjardins PJ A randomized double-blind parallel-group study comparing the analgesic effect of etoricoxib to placebo naproxen sodium and acetaminophen with codeine using the dental impaction pain model Clinical Journal of Pain 200420(3)147ndash 55
4 Malmstrom K Ang J Fricke JR Shingo S Reicin A The analgesic effect of etoricoxib relative to that of cetaminophen analgesics a randomized controlled single-dose study in acute dental impaction pain Current Medical Research and Opinion 200521(1)141ndash9 Rasmussen 2005 published data only
5 Rasmussen GL Malmstrom K Bourne MH Jove M Rhondeau SM Kotey P Etoricoxib provides analgesic efficacy to patients after knee or hip replacement surgery a randomized double-blind placebo-controlled study Anaesthesia and Analgesia 2005101(4) 1104ndash11
Etoricoxib in acute pain bull Indirect comparisons of NNTs for at least 50 pain
relief over 4 to 6 hours in reviews of other analgesics using identical methods indicate that etoricoxib 120 mg
-- has slightly better efficacy than rofecoxib 50 mg (22 (19 to 24) Barden 2005)
-- is significantly better than lumiracoxib 400mg (27 (22 to 35) Roy 2007) or-- celecoxib 400 mg (25 (22 to 29) Derry 2008)
-- better than the non-selective NSAIDs ibuprofen 400 mg (27 (25 to 30) Collins 1999) naproxen 500 mg (27 (23 to 32 Derry 2009a) and diclofenac 50mg (24 (18 to 33Derry 2009b)
Placebo
Paracetamol 10007
Paracetamolcodeine 1000606
Ibuprofen 4005
Celecoxib 4004
Naproxen 5005503
Rofecoxib 502
Etoricoxib 1201
0 4 8 12 16 20 24Median remedication time (hr)
Each bar is from a Cochrane review
Acute pain Time for patients to Re-medication
The weighted median time to re-medication with ARCOXIA 120mg is about 24hrs
vs placebo at 18hrs
1 Clarke R et al Cochrane Database Syst Rev 2009 Apr 15(2)CD004309 2 Bulley S et al Cochrane Database Syst Rev 2009 Oct 7(4)CD0046043 Derry C et al Cochrane Database Syst Rev 2009 Jan 21(1)CD004234 4 Derry S Cochrane Database Syst Rev 2008 Oct 8(4)CD0042335 Derry C et al Cochrane Database Syst Rev 2009 Jul 8(3)CD0015486 Toms L et al Cochrane Database Syst Rev 2009 Jan 21(1)CD0015477 Toms L et al Cochrane Database Syst Rev 2008 Oct 8(4)CD004602
Placebo (n=56)
Etoricoxib 60 mg (n=224)
Naproxen 1000 mgc
(n=221)
a0-
to 100-mm VAS (0 = none to 100 = extreme)
b0-
to 100-mm VAS (0 = very well to 100 = very poor) c500 mg twice dailyPlt0001 vs placebo for both etoricoxib and naproxen P = NS etoricoxib vs naproxen
Leung AT et al Curr Med Res Opin 200218(2)49ndash58
LS M
ean
Cha
nge
plusmnSE
Weeks Postrandomization
Osteoarthritis Etoricoxib 60 mg vs Naproxen
Results Etoricoxib relieved pain and improved mobility and disease statuEtoricoxib relieved pain and improved mobility and disease statuss
ndash35
ndash25
ndash5
5
ndash15
WOMAC Pain Subscalea
S R 4 82 12
WOMAC Physical Function Subscalea PGADSb
ndash35
ndash25
ndash5
5
ndash15
S R 4 82 12ndash35
ndash25
ndash5
5
ndash15
S R 4 82 12Weeks Postrandomization Weeks Postrandomization
Adverse effects of NSAIDsAdverse effects of NSAIDs
BNF March 2002
Dose-dependent toxicityIntolerability dyspepsiaGI bleedingUlcers ndash bleeds perforations
Upper-GI
Renal
Contributes to blood loss
Fluid retention oedema hypertensionRenal dysfunction failure ndash acute chronicHeart failure
Anti-platelet effects
Angioedema bronchospasmHypersensitivity
No Short-Term Adverse GI Effects -
The Big Mistake
bull Study designed to evaluate short-term GI effects in elderly
bull Study planned to enrol 160 patientsbull Study terminated by investigator at 17 subjects
ndash 8 patients had ulcersndash 4 of 4 in ketorolac group
lsquo hellip because of the unexpectedly high incidence of gastroduodenal ulcers observedhelliprsquo
Harris et al ClinTher 2001231422
Class Effect of All NSAIDs
httpwwwfdagovcderdruginfopageCOX2NSAIDdecisionMemopdf
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
33
Cardiovascular Safetybull Arthritis patients often have concomitant CV
disease1
bull Pain is an important predictor of CV risk23
bull Randomized controlled trials and observational data demonstrate that CV risk of etoricoxib appears similar to that of traditional NSAIDs4-6
bull Recent data suggest that differential CV effects of NSAIDs (selective and nonselective) may be independent of COX-2 inhibition78
References 1 Singh G et al Am J Manag Care 20028(suppl)S383-S391 2
Sokka T Pincus T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 3
Pincus T Sokka T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 4
httpwwwfdagovohrmsdocketsac05slides2005-4090S1_06_01_Pfizer-celecoxibppt (accessed 14 February 2006) 5
White WB et al Am J Cardiol 200289425ndash430 6
Graham DJ et al Lancet 2005365475ndash481 7 Yang HM et al Circulation 2004110301ndash308 8 Steffel J et al Circulation 20051111685ndash1689
Events per 100 patient years
Coxib Coxib Placebo Coxib NSAID Percent naproxen
Rofecoxib 17 19 11 08 73
Celecoxib 13 15 11 11 20
Valdecoxib 13 12 13 20 about 50
Etoricoxib 13 12 12 08 67
Lumiracoxib 09 08 52
34
APTC endpoint (cardiovascular haemorrhagic and unknown death and nonfatal myocardial infarction and stroke)
1
MR Weir et al Selective COX-2 inhibition and cardiovascular effects a review of the rofecoxib development program American heart Journal 2003 146 591-604
2
WB White et al Cardiovascular thrombotic events in arthritis trials of the cyclooxygenase-2 inhibitor celecoxib American Journal of cardiology 2003 92 411-418
3
WB White et al Effects of the cyclooxygenase-2 specific inhibitor valdecoxib versus nonsteroidal anti-inflammatory agents and placebo on cardiovascular thrombotic events in patients with arthritis American Journal of Therapeutics 2004 11 244-250
4
S Curtis et al Cardiovascular safety summary associated with the etoricoxib development programme Arthritis amp Rheumatism 2003 48 Suppl S616
5
ME Farkouh et al Comparison of lumiracoxib with naproxen and ibuprofen in the therapeutic arthritis research and gastrointestinal event trial (TARGET) cardiovascular outcomes randomised controlled trial Lancet 2004 364 675-684
RECOMMENDATIONS
NSAIDs COXIBs
bull Use lowest effective dose shortest duration
bull Not for patients who have recently undergone coronary artery bypass graft (CABG) surgery and revascularisation procedures
bull Coxibs should not be prescribed for patients with established ischaemic heart disease stroke or congestive heart failure
bull Caution for Coxibs for patients who have hypertension hyperlipidaemia diabetes and smoking as well as peripheral arterial disease
bull Etoricoxib should not be prescribed for patients with hypertension whose blood pressure has not been adequately controlled
The EU Summit is supported by Pfizer
Tricyclic Agents
bull best documented analgesics here (NNT 22)bull amitriptyline best investigatedbull desipraminenortriptyline less AEs
bull start on low doses increases compliancebullOften adverse effects (NNH 28)bull effect needs timebull SSRIs not as effective (NNT 67)
bull noradrenergic effect necessarybull venlafaxine another option
Antidepressants Compared with Placebo
Condition Number of trials
Antidepressant improvedtotal
Placebo improvedtotal
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 13 180260 73205 19 (16 to
24)30 (24 to 40)
Postherpetic neuralgia 3 4377 868 48 (24 to
94)23 (17 to 33)
Atypical facial pain 2 6288 3085 20 (15 to
28)28 (20 to 47)
Central pain 1 1015 115 10 (15 to 69)
17 (11 to 30)
Bandolier
Anticonvulsants as Membrane Stabilisers
bull pregabalinbull gabapentin bull carbamazepinebull clonazepam pooled NNT 27bull valproatebull lamotriginebull baclofen
Anticonvulsants Compared with Placebo
Condition Number of trials
Anticonvulsant improvedtotal
Placebo improvedtot
al
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 3 5668 2668 19 (14 to 27) 25 (18
to 40)
Trigeminal neuralgia 3 178315 41224 31 (23 to 41) 26 (22
to 33)
Migraine prophylaxis 2 6374 1777 37 (24 to 59) 16 (13
to 20)
Other pain syndromes 1 514 115 54 (07 to 40)
not calculat ed
Bandolier
Relative Activity on Serotonin and Norepinephrine Reuptake Among
Antidepressants
CitalopramFluvoxamineSertralineParoxetineFluoxetine
VenlafaxineDuloxetine
MaprotilineDesipramineNortriptylineReboxetine
AmitriptylineMilnacipranImipramine
Serotonin Mixed Norepinephrine
Antidepressant Analgesic Antidepressant
Fishbain et al Pain Med 20001310-316
Opioidsbull In principle opioids are effective in nociceptive
and some neuropathic pain however not always and not necessarily completely for dynamic pain
bull Possibly preferable opioids here arendash tramadol
bull noradrenergic and serotoninergic effectndash morphine
bull Mu receptor anatagonistmonaminergic effect
ndash oxycodonebull kappa receptor effect
Opioids
bull lsquoLack of analgesic effect of opioids on neuropathic hellip painrsquo Pain 19883311
bull lsquohellip intravenous hellip morphine reduce the pain of Osteoarthritisrsquo Neurology
1991411024bull lsquoA call for more science not more
rhetoric regarding opioids and arthritic painrsquo Pain 2001471
bull lsquoEfficacy of oxycodone in neuropathic painhelliprsquo Neurology 1998501837
OPIOIDS FOR OA PAINbull Osteoarthritis guidelines provide limited guidance on opioid use bull The 1995 ACR guidelines for hip OA suggest opioids be avoided for
long term use but short term use may be helpful without reference to primary data15
bull The 1995 ACR knee OA guidelines do not discuss opioids directly16 bull The 1998 UK guidelines on degenerative arthritis suggest that if
relief is inadequate with 24 grams of ibuprofen and 40 grams of paracetamol a day other antiinflammatories or opioids may be considered18
bull The 2000 update of the ACR OA guidelines suggests that opioids might be used as a medication of last resort17
bull Opioids are effective in OA hip and knee pain and have predictable side effects
bull It would be unwise were physicians to discount an entire class of medications over unfounded fears and incomplete knowledge of their benefits44
USE OF ULTRACET IN OA KNEESbull The efficacy of tramadolacetaminophen combination tablets (Ultracetreg) as add-
on and maintenance therapy in knee osteoarthritis pain inadequately controlled by nonsteroidal anti-inflammatory drug (NSAID)
Park KS Choi JJ Kim WU Min JK Park SH Cho CS
bull TramadolAPAP add-on significantly improved knee OA pain which had been inadequately controlled by NSAIDs In those subjects who showed favorable response to tramadolAPAP and NSAID combination therapy both tramadolAPAP and NSAIDs were effective at maintaining the pain-reduced state and there was no significant difference in efficacy between tramadolAPAP and NSAIDs
Clinical Rheumatology 2011 3 Aug
Opioid Sparing Regimes
bull Multimodal analgesia (Kehlet et al 1999)
bull NSAIDs and COX-2 (Romsing Moiniche 2004)
bull Paracetamol (Romsing 2002)
bull Ketamine (Elia Tramer 2005)
bull Gabapentin and Pregabalin (Dahl et al 2004)
bull Gabapentin and Rofecoxib (Gilron et al 2005)
Opioid reduction 20 ndash 40 Reduction of PONV 30
Clinical effects
Single-modality treatment of a Multi- modality problem is
futile
ldquoTherersquos no pain thatrsquos so easy to bear than that of
someone elserdquo
ndashLeriche
Van Gogh ldquoOld Man in Sorrowrdquo
COX-2 and Peripheral Sensitisation
EP EP receptorreceptor PKAPKA
PKCPKCεε
IncreasedIncreasedneuronal neuronal
membrane membrane excitabilityexcitability
PGEPGE22
SNSPN3SNSPN3
TTx resistantTTx resistantsodium sodium channelchannel
Neurone Neurone firing thresholdfiring threshold
decreasesdecreases
Tissue InjuryTissue Injury
COXCOX--2 expressed2 expressed
P
COXCOX--2 and Central 2 and Central SensitisationSensitisation
Interleukin-1szlig-mediated induction of COX-2 in the CNS contributes to inflammatory pain hypersensitivityTAREK A SAMAD KIMBERLY A MOORE ADAM SAPIRSTEINdagger SARA BILLET ANDREW ALLCHORNEDagger STEPHEN POOLEsect JOSEPH V BONVENTRE amp CLIFFORD J WOOLFDagger
Neural Plasticity Research Group Department of Anesthesia amp Critical Care Department of Anesthesia amp Critical Care and Department of Medicine Massachusetts General Hospital and Harvard Medical School Charlestown Massachusetts 02129 USA
Dagger
Department of Anatomy University College London London WC1E 6BT UK
sect National Institute for Biological Standards and Control Blanche Lane South Mimms Hertfordshire EN6 3QG UK
Nature 2001410471 ndash 475
Convergence at WDR Neurone
Central Sensitisation
tissue or nerve injury
release of EAAsand neuropeptides
increased depolarizationat the NMDA receptor
expanded receptive fieldsand hyperexcitability
Increased Pain
excitotoxicity
loss of inhibition
adapted from Dubner
CNS
Central Sensitization May Have Contributed to OA Pain and Neuropathic
Pain Symptoms1
bull Focus group transcripts from participants with knee OA (N=80) were analyzed to determine the use of unprompted NP descriptors to characterize their pain (including burning tingling pins and needles and numbness) to determine whether people with chronic symptomatic knee OA use pain descriptors suggestive of underlying NP
bull The proportion of participants who used NP descriptors to characterize their pain was 34 (95 CI 24 to 45)
bull Participants using NP descriptors were younger than those who did not (mean age plusmn SD age 648 plusmn 97 years vs 720 plusmn 100 years respectively P=0003)
bull Characteristics that did not statistically distinguish participants who used NP descriptors from those who did included duration of OA pain intensity OA severity and gender
OA = osteoarthritis NP = neuropathic pain CI = confidence interval SD = standard deviation
1 Hochman JR et al Arthritis Care Res (Hoboken) 2010621019ndash1023
Central Sensitization in OA Expansion of Symptoms Beyond the
Joint
bull Quantitative sensory testing of PPTs in patients with knee OA pain (n=48) and matched controls without knee pain (n=24) revealed that subjects with OA pain exhibited sensitization in both OA-affected and unaffected areasndash Increasing pain intensity in
the OA-affected (knee) joint was associated with lower PPT in OA-unaffected areas (eg arm)1
PPT at arm (OA-unaffected area)
R = -032 Plt005
VAS at OA-affected Knee Joint
1500
1000
500
0 1 2 3 4 5 6 7 8 9 10PP
T k
Pa
Arendt-Nielsen L et al Pain 2010149573ndash581
OA = osteoarthritis PPT = pressure pain threshold VAS = visual analog scale
OA = osteoarthritis PPT = pressure pain threshold VAS = visual analog scale WOMAC = Western Ontario and McMaster Universities SF-36 = short form-36 health survey
Central Sensitization in OA Increased Pain Severity and Worse Pain-Associated
OutcomesImamura M et al Arthritis Rheum 2008591424ndash1431
Measure Spearmanrsquos rank correlation coefficient r P Value
VASPatellar tendon Sacral 2 subcutaneous dermatome levelAdductor longus muscle
-0545 -0546 -0561
lt0001 lt0001 lt0001
WOMAC painPatellar tendon Sacral 2 subcutaneous dermatome levelAdductor longus muscle
-0589-0601 -0540
lt0001 lt0001lt0001
WOMAC physical activityLumbar 2 subcutaneous dermatome level Sacral 2 subcutaneous dermatome level Peroneus longus muscle
-0550 -0509 -0571
lt0001lt0001 lt0001
SF-36 bodily painLumbar 1ndashLumbar 2 supraspinous ligamentLumbar 2 subcutaneous dermatome level Adductor longus muscle
0534 0606 0569
lt0001 lt0001 lt0001
A cross-sectional study that assessed hyperalgesia in patients with refractory OA-associated pain (n=62) reported significant correlations between PPT values at each listed site and VAS WOMAC pain and physical activity subscales and SF-36 bodily pain score
SKIN
SPINAL CORD
Dorsal horn
PRIMARY AFFERENT NERVE
Dorsal root ganglion
POSTSYNAPTIC PROCESSPRESYNAPTIC PROCESS
NMDA receptor
Ca2+ Second messengers
kinases (eg PKC) diacylglycerol cAMP
Gene transcription
P
CELL NUCLEUS
Long term changes
(receptor function transmitter production)
Glutamate release
C-fosoncogene
Cortical Reorganisation
I will show that my client is welltolerated amp effectivehelliphellip
I will showthat my clientis well tolerated and effective
bull For chronic pain most measures of treatment response involve patient- reported outcomes for which the patient is the most important judge of whether changes are important or meaningful12
ndash Determinations of statistical significance must be supplemented by consideration of the clinical importance of changes in outcome measures1
bull The IMMPACT consensus meeting proposed provisional benchmarks for identifying clinically important changes in the specific outcome measures for chronic pain clinical trials1
Using NNT Analyses in the Treatment of Pain IMMPACT Consensus Meeting Recommendations
NNT = number needed to treat IMMPACT = Initiative on Methods Measurement and Pain Assessment in Clinical Trials1 Dworkin RH et al J Pain 20089105ndash121 2 Acquadro C et al Value Health 20036522ndash531
10ndash20Reduction in pain intensity
ge50Reduction in pain intensity
ge30Reduction in pain intensity
Minimally Important Improvement
Moderately Important Improvement
Substantial Improvement
132
253
353638
4244
55788
1718
0 4 8 12 16 20
Oxycodone 5Codeine 60Tramadol 50Propoxyphene 65APAP 325Oxycodone 5ASA 650Codeine 60Tramadol 100APAP 650Propox 100APAP 1000APAP 600Cod 60Morphine 10APAP 1000Oxyc 10Ibuprofen 400Oxycodone 15
McQuay H BMJ 1997
Patients with 50 reduction Patients with 50 reduction in pain vs placeboin pain vs placebo
NNT
USE OF PARACETAMOL IN TREATMENT OF OA PAIN
22
How effective was paracetamol
How effective was paracetamol compared with NSAIDs
F Wolfe S Zhao N Lane Preference for nonsteroidal antiinflammatory drugs over acetaminophen by rheumatic disease patients Arthritis amp Rheumatism 2000 43 378-385
2007 League table of NNT for at least 50 pain relief over 4-6 hrs in patients with moderate to severe pain
(all oral analgesics except IM morphine )
[httpwwwmedicineoxacukbandolierboothpainpagacutrevanalgesicsleagtabhtml
ETORICOXIB IN ACUTE PAIN
bull Etoricoxib 120 mg has been approved for treating acute pain which includes post-operative pain and other acute pain such as primary dysmenorrhea and acute gouty arthritis
bull Efficacy of etoricoxib in the post-operative setting as evaluated by NNT bull COCHRANE REVIEW Five randomized placebo-controlled studies
with a total number of 880 patients were included -- Four studies on patients with dental pain following extraction of at least one impacted third molar
--One study on patients with pain following uncomplicated orthopaedic surgery
bull NNT were calculated to measure at least 50 pain relief over 4-6 hrs (substantial pain relief) based on TOPAR scores
Results 120 mg etoricoxib with a NNT of 19 for acute post-operative pain
1 Chang DJ Desjardins PJ King TR Erb T Geba GP The analgesic efficacy of etoricoxib compared with oxycodoneacetaminophen in an acute postoperative pain model a randomized double-blind clinical trial Anesthesia and Analgesia 200499(3)807ndash15
2 Malmstrom K Sapre A Couglin H Agrawal NG Mazenko RS Fricke JR Jr Etoricoxib in acute pain associated with dental surgery a randomized double-blind placebo- and active comparator-controlled dose-ranging study Clinical Therapeutics 200426(5)667ndash79
3 Malmstrom K Kotey P Coughlin H Desjardins PJ A randomized double-blind parallel-group study comparing the analgesic effect of etoricoxib to placebo naproxen sodium and acetaminophen with codeine using the dental impaction pain model Clinical Journal of Pain 200420(3)147ndash 55
4 Malmstrom K Ang J Fricke JR Shingo S Reicin A The analgesic effect of etoricoxib relative to that of cetaminophen analgesics a randomized controlled single-dose study in acute dental impaction pain Current Medical Research and Opinion 200521(1)141ndash9 Rasmussen 2005 published data only
5 Rasmussen GL Malmstrom K Bourne MH Jove M Rhondeau SM Kotey P Etoricoxib provides analgesic efficacy to patients after knee or hip replacement surgery a randomized double-blind placebo-controlled study Anaesthesia and Analgesia 2005101(4) 1104ndash11
Etoricoxib in acute pain bull Indirect comparisons of NNTs for at least 50 pain
relief over 4 to 6 hours in reviews of other analgesics using identical methods indicate that etoricoxib 120 mg
-- has slightly better efficacy than rofecoxib 50 mg (22 (19 to 24) Barden 2005)
-- is significantly better than lumiracoxib 400mg (27 (22 to 35) Roy 2007) or-- celecoxib 400 mg (25 (22 to 29) Derry 2008)
-- better than the non-selective NSAIDs ibuprofen 400 mg (27 (25 to 30) Collins 1999) naproxen 500 mg (27 (23 to 32 Derry 2009a) and diclofenac 50mg (24 (18 to 33Derry 2009b)
Placebo
Paracetamol 10007
Paracetamolcodeine 1000606
Ibuprofen 4005
Celecoxib 4004
Naproxen 5005503
Rofecoxib 502
Etoricoxib 1201
0 4 8 12 16 20 24Median remedication time (hr)
Each bar is from a Cochrane review
Acute pain Time for patients to Re-medication
The weighted median time to re-medication with ARCOXIA 120mg is about 24hrs
vs placebo at 18hrs
1 Clarke R et al Cochrane Database Syst Rev 2009 Apr 15(2)CD004309 2 Bulley S et al Cochrane Database Syst Rev 2009 Oct 7(4)CD0046043 Derry C et al Cochrane Database Syst Rev 2009 Jan 21(1)CD004234 4 Derry S Cochrane Database Syst Rev 2008 Oct 8(4)CD0042335 Derry C et al Cochrane Database Syst Rev 2009 Jul 8(3)CD0015486 Toms L et al Cochrane Database Syst Rev 2009 Jan 21(1)CD0015477 Toms L et al Cochrane Database Syst Rev 2008 Oct 8(4)CD004602
Placebo (n=56)
Etoricoxib 60 mg (n=224)
Naproxen 1000 mgc
(n=221)
a0-
to 100-mm VAS (0 = none to 100 = extreme)
b0-
to 100-mm VAS (0 = very well to 100 = very poor) c500 mg twice dailyPlt0001 vs placebo for both etoricoxib and naproxen P = NS etoricoxib vs naproxen
Leung AT et al Curr Med Res Opin 200218(2)49ndash58
LS M
ean
Cha
nge
plusmnSE
Weeks Postrandomization
Osteoarthritis Etoricoxib 60 mg vs Naproxen
Results Etoricoxib relieved pain and improved mobility and disease statuEtoricoxib relieved pain and improved mobility and disease statuss
ndash35
ndash25
ndash5
5
ndash15
WOMAC Pain Subscalea
S R 4 82 12
WOMAC Physical Function Subscalea PGADSb
ndash35
ndash25
ndash5
5
ndash15
S R 4 82 12ndash35
ndash25
ndash5
5
ndash15
S R 4 82 12Weeks Postrandomization Weeks Postrandomization
Adverse effects of NSAIDsAdverse effects of NSAIDs
BNF March 2002
Dose-dependent toxicityIntolerability dyspepsiaGI bleedingUlcers ndash bleeds perforations
Upper-GI
Renal
Contributes to blood loss
Fluid retention oedema hypertensionRenal dysfunction failure ndash acute chronicHeart failure
Anti-platelet effects
Angioedema bronchospasmHypersensitivity
No Short-Term Adverse GI Effects -
The Big Mistake
bull Study designed to evaluate short-term GI effects in elderly
bull Study planned to enrol 160 patientsbull Study terminated by investigator at 17 subjects
ndash 8 patients had ulcersndash 4 of 4 in ketorolac group
lsquo hellip because of the unexpectedly high incidence of gastroduodenal ulcers observedhelliprsquo
Harris et al ClinTher 2001231422
Class Effect of All NSAIDs
httpwwwfdagovcderdruginfopageCOX2NSAIDdecisionMemopdf
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
33
Cardiovascular Safetybull Arthritis patients often have concomitant CV
disease1
bull Pain is an important predictor of CV risk23
bull Randomized controlled trials and observational data demonstrate that CV risk of etoricoxib appears similar to that of traditional NSAIDs4-6
bull Recent data suggest that differential CV effects of NSAIDs (selective and nonselective) may be independent of COX-2 inhibition78
References 1 Singh G et al Am J Manag Care 20028(suppl)S383-S391 2
Sokka T Pincus T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 3
Pincus T Sokka T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 4
httpwwwfdagovohrmsdocketsac05slides2005-4090S1_06_01_Pfizer-celecoxibppt (accessed 14 February 2006) 5
White WB et al Am J Cardiol 200289425ndash430 6
Graham DJ et al Lancet 2005365475ndash481 7 Yang HM et al Circulation 2004110301ndash308 8 Steffel J et al Circulation 20051111685ndash1689
Events per 100 patient years
Coxib Coxib Placebo Coxib NSAID Percent naproxen
Rofecoxib 17 19 11 08 73
Celecoxib 13 15 11 11 20
Valdecoxib 13 12 13 20 about 50
Etoricoxib 13 12 12 08 67
Lumiracoxib 09 08 52
34
APTC endpoint (cardiovascular haemorrhagic and unknown death and nonfatal myocardial infarction and stroke)
1
MR Weir et al Selective COX-2 inhibition and cardiovascular effects a review of the rofecoxib development program American heart Journal 2003 146 591-604
2
WB White et al Cardiovascular thrombotic events in arthritis trials of the cyclooxygenase-2 inhibitor celecoxib American Journal of cardiology 2003 92 411-418
3
WB White et al Effects of the cyclooxygenase-2 specific inhibitor valdecoxib versus nonsteroidal anti-inflammatory agents and placebo on cardiovascular thrombotic events in patients with arthritis American Journal of Therapeutics 2004 11 244-250
4
S Curtis et al Cardiovascular safety summary associated with the etoricoxib development programme Arthritis amp Rheumatism 2003 48 Suppl S616
5
ME Farkouh et al Comparison of lumiracoxib with naproxen and ibuprofen in the therapeutic arthritis research and gastrointestinal event trial (TARGET) cardiovascular outcomes randomised controlled trial Lancet 2004 364 675-684
RECOMMENDATIONS
NSAIDs COXIBs
bull Use lowest effective dose shortest duration
bull Not for patients who have recently undergone coronary artery bypass graft (CABG) surgery and revascularisation procedures
bull Coxibs should not be prescribed for patients with established ischaemic heart disease stroke or congestive heart failure
bull Caution for Coxibs for patients who have hypertension hyperlipidaemia diabetes and smoking as well as peripheral arterial disease
bull Etoricoxib should not be prescribed for patients with hypertension whose blood pressure has not been adequately controlled
The EU Summit is supported by Pfizer
Tricyclic Agents
bull best documented analgesics here (NNT 22)bull amitriptyline best investigatedbull desipraminenortriptyline less AEs
bull start on low doses increases compliancebullOften adverse effects (NNH 28)bull effect needs timebull SSRIs not as effective (NNT 67)
bull noradrenergic effect necessarybull venlafaxine another option
Antidepressants Compared with Placebo
Condition Number of trials
Antidepressant improvedtotal
Placebo improvedtotal
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 13 180260 73205 19 (16 to
24)30 (24 to 40)
Postherpetic neuralgia 3 4377 868 48 (24 to
94)23 (17 to 33)
Atypical facial pain 2 6288 3085 20 (15 to
28)28 (20 to 47)
Central pain 1 1015 115 10 (15 to 69)
17 (11 to 30)
Bandolier
Anticonvulsants as Membrane Stabilisers
bull pregabalinbull gabapentin bull carbamazepinebull clonazepam pooled NNT 27bull valproatebull lamotriginebull baclofen
Anticonvulsants Compared with Placebo
Condition Number of trials
Anticonvulsant improvedtotal
Placebo improvedtot
al
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 3 5668 2668 19 (14 to 27) 25 (18
to 40)
Trigeminal neuralgia 3 178315 41224 31 (23 to 41) 26 (22
to 33)
Migraine prophylaxis 2 6374 1777 37 (24 to 59) 16 (13
to 20)
Other pain syndromes 1 514 115 54 (07 to 40)
not calculat ed
Bandolier
Relative Activity on Serotonin and Norepinephrine Reuptake Among
Antidepressants
CitalopramFluvoxamineSertralineParoxetineFluoxetine
VenlafaxineDuloxetine
MaprotilineDesipramineNortriptylineReboxetine
AmitriptylineMilnacipranImipramine
Serotonin Mixed Norepinephrine
Antidepressant Analgesic Antidepressant
Fishbain et al Pain Med 20001310-316
Opioidsbull In principle opioids are effective in nociceptive
and some neuropathic pain however not always and not necessarily completely for dynamic pain
bull Possibly preferable opioids here arendash tramadol
bull noradrenergic and serotoninergic effectndash morphine
bull Mu receptor anatagonistmonaminergic effect
ndash oxycodonebull kappa receptor effect
Opioids
bull lsquoLack of analgesic effect of opioids on neuropathic hellip painrsquo Pain 19883311
bull lsquohellip intravenous hellip morphine reduce the pain of Osteoarthritisrsquo Neurology
1991411024bull lsquoA call for more science not more
rhetoric regarding opioids and arthritic painrsquo Pain 2001471
bull lsquoEfficacy of oxycodone in neuropathic painhelliprsquo Neurology 1998501837
OPIOIDS FOR OA PAINbull Osteoarthritis guidelines provide limited guidance on opioid use bull The 1995 ACR guidelines for hip OA suggest opioids be avoided for
long term use but short term use may be helpful without reference to primary data15
bull The 1995 ACR knee OA guidelines do not discuss opioids directly16 bull The 1998 UK guidelines on degenerative arthritis suggest that if
relief is inadequate with 24 grams of ibuprofen and 40 grams of paracetamol a day other antiinflammatories or opioids may be considered18
bull The 2000 update of the ACR OA guidelines suggests that opioids might be used as a medication of last resort17
bull Opioids are effective in OA hip and knee pain and have predictable side effects
bull It would be unwise were physicians to discount an entire class of medications over unfounded fears and incomplete knowledge of their benefits44
USE OF ULTRACET IN OA KNEESbull The efficacy of tramadolacetaminophen combination tablets (Ultracetreg) as add-
on and maintenance therapy in knee osteoarthritis pain inadequately controlled by nonsteroidal anti-inflammatory drug (NSAID)
Park KS Choi JJ Kim WU Min JK Park SH Cho CS
bull TramadolAPAP add-on significantly improved knee OA pain which had been inadequately controlled by NSAIDs In those subjects who showed favorable response to tramadolAPAP and NSAID combination therapy both tramadolAPAP and NSAIDs were effective at maintaining the pain-reduced state and there was no significant difference in efficacy between tramadolAPAP and NSAIDs
Clinical Rheumatology 2011 3 Aug
Opioid Sparing Regimes
bull Multimodal analgesia (Kehlet et al 1999)
bull NSAIDs and COX-2 (Romsing Moiniche 2004)
bull Paracetamol (Romsing 2002)
bull Ketamine (Elia Tramer 2005)
bull Gabapentin and Pregabalin (Dahl et al 2004)
bull Gabapentin and Rofecoxib (Gilron et al 2005)
Opioid reduction 20 ndash 40 Reduction of PONV 30
Clinical effects
Single-modality treatment of a Multi- modality problem is
futile
ldquoTherersquos no pain thatrsquos so easy to bear than that of
someone elserdquo
ndashLeriche
Van Gogh ldquoOld Man in Sorrowrdquo
COXCOX--2 and Central 2 and Central SensitisationSensitisation
Interleukin-1szlig-mediated induction of COX-2 in the CNS contributes to inflammatory pain hypersensitivityTAREK A SAMAD KIMBERLY A MOORE ADAM SAPIRSTEINdagger SARA BILLET ANDREW ALLCHORNEDagger STEPHEN POOLEsect JOSEPH V BONVENTRE amp CLIFFORD J WOOLFDagger
Neural Plasticity Research Group Department of Anesthesia amp Critical Care Department of Anesthesia amp Critical Care and Department of Medicine Massachusetts General Hospital and Harvard Medical School Charlestown Massachusetts 02129 USA
Dagger
Department of Anatomy University College London London WC1E 6BT UK
sect National Institute for Biological Standards and Control Blanche Lane South Mimms Hertfordshire EN6 3QG UK
Nature 2001410471 ndash 475
Convergence at WDR Neurone
Central Sensitisation
tissue or nerve injury
release of EAAsand neuropeptides
increased depolarizationat the NMDA receptor
expanded receptive fieldsand hyperexcitability
Increased Pain
excitotoxicity
loss of inhibition
adapted from Dubner
CNS
Central Sensitization May Have Contributed to OA Pain and Neuropathic
Pain Symptoms1
bull Focus group transcripts from participants with knee OA (N=80) were analyzed to determine the use of unprompted NP descriptors to characterize their pain (including burning tingling pins and needles and numbness) to determine whether people with chronic symptomatic knee OA use pain descriptors suggestive of underlying NP
bull The proportion of participants who used NP descriptors to characterize their pain was 34 (95 CI 24 to 45)
bull Participants using NP descriptors were younger than those who did not (mean age plusmn SD age 648 plusmn 97 years vs 720 plusmn 100 years respectively P=0003)
bull Characteristics that did not statistically distinguish participants who used NP descriptors from those who did included duration of OA pain intensity OA severity and gender
OA = osteoarthritis NP = neuropathic pain CI = confidence interval SD = standard deviation
1 Hochman JR et al Arthritis Care Res (Hoboken) 2010621019ndash1023
Central Sensitization in OA Expansion of Symptoms Beyond the
Joint
bull Quantitative sensory testing of PPTs in patients with knee OA pain (n=48) and matched controls without knee pain (n=24) revealed that subjects with OA pain exhibited sensitization in both OA-affected and unaffected areasndash Increasing pain intensity in
the OA-affected (knee) joint was associated with lower PPT in OA-unaffected areas (eg arm)1
PPT at arm (OA-unaffected area)
R = -032 Plt005
VAS at OA-affected Knee Joint
1500
1000
500
0 1 2 3 4 5 6 7 8 9 10PP
T k
Pa
Arendt-Nielsen L et al Pain 2010149573ndash581
OA = osteoarthritis PPT = pressure pain threshold VAS = visual analog scale
OA = osteoarthritis PPT = pressure pain threshold VAS = visual analog scale WOMAC = Western Ontario and McMaster Universities SF-36 = short form-36 health survey
Central Sensitization in OA Increased Pain Severity and Worse Pain-Associated
OutcomesImamura M et al Arthritis Rheum 2008591424ndash1431
Measure Spearmanrsquos rank correlation coefficient r P Value
VASPatellar tendon Sacral 2 subcutaneous dermatome levelAdductor longus muscle
-0545 -0546 -0561
lt0001 lt0001 lt0001
WOMAC painPatellar tendon Sacral 2 subcutaneous dermatome levelAdductor longus muscle
-0589-0601 -0540
lt0001 lt0001lt0001
WOMAC physical activityLumbar 2 subcutaneous dermatome level Sacral 2 subcutaneous dermatome level Peroneus longus muscle
-0550 -0509 -0571
lt0001lt0001 lt0001
SF-36 bodily painLumbar 1ndashLumbar 2 supraspinous ligamentLumbar 2 subcutaneous dermatome level Adductor longus muscle
0534 0606 0569
lt0001 lt0001 lt0001
A cross-sectional study that assessed hyperalgesia in patients with refractory OA-associated pain (n=62) reported significant correlations between PPT values at each listed site and VAS WOMAC pain and physical activity subscales and SF-36 bodily pain score
SKIN
SPINAL CORD
Dorsal horn
PRIMARY AFFERENT NERVE
Dorsal root ganglion
POSTSYNAPTIC PROCESSPRESYNAPTIC PROCESS
NMDA receptor
Ca2+ Second messengers
kinases (eg PKC) diacylglycerol cAMP
Gene transcription
P
CELL NUCLEUS
Long term changes
(receptor function transmitter production)
Glutamate release
C-fosoncogene
Cortical Reorganisation
I will show that my client is welltolerated amp effectivehelliphellip
I will showthat my clientis well tolerated and effective
bull For chronic pain most measures of treatment response involve patient- reported outcomes for which the patient is the most important judge of whether changes are important or meaningful12
ndash Determinations of statistical significance must be supplemented by consideration of the clinical importance of changes in outcome measures1
bull The IMMPACT consensus meeting proposed provisional benchmarks for identifying clinically important changes in the specific outcome measures for chronic pain clinical trials1
Using NNT Analyses in the Treatment of Pain IMMPACT Consensus Meeting Recommendations
NNT = number needed to treat IMMPACT = Initiative on Methods Measurement and Pain Assessment in Clinical Trials1 Dworkin RH et al J Pain 20089105ndash121 2 Acquadro C et al Value Health 20036522ndash531
10ndash20Reduction in pain intensity
ge50Reduction in pain intensity
ge30Reduction in pain intensity
Minimally Important Improvement
Moderately Important Improvement
Substantial Improvement
132
253
353638
4244
55788
1718
0 4 8 12 16 20
Oxycodone 5Codeine 60Tramadol 50Propoxyphene 65APAP 325Oxycodone 5ASA 650Codeine 60Tramadol 100APAP 650Propox 100APAP 1000APAP 600Cod 60Morphine 10APAP 1000Oxyc 10Ibuprofen 400Oxycodone 15
McQuay H BMJ 1997
Patients with 50 reduction Patients with 50 reduction in pain vs placeboin pain vs placebo
NNT
USE OF PARACETAMOL IN TREATMENT OF OA PAIN
22
How effective was paracetamol
How effective was paracetamol compared with NSAIDs
F Wolfe S Zhao N Lane Preference for nonsteroidal antiinflammatory drugs over acetaminophen by rheumatic disease patients Arthritis amp Rheumatism 2000 43 378-385
2007 League table of NNT for at least 50 pain relief over 4-6 hrs in patients with moderate to severe pain
(all oral analgesics except IM morphine )
[httpwwwmedicineoxacukbandolierboothpainpagacutrevanalgesicsleagtabhtml
ETORICOXIB IN ACUTE PAIN
bull Etoricoxib 120 mg has been approved for treating acute pain which includes post-operative pain and other acute pain such as primary dysmenorrhea and acute gouty arthritis
bull Efficacy of etoricoxib in the post-operative setting as evaluated by NNT bull COCHRANE REVIEW Five randomized placebo-controlled studies
with a total number of 880 patients were included -- Four studies on patients with dental pain following extraction of at least one impacted third molar
--One study on patients with pain following uncomplicated orthopaedic surgery
bull NNT were calculated to measure at least 50 pain relief over 4-6 hrs (substantial pain relief) based on TOPAR scores
Results 120 mg etoricoxib with a NNT of 19 for acute post-operative pain
1 Chang DJ Desjardins PJ King TR Erb T Geba GP The analgesic efficacy of etoricoxib compared with oxycodoneacetaminophen in an acute postoperative pain model a randomized double-blind clinical trial Anesthesia and Analgesia 200499(3)807ndash15
2 Malmstrom K Sapre A Couglin H Agrawal NG Mazenko RS Fricke JR Jr Etoricoxib in acute pain associated with dental surgery a randomized double-blind placebo- and active comparator-controlled dose-ranging study Clinical Therapeutics 200426(5)667ndash79
3 Malmstrom K Kotey P Coughlin H Desjardins PJ A randomized double-blind parallel-group study comparing the analgesic effect of etoricoxib to placebo naproxen sodium and acetaminophen with codeine using the dental impaction pain model Clinical Journal of Pain 200420(3)147ndash 55
4 Malmstrom K Ang J Fricke JR Shingo S Reicin A The analgesic effect of etoricoxib relative to that of cetaminophen analgesics a randomized controlled single-dose study in acute dental impaction pain Current Medical Research and Opinion 200521(1)141ndash9 Rasmussen 2005 published data only
5 Rasmussen GL Malmstrom K Bourne MH Jove M Rhondeau SM Kotey P Etoricoxib provides analgesic efficacy to patients after knee or hip replacement surgery a randomized double-blind placebo-controlled study Anaesthesia and Analgesia 2005101(4) 1104ndash11
Etoricoxib in acute pain bull Indirect comparisons of NNTs for at least 50 pain
relief over 4 to 6 hours in reviews of other analgesics using identical methods indicate that etoricoxib 120 mg
-- has slightly better efficacy than rofecoxib 50 mg (22 (19 to 24) Barden 2005)
-- is significantly better than lumiracoxib 400mg (27 (22 to 35) Roy 2007) or-- celecoxib 400 mg (25 (22 to 29) Derry 2008)
-- better than the non-selective NSAIDs ibuprofen 400 mg (27 (25 to 30) Collins 1999) naproxen 500 mg (27 (23 to 32 Derry 2009a) and diclofenac 50mg (24 (18 to 33Derry 2009b)
Placebo
Paracetamol 10007
Paracetamolcodeine 1000606
Ibuprofen 4005
Celecoxib 4004
Naproxen 5005503
Rofecoxib 502
Etoricoxib 1201
0 4 8 12 16 20 24Median remedication time (hr)
Each bar is from a Cochrane review
Acute pain Time for patients to Re-medication
The weighted median time to re-medication with ARCOXIA 120mg is about 24hrs
vs placebo at 18hrs
1 Clarke R et al Cochrane Database Syst Rev 2009 Apr 15(2)CD004309 2 Bulley S et al Cochrane Database Syst Rev 2009 Oct 7(4)CD0046043 Derry C et al Cochrane Database Syst Rev 2009 Jan 21(1)CD004234 4 Derry S Cochrane Database Syst Rev 2008 Oct 8(4)CD0042335 Derry C et al Cochrane Database Syst Rev 2009 Jul 8(3)CD0015486 Toms L et al Cochrane Database Syst Rev 2009 Jan 21(1)CD0015477 Toms L et al Cochrane Database Syst Rev 2008 Oct 8(4)CD004602
Placebo (n=56)
Etoricoxib 60 mg (n=224)
Naproxen 1000 mgc
(n=221)
a0-
to 100-mm VAS (0 = none to 100 = extreme)
b0-
to 100-mm VAS (0 = very well to 100 = very poor) c500 mg twice dailyPlt0001 vs placebo for both etoricoxib and naproxen P = NS etoricoxib vs naproxen
Leung AT et al Curr Med Res Opin 200218(2)49ndash58
LS M
ean
Cha
nge
plusmnSE
Weeks Postrandomization
Osteoarthritis Etoricoxib 60 mg vs Naproxen
Results Etoricoxib relieved pain and improved mobility and disease statuEtoricoxib relieved pain and improved mobility and disease statuss
ndash35
ndash25
ndash5
5
ndash15
WOMAC Pain Subscalea
S R 4 82 12
WOMAC Physical Function Subscalea PGADSb
ndash35
ndash25
ndash5
5
ndash15
S R 4 82 12ndash35
ndash25
ndash5
5
ndash15
S R 4 82 12Weeks Postrandomization Weeks Postrandomization
Adverse effects of NSAIDsAdverse effects of NSAIDs
BNF March 2002
Dose-dependent toxicityIntolerability dyspepsiaGI bleedingUlcers ndash bleeds perforations
Upper-GI
Renal
Contributes to blood loss
Fluid retention oedema hypertensionRenal dysfunction failure ndash acute chronicHeart failure
Anti-platelet effects
Angioedema bronchospasmHypersensitivity
No Short-Term Adverse GI Effects -
The Big Mistake
bull Study designed to evaluate short-term GI effects in elderly
bull Study planned to enrol 160 patientsbull Study terminated by investigator at 17 subjects
ndash 8 patients had ulcersndash 4 of 4 in ketorolac group
lsquo hellip because of the unexpectedly high incidence of gastroduodenal ulcers observedhelliprsquo
Harris et al ClinTher 2001231422
Class Effect of All NSAIDs
httpwwwfdagovcderdruginfopageCOX2NSAIDdecisionMemopdf
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
33
Cardiovascular Safetybull Arthritis patients often have concomitant CV
disease1
bull Pain is an important predictor of CV risk23
bull Randomized controlled trials and observational data demonstrate that CV risk of etoricoxib appears similar to that of traditional NSAIDs4-6
bull Recent data suggest that differential CV effects of NSAIDs (selective and nonselective) may be independent of COX-2 inhibition78
References 1 Singh G et al Am J Manag Care 20028(suppl)S383-S391 2
Sokka T Pincus T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 3
Pincus T Sokka T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 4
httpwwwfdagovohrmsdocketsac05slides2005-4090S1_06_01_Pfizer-celecoxibppt (accessed 14 February 2006) 5
White WB et al Am J Cardiol 200289425ndash430 6
Graham DJ et al Lancet 2005365475ndash481 7 Yang HM et al Circulation 2004110301ndash308 8 Steffel J et al Circulation 20051111685ndash1689
Events per 100 patient years
Coxib Coxib Placebo Coxib NSAID Percent naproxen
Rofecoxib 17 19 11 08 73
Celecoxib 13 15 11 11 20
Valdecoxib 13 12 13 20 about 50
Etoricoxib 13 12 12 08 67
Lumiracoxib 09 08 52
34
APTC endpoint (cardiovascular haemorrhagic and unknown death and nonfatal myocardial infarction and stroke)
1
MR Weir et al Selective COX-2 inhibition and cardiovascular effects a review of the rofecoxib development program American heart Journal 2003 146 591-604
2
WB White et al Cardiovascular thrombotic events in arthritis trials of the cyclooxygenase-2 inhibitor celecoxib American Journal of cardiology 2003 92 411-418
3
WB White et al Effects of the cyclooxygenase-2 specific inhibitor valdecoxib versus nonsteroidal anti-inflammatory agents and placebo on cardiovascular thrombotic events in patients with arthritis American Journal of Therapeutics 2004 11 244-250
4
S Curtis et al Cardiovascular safety summary associated with the etoricoxib development programme Arthritis amp Rheumatism 2003 48 Suppl S616
5
ME Farkouh et al Comparison of lumiracoxib with naproxen and ibuprofen in the therapeutic arthritis research and gastrointestinal event trial (TARGET) cardiovascular outcomes randomised controlled trial Lancet 2004 364 675-684
RECOMMENDATIONS
NSAIDs COXIBs
bull Use lowest effective dose shortest duration
bull Not for patients who have recently undergone coronary artery bypass graft (CABG) surgery and revascularisation procedures
bull Coxibs should not be prescribed for patients with established ischaemic heart disease stroke or congestive heart failure
bull Caution for Coxibs for patients who have hypertension hyperlipidaemia diabetes and smoking as well as peripheral arterial disease
bull Etoricoxib should not be prescribed for patients with hypertension whose blood pressure has not been adequately controlled
The EU Summit is supported by Pfizer
Tricyclic Agents
bull best documented analgesics here (NNT 22)bull amitriptyline best investigatedbull desipraminenortriptyline less AEs
bull start on low doses increases compliancebullOften adverse effects (NNH 28)bull effect needs timebull SSRIs not as effective (NNT 67)
bull noradrenergic effect necessarybull venlafaxine another option
Antidepressants Compared with Placebo
Condition Number of trials
Antidepressant improvedtotal
Placebo improvedtotal
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 13 180260 73205 19 (16 to
24)30 (24 to 40)
Postherpetic neuralgia 3 4377 868 48 (24 to
94)23 (17 to 33)
Atypical facial pain 2 6288 3085 20 (15 to
28)28 (20 to 47)
Central pain 1 1015 115 10 (15 to 69)
17 (11 to 30)
Bandolier
Anticonvulsants as Membrane Stabilisers
bull pregabalinbull gabapentin bull carbamazepinebull clonazepam pooled NNT 27bull valproatebull lamotriginebull baclofen
Anticonvulsants Compared with Placebo
Condition Number of trials
Anticonvulsant improvedtotal
Placebo improvedtot
al
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 3 5668 2668 19 (14 to 27) 25 (18
to 40)
Trigeminal neuralgia 3 178315 41224 31 (23 to 41) 26 (22
to 33)
Migraine prophylaxis 2 6374 1777 37 (24 to 59) 16 (13
to 20)
Other pain syndromes 1 514 115 54 (07 to 40)
not calculat ed
Bandolier
Relative Activity on Serotonin and Norepinephrine Reuptake Among
Antidepressants
CitalopramFluvoxamineSertralineParoxetineFluoxetine
VenlafaxineDuloxetine
MaprotilineDesipramineNortriptylineReboxetine
AmitriptylineMilnacipranImipramine
Serotonin Mixed Norepinephrine
Antidepressant Analgesic Antidepressant
Fishbain et al Pain Med 20001310-316
Opioidsbull In principle opioids are effective in nociceptive
and some neuropathic pain however not always and not necessarily completely for dynamic pain
bull Possibly preferable opioids here arendash tramadol
bull noradrenergic and serotoninergic effectndash morphine
bull Mu receptor anatagonistmonaminergic effect
ndash oxycodonebull kappa receptor effect
Opioids
bull lsquoLack of analgesic effect of opioids on neuropathic hellip painrsquo Pain 19883311
bull lsquohellip intravenous hellip morphine reduce the pain of Osteoarthritisrsquo Neurology
1991411024bull lsquoA call for more science not more
rhetoric regarding opioids and arthritic painrsquo Pain 2001471
bull lsquoEfficacy of oxycodone in neuropathic painhelliprsquo Neurology 1998501837
OPIOIDS FOR OA PAINbull Osteoarthritis guidelines provide limited guidance on opioid use bull The 1995 ACR guidelines for hip OA suggest opioids be avoided for
long term use but short term use may be helpful without reference to primary data15
bull The 1995 ACR knee OA guidelines do not discuss opioids directly16 bull The 1998 UK guidelines on degenerative arthritis suggest that if
relief is inadequate with 24 grams of ibuprofen and 40 grams of paracetamol a day other antiinflammatories or opioids may be considered18
bull The 2000 update of the ACR OA guidelines suggests that opioids might be used as a medication of last resort17
bull Opioids are effective in OA hip and knee pain and have predictable side effects
bull It would be unwise were physicians to discount an entire class of medications over unfounded fears and incomplete knowledge of their benefits44
USE OF ULTRACET IN OA KNEESbull The efficacy of tramadolacetaminophen combination tablets (Ultracetreg) as add-
on and maintenance therapy in knee osteoarthritis pain inadequately controlled by nonsteroidal anti-inflammatory drug (NSAID)
Park KS Choi JJ Kim WU Min JK Park SH Cho CS
bull TramadolAPAP add-on significantly improved knee OA pain which had been inadequately controlled by NSAIDs In those subjects who showed favorable response to tramadolAPAP and NSAID combination therapy both tramadolAPAP and NSAIDs were effective at maintaining the pain-reduced state and there was no significant difference in efficacy between tramadolAPAP and NSAIDs
Clinical Rheumatology 2011 3 Aug
Opioid Sparing Regimes
bull Multimodal analgesia (Kehlet et al 1999)
bull NSAIDs and COX-2 (Romsing Moiniche 2004)
bull Paracetamol (Romsing 2002)
bull Ketamine (Elia Tramer 2005)
bull Gabapentin and Pregabalin (Dahl et al 2004)
bull Gabapentin and Rofecoxib (Gilron et al 2005)
Opioid reduction 20 ndash 40 Reduction of PONV 30
Clinical effects
Single-modality treatment of a Multi- modality problem is
futile
ldquoTherersquos no pain thatrsquos so easy to bear than that of
someone elserdquo
ndashLeriche
Van Gogh ldquoOld Man in Sorrowrdquo
Convergence at WDR Neurone
Central Sensitisation
tissue or nerve injury
release of EAAsand neuropeptides
increased depolarizationat the NMDA receptor
expanded receptive fieldsand hyperexcitability
Increased Pain
excitotoxicity
loss of inhibition
adapted from Dubner
CNS
Central Sensitization May Have Contributed to OA Pain and Neuropathic
Pain Symptoms1
bull Focus group transcripts from participants with knee OA (N=80) were analyzed to determine the use of unprompted NP descriptors to characterize their pain (including burning tingling pins and needles and numbness) to determine whether people with chronic symptomatic knee OA use pain descriptors suggestive of underlying NP
bull The proportion of participants who used NP descriptors to characterize their pain was 34 (95 CI 24 to 45)
bull Participants using NP descriptors were younger than those who did not (mean age plusmn SD age 648 plusmn 97 years vs 720 plusmn 100 years respectively P=0003)
bull Characteristics that did not statistically distinguish participants who used NP descriptors from those who did included duration of OA pain intensity OA severity and gender
OA = osteoarthritis NP = neuropathic pain CI = confidence interval SD = standard deviation
1 Hochman JR et al Arthritis Care Res (Hoboken) 2010621019ndash1023
Central Sensitization in OA Expansion of Symptoms Beyond the
Joint
bull Quantitative sensory testing of PPTs in patients with knee OA pain (n=48) and matched controls without knee pain (n=24) revealed that subjects with OA pain exhibited sensitization in both OA-affected and unaffected areasndash Increasing pain intensity in
the OA-affected (knee) joint was associated with lower PPT in OA-unaffected areas (eg arm)1
PPT at arm (OA-unaffected area)
R = -032 Plt005
VAS at OA-affected Knee Joint
1500
1000
500
0 1 2 3 4 5 6 7 8 9 10PP
T k
Pa
Arendt-Nielsen L et al Pain 2010149573ndash581
OA = osteoarthritis PPT = pressure pain threshold VAS = visual analog scale
OA = osteoarthritis PPT = pressure pain threshold VAS = visual analog scale WOMAC = Western Ontario and McMaster Universities SF-36 = short form-36 health survey
Central Sensitization in OA Increased Pain Severity and Worse Pain-Associated
OutcomesImamura M et al Arthritis Rheum 2008591424ndash1431
Measure Spearmanrsquos rank correlation coefficient r P Value
VASPatellar tendon Sacral 2 subcutaneous dermatome levelAdductor longus muscle
-0545 -0546 -0561
lt0001 lt0001 lt0001
WOMAC painPatellar tendon Sacral 2 subcutaneous dermatome levelAdductor longus muscle
-0589-0601 -0540
lt0001 lt0001lt0001
WOMAC physical activityLumbar 2 subcutaneous dermatome level Sacral 2 subcutaneous dermatome level Peroneus longus muscle
-0550 -0509 -0571
lt0001lt0001 lt0001
SF-36 bodily painLumbar 1ndashLumbar 2 supraspinous ligamentLumbar 2 subcutaneous dermatome level Adductor longus muscle
0534 0606 0569
lt0001 lt0001 lt0001
A cross-sectional study that assessed hyperalgesia in patients with refractory OA-associated pain (n=62) reported significant correlations between PPT values at each listed site and VAS WOMAC pain and physical activity subscales and SF-36 bodily pain score
SKIN
SPINAL CORD
Dorsal horn
PRIMARY AFFERENT NERVE
Dorsal root ganglion
POSTSYNAPTIC PROCESSPRESYNAPTIC PROCESS
NMDA receptor
Ca2+ Second messengers
kinases (eg PKC) diacylglycerol cAMP
Gene transcription
P
CELL NUCLEUS
Long term changes
(receptor function transmitter production)
Glutamate release
C-fosoncogene
Cortical Reorganisation
I will show that my client is welltolerated amp effectivehelliphellip
I will showthat my clientis well tolerated and effective
bull For chronic pain most measures of treatment response involve patient- reported outcomes for which the patient is the most important judge of whether changes are important or meaningful12
ndash Determinations of statistical significance must be supplemented by consideration of the clinical importance of changes in outcome measures1
bull The IMMPACT consensus meeting proposed provisional benchmarks for identifying clinically important changes in the specific outcome measures for chronic pain clinical trials1
Using NNT Analyses in the Treatment of Pain IMMPACT Consensus Meeting Recommendations
NNT = number needed to treat IMMPACT = Initiative on Methods Measurement and Pain Assessment in Clinical Trials1 Dworkin RH et al J Pain 20089105ndash121 2 Acquadro C et al Value Health 20036522ndash531
10ndash20Reduction in pain intensity
ge50Reduction in pain intensity
ge30Reduction in pain intensity
Minimally Important Improvement
Moderately Important Improvement
Substantial Improvement
132
253
353638
4244
55788
1718
0 4 8 12 16 20
Oxycodone 5Codeine 60Tramadol 50Propoxyphene 65APAP 325Oxycodone 5ASA 650Codeine 60Tramadol 100APAP 650Propox 100APAP 1000APAP 600Cod 60Morphine 10APAP 1000Oxyc 10Ibuprofen 400Oxycodone 15
McQuay H BMJ 1997
Patients with 50 reduction Patients with 50 reduction in pain vs placeboin pain vs placebo
NNT
USE OF PARACETAMOL IN TREATMENT OF OA PAIN
22
How effective was paracetamol
How effective was paracetamol compared with NSAIDs
F Wolfe S Zhao N Lane Preference for nonsteroidal antiinflammatory drugs over acetaminophen by rheumatic disease patients Arthritis amp Rheumatism 2000 43 378-385
2007 League table of NNT for at least 50 pain relief over 4-6 hrs in patients with moderate to severe pain
(all oral analgesics except IM morphine )
[httpwwwmedicineoxacukbandolierboothpainpagacutrevanalgesicsleagtabhtml
ETORICOXIB IN ACUTE PAIN
bull Etoricoxib 120 mg has been approved for treating acute pain which includes post-operative pain and other acute pain such as primary dysmenorrhea and acute gouty arthritis
bull Efficacy of etoricoxib in the post-operative setting as evaluated by NNT bull COCHRANE REVIEW Five randomized placebo-controlled studies
with a total number of 880 patients were included -- Four studies on patients with dental pain following extraction of at least one impacted third molar
--One study on patients with pain following uncomplicated orthopaedic surgery
bull NNT were calculated to measure at least 50 pain relief over 4-6 hrs (substantial pain relief) based on TOPAR scores
Results 120 mg etoricoxib with a NNT of 19 for acute post-operative pain
1 Chang DJ Desjardins PJ King TR Erb T Geba GP The analgesic efficacy of etoricoxib compared with oxycodoneacetaminophen in an acute postoperative pain model a randomized double-blind clinical trial Anesthesia and Analgesia 200499(3)807ndash15
2 Malmstrom K Sapre A Couglin H Agrawal NG Mazenko RS Fricke JR Jr Etoricoxib in acute pain associated with dental surgery a randomized double-blind placebo- and active comparator-controlled dose-ranging study Clinical Therapeutics 200426(5)667ndash79
3 Malmstrom K Kotey P Coughlin H Desjardins PJ A randomized double-blind parallel-group study comparing the analgesic effect of etoricoxib to placebo naproxen sodium and acetaminophen with codeine using the dental impaction pain model Clinical Journal of Pain 200420(3)147ndash 55
4 Malmstrom K Ang J Fricke JR Shingo S Reicin A The analgesic effect of etoricoxib relative to that of cetaminophen analgesics a randomized controlled single-dose study in acute dental impaction pain Current Medical Research and Opinion 200521(1)141ndash9 Rasmussen 2005 published data only
5 Rasmussen GL Malmstrom K Bourne MH Jove M Rhondeau SM Kotey P Etoricoxib provides analgesic efficacy to patients after knee or hip replacement surgery a randomized double-blind placebo-controlled study Anaesthesia and Analgesia 2005101(4) 1104ndash11
Etoricoxib in acute pain bull Indirect comparisons of NNTs for at least 50 pain
relief over 4 to 6 hours in reviews of other analgesics using identical methods indicate that etoricoxib 120 mg
-- has slightly better efficacy than rofecoxib 50 mg (22 (19 to 24) Barden 2005)
-- is significantly better than lumiracoxib 400mg (27 (22 to 35) Roy 2007) or-- celecoxib 400 mg (25 (22 to 29) Derry 2008)
-- better than the non-selective NSAIDs ibuprofen 400 mg (27 (25 to 30) Collins 1999) naproxen 500 mg (27 (23 to 32 Derry 2009a) and diclofenac 50mg (24 (18 to 33Derry 2009b)
Placebo
Paracetamol 10007
Paracetamolcodeine 1000606
Ibuprofen 4005
Celecoxib 4004
Naproxen 5005503
Rofecoxib 502
Etoricoxib 1201
0 4 8 12 16 20 24Median remedication time (hr)
Each bar is from a Cochrane review
Acute pain Time for patients to Re-medication
The weighted median time to re-medication with ARCOXIA 120mg is about 24hrs
vs placebo at 18hrs
1 Clarke R et al Cochrane Database Syst Rev 2009 Apr 15(2)CD004309 2 Bulley S et al Cochrane Database Syst Rev 2009 Oct 7(4)CD0046043 Derry C et al Cochrane Database Syst Rev 2009 Jan 21(1)CD004234 4 Derry S Cochrane Database Syst Rev 2008 Oct 8(4)CD0042335 Derry C et al Cochrane Database Syst Rev 2009 Jul 8(3)CD0015486 Toms L et al Cochrane Database Syst Rev 2009 Jan 21(1)CD0015477 Toms L et al Cochrane Database Syst Rev 2008 Oct 8(4)CD004602
Placebo (n=56)
Etoricoxib 60 mg (n=224)
Naproxen 1000 mgc
(n=221)
a0-
to 100-mm VAS (0 = none to 100 = extreme)
b0-
to 100-mm VAS (0 = very well to 100 = very poor) c500 mg twice dailyPlt0001 vs placebo for both etoricoxib and naproxen P = NS etoricoxib vs naproxen
Leung AT et al Curr Med Res Opin 200218(2)49ndash58
LS M
ean
Cha
nge
plusmnSE
Weeks Postrandomization
Osteoarthritis Etoricoxib 60 mg vs Naproxen
Results Etoricoxib relieved pain and improved mobility and disease statuEtoricoxib relieved pain and improved mobility and disease statuss
ndash35
ndash25
ndash5
5
ndash15
WOMAC Pain Subscalea
S R 4 82 12
WOMAC Physical Function Subscalea PGADSb
ndash35
ndash25
ndash5
5
ndash15
S R 4 82 12ndash35
ndash25
ndash5
5
ndash15
S R 4 82 12Weeks Postrandomization Weeks Postrandomization
Adverse effects of NSAIDsAdverse effects of NSAIDs
BNF March 2002
Dose-dependent toxicityIntolerability dyspepsiaGI bleedingUlcers ndash bleeds perforations
Upper-GI
Renal
Contributes to blood loss
Fluid retention oedema hypertensionRenal dysfunction failure ndash acute chronicHeart failure
Anti-platelet effects
Angioedema bronchospasmHypersensitivity
No Short-Term Adverse GI Effects -
The Big Mistake
bull Study designed to evaluate short-term GI effects in elderly
bull Study planned to enrol 160 patientsbull Study terminated by investigator at 17 subjects
ndash 8 patients had ulcersndash 4 of 4 in ketorolac group
lsquo hellip because of the unexpectedly high incidence of gastroduodenal ulcers observedhelliprsquo
Harris et al ClinTher 2001231422
Class Effect of All NSAIDs
httpwwwfdagovcderdruginfopageCOX2NSAIDdecisionMemopdf
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
33
Cardiovascular Safetybull Arthritis patients often have concomitant CV
disease1
bull Pain is an important predictor of CV risk23
bull Randomized controlled trials and observational data demonstrate that CV risk of etoricoxib appears similar to that of traditional NSAIDs4-6
bull Recent data suggest that differential CV effects of NSAIDs (selective and nonselective) may be independent of COX-2 inhibition78
References 1 Singh G et al Am J Manag Care 20028(suppl)S383-S391 2
Sokka T Pincus T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 3
Pincus T Sokka T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 4
httpwwwfdagovohrmsdocketsac05slides2005-4090S1_06_01_Pfizer-celecoxibppt (accessed 14 February 2006) 5
White WB et al Am J Cardiol 200289425ndash430 6
Graham DJ et al Lancet 2005365475ndash481 7 Yang HM et al Circulation 2004110301ndash308 8 Steffel J et al Circulation 20051111685ndash1689
Events per 100 patient years
Coxib Coxib Placebo Coxib NSAID Percent naproxen
Rofecoxib 17 19 11 08 73
Celecoxib 13 15 11 11 20
Valdecoxib 13 12 13 20 about 50
Etoricoxib 13 12 12 08 67
Lumiracoxib 09 08 52
34
APTC endpoint (cardiovascular haemorrhagic and unknown death and nonfatal myocardial infarction and stroke)
1
MR Weir et al Selective COX-2 inhibition and cardiovascular effects a review of the rofecoxib development program American heart Journal 2003 146 591-604
2
WB White et al Cardiovascular thrombotic events in arthritis trials of the cyclooxygenase-2 inhibitor celecoxib American Journal of cardiology 2003 92 411-418
3
WB White et al Effects of the cyclooxygenase-2 specific inhibitor valdecoxib versus nonsteroidal anti-inflammatory agents and placebo on cardiovascular thrombotic events in patients with arthritis American Journal of Therapeutics 2004 11 244-250
4
S Curtis et al Cardiovascular safety summary associated with the etoricoxib development programme Arthritis amp Rheumatism 2003 48 Suppl S616
5
ME Farkouh et al Comparison of lumiracoxib with naproxen and ibuprofen in the therapeutic arthritis research and gastrointestinal event trial (TARGET) cardiovascular outcomes randomised controlled trial Lancet 2004 364 675-684
RECOMMENDATIONS
NSAIDs COXIBs
bull Use lowest effective dose shortest duration
bull Not for patients who have recently undergone coronary artery bypass graft (CABG) surgery and revascularisation procedures
bull Coxibs should not be prescribed for patients with established ischaemic heart disease stroke or congestive heart failure
bull Caution for Coxibs for patients who have hypertension hyperlipidaemia diabetes and smoking as well as peripheral arterial disease
bull Etoricoxib should not be prescribed for patients with hypertension whose blood pressure has not been adequately controlled
The EU Summit is supported by Pfizer
Tricyclic Agents
bull best documented analgesics here (NNT 22)bull amitriptyline best investigatedbull desipraminenortriptyline less AEs
bull start on low doses increases compliancebullOften adverse effects (NNH 28)bull effect needs timebull SSRIs not as effective (NNT 67)
bull noradrenergic effect necessarybull venlafaxine another option
Antidepressants Compared with Placebo
Condition Number of trials
Antidepressant improvedtotal
Placebo improvedtotal
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 13 180260 73205 19 (16 to
24)30 (24 to 40)
Postherpetic neuralgia 3 4377 868 48 (24 to
94)23 (17 to 33)
Atypical facial pain 2 6288 3085 20 (15 to
28)28 (20 to 47)
Central pain 1 1015 115 10 (15 to 69)
17 (11 to 30)
Bandolier
Anticonvulsants as Membrane Stabilisers
bull pregabalinbull gabapentin bull carbamazepinebull clonazepam pooled NNT 27bull valproatebull lamotriginebull baclofen
Anticonvulsants Compared with Placebo
Condition Number of trials
Anticonvulsant improvedtotal
Placebo improvedtot
al
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 3 5668 2668 19 (14 to 27) 25 (18
to 40)
Trigeminal neuralgia 3 178315 41224 31 (23 to 41) 26 (22
to 33)
Migraine prophylaxis 2 6374 1777 37 (24 to 59) 16 (13
to 20)
Other pain syndromes 1 514 115 54 (07 to 40)
not calculat ed
Bandolier
Relative Activity on Serotonin and Norepinephrine Reuptake Among
Antidepressants
CitalopramFluvoxamineSertralineParoxetineFluoxetine
VenlafaxineDuloxetine
MaprotilineDesipramineNortriptylineReboxetine
AmitriptylineMilnacipranImipramine
Serotonin Mixed Norepinephrine
Antidepressant Analgesic Antidepressant
Fishbain et al Pain Med 20001310-316
Opioidsbull In principle opioids are effective in nociceptive
and some neuropathic pain however not always and not necessarily completely for dynamic pain
bull Possibly preferable opioids here arendash tramadol
bull noradrenergic and serotoninergic effectndash morphine
bull Mu receptor anatagonistmonaminergic effect
ndash oxycodonebull kappa receptor effect
Opioids
bull lsquoLack of analgesic effect of opioids on neuropathic hellip painrsquo Pain 19883311
bull lsquohellip intravenous hellip morphine reduce the pain of Osteoarthritisrsquo Neurology
1991411024bull lsquoA call for more science not more
rhetoric regarding opioids and arthritic painrsquo Pain 2001471
bull lsquoEfficacy of oxycodone in neuropathic painhelliprsquo Neurology 1998501837
OPIOIDS FOR OA PAINbull Osteoarthritis guidelines provide limited guidance on opioid use bull The 1995 ACR guidelines for hip OA suggest opioids be avoided for
long term use but short term use may be helpful without reference to primary data15
bull The 1995 ACR knee OA guidelines do not discuss opioids directly16 bull The 1998 UK guidelines on degenerative arthritis suggest that if
relief is inadequate with 24 grams of ibuprofen and 40 grams of paracetamol a day other antiinflammatories or opioids may be considered18
bull The 2000 update of the ACR OA guidelines suggests that opioids might be used as a medication of last resort17
bull Opioids are effective in OA hip and knee pain and have predictable side effects
bull It would be unwise were physicians to discount an entire class of medications over unfounded fears and incomplete knowledge of their benefits44
USE OF ULTRACET IN OA KNEESbull The efficacy of tramadolacetaminophen combination tablets (Ultracetreg) as add-
on and maintenance therapy in knee osteoarthritis pain inadequately controlled by nonsteroidal anti-inflammatory drug (NSAID)
Park KS Choi JJ Kim WU Min JK Park SH Cho CS
bull TramadolAPAP add-on significantly improved knee OA pain which had been inadequately controlled by NSAIDs In those subjects who showed favorable response to tramadolAPAP and NSAID combination therapy both tramadolAPAP and NSAIDs were effective at maintaining the pain-reduced state and there was no significant difference in efficacy between tramadolAPAP and NSAIDs
Clinical Rheumatology 2011 3 Aug
Opioid Sparing Regimes
bull Multimodal analgesia (Kehlet et al 1999)
bull NSAIDs and COX-2 (Romsing Moiniche 2004)
bull Paracetamol (Romsing 2002)
bull Ketamine (Elia Tramer 2005)
bull Gabapentin and Pregabalin (Dahl et al 2004)
bull Gabapentin and Rofecoxib (Gilron et al 2005)
Opioid reduction 20 ndash 40 Reduction of PONV 30
Clinical effects
Single-modality treatment of a Multi- modality problem is
futile
ldquoTherersquos no pain thatrsquos so easy to bear than that of
someone elserdquo
ndashLeriche
Van Gogh ldquoOld Man in Sorrowrdquo
Central Sensitisation
tissue or nerve injury
release of EAAsand neuropeptides
increased depolarizationat the NMDA receptor
expanded receptive fieldsand hyperexcitability
Increased Pain
excitotoxicity
loss of inhibition
adapted from Dubner
CNS
Central Sensitization May Have Contributed to OA Pain and Neuropathic
Pain Symptoms1
bull Focus group transcripts from participants with knee OA (N=80) were analyzed to determine the use of unprompted NP descriptors to characterize their pain (including burning tingling pins and needles and numbness) to determine whether people with chronic symptomatic knee OA use pain descriptors suggestive of underlying NP
bull The proportion of participants who used NP descriptors to characterize their pain was 34 (95 CI 24 to 45)
bull Participants using NP descriptors were younger than those who did not (mean age plusmn SD age 648 plusmn 97 years vs 720 plusmn 100 years respectively P=0003)
bull Characteristics that did not statistically distinguish participants who used NP descriptors from those who did included duration of OA pain intensity OA severity and gender
OA = osteoarthritis NP = neuropathic pain CI = confidence interval SD = standard deviation
1 Hochman JR et al Arthritis Care Res (Hoboken) 2010621019ndash1023
Central Sensitization in OA Expansion of Symptoms Beyond the
Joint
bull Quantitative sensory testing of PPTs in patients with knee OA pain (n=48) and matched controls without knee pain (n=24) revealed that subjects with OA pain exhibited sensitization in both OA-affected and unaffected areasndash Increasing pain intensity in
the OA-affected (knee) joint was associated with lower PPT in OA-unaffected areas (eg arm)1
PPT at arm (OA-unaffected area)
R = -032 Plt005
VAS at OA-affected Knee Joint
1500
1000
500
0 1 2 3 4 5 6 7 8 9 10PP
T k
Pa
Arendt-Nielsen L et al Pain 2010149573ndash581
OA = osteoarthritis PPT = pressure pain threshold VAS = visual analog scale
OA = osteoarthritis PPT = pressure pain threshold VAS = visual analog scale WOMAC = Western Ontario and McMaster Universities SF-36 = short form-36 health survey
Central Sensitization in OA Increased Pain Severity and Worse Pain-Associated
OutcomesImamura M et al Arthritis Rheum 2008591424ndash1431
Measure Spearmanrsquos rank correlation coefficient r P Value
VASPatellar tendon Sacral 2 subcutaneous dermatome levelAdductor longus muscle
-0545 -0546 -0561
lt0001 lt0001 lt0001
WOMAC painPatellar tendon Sacral 2 subcutaneous dermatome levelAdductor longus muscle
-0589-0601 -0540
lt0001 lt0001lt0001
WOMAC physical activityLumbar 2 subcutaneous dermatome level Sacral 2 subcutaneous dermatome level Peroneus longus muscle
-0550 -0509 -0571
lt0001lt0001 lt0001
SF-36 bodily painLumbar 1ndashLumbar 2 supraspinous ligamentLumbar 2 subcutaneous dermatome level Adductor longus muscle
0534 0606 0569
lt0001 lt0001 lt0001
A cross-sectional study that assessed hyperalgesia in patients with refractory OA-associated pain (n=62) reported significant correlations between PPT values at each listed site and VAS WOMAC pain and physical activity subscales and SF-36 bodily pain score
SKIN
SPINAL CORD
Dorsal horn
PRIMARY AFFERENT NERVE
Dorsal root ganglion
POSTSYNAPTIC PROCESSPRESYNAPTIC PROCESS
NMDA receptor
Ca2+ Second messengers
kinases (eg PKC) diacylglycerol cAMP
Gene transcription
P
CELL NUCLEUS
Long term changes
(receptor function transmitter production)
Glutamate release
C-fosoncogene
Cortical Reorganisation
I will show that my client is welltolerated amp effectivehelliphellip
I will showthat my clientis well tolerated and effective
bull For chronic pain most measures of treatment response involve patient- reported outcomes for which the patient is the most important judge of whether changes are important or meaningful12
ndash Determinations of statistical significance must be supplemented by consideration of the clinical importance of changes in outcome measures1
bull The IMMPACT consensus meeting proposed provisional benchmarks for identifying clinically important changes in the specific outcome measures for chronic pain clinical trials1
Using NNT Analyses in the Treatment of Pain IMMPACT Consensus Meeting Recommendations
NNT = number needed to treat IMMPACT = Initiative on Methods Measurement and Pain Assessment in Clinical Trials1 Dworkin RH et al J Pain 20089105ndash121 2 Acquadro C et al Value Health 20036522ndash531
10ndash20Reduction in pain intensity
ge50Reduction in pain intensity
ge30Reduction in pain intensity
Minimally Important Improvement
Moderately Important Improvement
Substantial Improvement
132
253
353638
4244
55788
1718
0 4 8 12 16 20
Oxycodone 5Codeine 60Tramadol 50Propoxyphene 65APAP 325Oxycodone 5ASA 650Codeine 60Tramadol 100APAP 650Propox 100APAP 1000APAP 600Cod 60Morphine 10APAP 1000Oxyc 10Ibuprofen 400Oxycodone 15
McQuay H BMJ 1997
Patients with 50 reduction Patients with 50 reduction in pain vs placeboin pain vs placebo
NNT
USE OF PARACETAMOL IN TREATMENT OF OA PAIN
22
How effective was paracetamol
How effective was paracetamol compared with NSAIDs
F Wolfe S Zhao N Lane Preference for nonsteroidal antiinflammatory drugs over acetaminophen by rheumatic disease patients Arthritis amp Rheumatism 2000 43 378-385
2007 League table of NNT for at least 50 pain relief over 4-6 hrs in patients with moderate to severe pain
(all oral analgesics except IM morphine )
[httpwwwmedicineoxacukbandolierboothpainpagacutrevanalgesicsleagtabhtml
ETORICOXIB IN ACUTE PAIN
bull Etoricoxib 120 mg has been approved for treating acute pain which includes post-operative pain and other acute pain such as primary dysmenorrhea and acute gouty arthritis
bull Efficacy of etoricoxib in the post-operative setting as evaluated by NNT bull COCHRANE REVIEW Five randomized placebo-controlled studies
with a total number of 880 patients were included -- Four studies on patients with dental pain following extraction of at least one impacted third molar
--One study on patients with pain following uncomplicated orthopaedic surgery
bull NNT were calculated to measure at least 50 pain relief over 4-6 hrs (substantial pain relief) based on TOPAR scores
Results 120 mg etoricoxib with a NNT of 19 for acute post-operative pain
1 Chang DJ Desjardins PJ King TR Erb T Geba GP The analgesic efficacy of etoricoxib compared with oxycodoneacetaminophen in an acute postoperative pain model a randomized double-blind clinical trial Anesthesia and Analgesia 200499(3)807ndash15
2 Malmstrom K Sapre A Couglin H Agrawal NG Mazenko RS Fricke JR Jr Etoricoxib in acute pain associated with dental surgery a randomized double-blind placebo- and active comparator-controlled dose-ranging study Clinical Therapeutics 200426(5)667ndash79
3 Malmstrom K Kotey P Coughlin H Desjardins PJ A randomized double-blind parallel-group study comparing the analgesic effect of etoricoxib to placebo naproxen sodium and acetaminophen with codeine using the dental impaction pain model Clinical Journal of Pain 200420(3)147ndash 55
4 Malmstrom K Ang J Fricke JR Shingo S Reicin A The analgesic effect of etoricoxib relative to that of cetaminophen analgesics a randomized controlled single-dose study in acute dental impaction pain Current Medical Research and Opinion 200521(1)141ndash9 Rasmussen 2005 published data only
5 Rasmussen GL Malmstrom K Bourne MH Jove M Rhondeau SM Kotey P Etoricoxib provides analgesic efficacy to patients after knee or hip replacement surgery a randomized double-blind placebo-controlled study Anaesthesia and Analgesia 2005101(4) 1104ndash11
Etoricoxib in acute pain bull Indirect comparisons of NNTs for at least 50 pain
relief over 4 to 6 hours in reviews of other analgesics using identical methods indicate that etoricoxib 120 mg
-- has slightly better efficacy than rofecoxib 50 mg (22 (19 to 24) Barden 2005)
-- is significantly better than lumiracoxib 400mg (27 (22 to 35) Roy 2007) or-- celecoxib 400 mg (25 (22 to 29) Derry 2008)
-- better than the non-selective NSAIDs ibuprofen 400 mg (27 (25 to 30) Collins 1999) naproxen 500 mg (27 (23 to 32 Derry 2009a) and diclofenac 50mg (24 (18 to 33Derry 2009b)
Placebo
Paracetamol 10007
Paracetamolcodeine 1000606
Ibuprofen 4005
Celecoxib 4004
Naproxen 5005503
Rofecoxib 502
Etoricoxib 1201
0 4 8 12 16 20 24Median remedication time (hr)
Each bar is from a Cochrane review
Acute pain Time for patients to Re-medication
The weighted median time to re-medication with ARCOXIA 120mg is about 24hrs
vs placebo at 18hrs
1 Clarke R et al Cochrane Database Syst Rev 2009 Apr 15(2)CD004309 2 Bulley S et al Cochrane Database Syst Rev 2009 Oct 7(4)CD0046043 Derry C et al Cochrane Database Syst Rev 2009 Jan 21(1)CD004234 4 Derry S Cochrane Database Syst Rev 2008 Oct 8(4)CD0042335 Derry C et al Cochrane Database Syst Rev 2009 Jul 8(3)CD0015486 Toms L et al Cochrane Database Syst Rev 2009 Jan 21(1)CD0015477 Toms L et al Cochrane Database Syst Rev 2008 Oct 8(4)CD004602
Placebo (n=56)
Etoricoxib 60 mg (n=224)
Naproxen 1000 mgc
(n=221)
a0-
to 100-mm VAS (0 = none to 100 = extreme)
b0-
to 100-mm VAS (0 = very well to 100 = very poor) c500 mg twice dailyPlt0001 vs placebo for both etoricoxib and naproxen P = NS etoricoxib vs naproxen
Leung AT et al Curr Med Res Opin 200218(2)49ndash58
LS M
ean
Cha
nge
plusmnSE
Weeks Postrandomization
Osteoarthritis Etoricoxib 60 mg vs Naproxen
Results Etoricoxib relieved pain and improved mobility and disease statuEtoricoxib relieved pain and improved mobility and disease statuss
ndash35
ndash25
ndash5
5
ndash15
WOMAC Pain Subscalea
S R 4 82 12
WOMAC Physical Function Subscalea PGADSb
ndash35
ndash25
ndash5
5
ndash15
S R 4 82 12ndash35
ndash25
ndash5
5
ndash15
S R 4 82 12Weeks Postrandomization Weeks Postrandomization
Adverse effects of NSAIDsAdverse effects of NSAIDs
BNF March 2002
Dose-dependent toxicityIntolerability dyspepsiaGI bleedingUlcers ndash bleeds perforations
Upper-GI
Renal
Contributes to blood loss
Fluid retention oedema hypertensionRenal dysfunction failure ndash acute chronicHeart failure
Anti-platelet effects
Angioedema bronchospasmHypersensitivity
No Short-Term Adverse GI Effects -
The Big Mistake
bull Study designed to evaluate short-term GI effects in elderly
bull Study planned to enrol 160 patientsbull Study terminated by investigator at 17 subjects
ndash 8 patients had ulcersndash 4 of 4 in ketorolac group
lsquo hellip because of the unexpectedly high incidence of gastroduodenal ulcers observedhelliprsquo
Harris et al ClinTher 2001231422
Class Effect of All NSAIDs
httpwwwfdagovcderdruginfopageCOX2NSAIDdecisionMemopdf
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
33
Cardiovascular Safetybull Arthritis patients often have concomitant CV
disease1
bull Pain is an important predictor of CV risk23
bull Randomized controlled trials and observational data demonstrate that CV risk of etoricoxib appears similar to that of traditional NSAIDs4-6
bull Recent data suggest that differential CV effects of NSAIDs (selective and nonselective) may be independent of COX-2 inhibition78
References 1 Singh G et al Am J Manag Care 20028(suppl)S383-S391 2
Sokka T Pincus T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 3
Pincus T Sokka T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 4
httpwwwfdagovohrmsdocketsac05slides2005-4090S1_06_01_Pfizer-celecoxibppt (accessed 14 February 2006) 5
White WB et al Am J Cardiol 200289425ndash430 6
Graham DJ et al Lancet 2005365475ndash481 7 Yang HM et al Circulation 2004110301ndash308 8 Steffel J et al Circulation 20051111685ndash1689
Events per 100 patient years
Coxib Coxib Placebo Coxib NSAID Percent naproxen
Rofecoxib 17 19 11 08 73
Celecoxib 13 15 11 11 20
Valdecoxib 13 12 13 20 about 50
Etoricoxib 13 12 12 08 67
Lumiracoxib 09 08 52
34
APTC endpoint (cardiovascular haemorrhagic and unknown death and nonfatal myocardial infarction and stroke)
1
MR Weir et al Selective COX-2 inhibition and cardiovascular effects a review of the rofecoxib development program American heart Journal 2003 146 591-604
2
WB White et al Cardiovascular thrombotic events in arthritis trials of the cyclooxygenase-2 inhibitor celecoxib American Journal of cardiology 2003 92 411-418
3
WB White et al Effects of the cyclooxygenase-2 specific inhibitor valdecoxib versus nonsteroidal anti-inflammatory agents and placebo on cardiovascular thrombotic events in patients with arthritis American Journal of Therapeutics 2004 11 244-250
4
S Curtis et al Cardiovascular safety summary associated with the etoricoxib development programme Arthritis amp Rheumatism 2003 48 Suppl S616
5
ME Farkouh et al Comparison of lumiracoxib with naproxen and ibuprofen in the therapeutic arthritis research and gastrointestinal event trial (TARGET) cardiovascular outcomes randomised controlled trial Lancet 2004 364 675-684
RECOMMENDATIONS
NSAIDs COXIBs
bull Use lowest effective dose shortest duration
bull Not for patients who have recently undergone coronary artery bypass graft (CABG) surgery and revascularisation procedures
bull Coxibs should not be prescribed for patients with established ischaemic heart disease stroke or congestive heart failure
bull Caution for Coxibs for patients who have hypertension hyperlipidaemia diabetes and smoking as well as peripheral arterial disease
bull Etoricoxib should not be prescribed for patients with hypertension whose blood pressure has not been adequately controlled
The EU Summit is supported by Pfizer
Tricyclic Agents
bull best documented analgesics here (NNT 22)bull amitriptyline best investigatedbull desipraminenortriptyline less AEs
bull start on low doses increases compliancebullOften adverse effects (NNH 28)bull effect needs timebull SSRIs not as effective (NNT 67)
bull noradrenergic effect necessarybull venlafaxine another option
Antidepressants Compared with Placebo
Condition Number of trials
Antidepressant improvedtotal
Placebo improvedtotal
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 13 180260 73205 19 (16 to
24)30 (24 to 40)
Postherpetic neuralgia 3 4377 868 48 (24 to
94)23 (17 to 33)
Atypical facial pain 2 6288 3085 20 (15 to
28)28 (20 to 47)
Central pain 1 1015 115 10 (15 to 69)
17 (11 to 30)
Bandolier
Anticonvulsants as Membrane Stabilisers
bull pregabalinbull gabapentin bull carbamazepinebull clonazepam pooled NNT 27bull valproatebull lamotriginebull baclofen
Anticonvulsants Compared with Placebo
Condition Number of trials
Anticonvulsant improvedtotal
Placebo improvedtot
al
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 3 5668 2668 19 (14 to 27) 25 (18
to 40)
Trigeminal neuralgia 3 178315 41224 31 (23 to 41) 26 (22
to 33)
Migraine prophylaxis 2 6374 1777 37 (24 to 59) 16 (13
to 20)
Other pain syndromes 1 514 115 54 (07 to 40)
not calculat ed
Bandolier
Relative Activity on Serotonin and Norepinephrine Reuptake Among
Antidepressants
CitalopramFluvoxamineSertralineParoxetineFluoxetine
VenlafaxineDuloxetine
MaprotilineDesipramineNortriptylineReboxetine
AmitriptylineMilnacipranImipramine
Serotonin Mixed Norepinephrine
Antidepressant Analgesic Antidepressant
Fishbain et al Pain Med 20001310-316
Opioidsbull In principle opioids are effective in nociceptive
and some neuropathic pain however not always and not necessarily completely for dynamic pain
bull Possibly preferable opioids here arendash tramadol
bull noradrenergic and serotoninergic effectndash morphine
bull Mu receptor anatagonistmonaminergic effect
ndash oxycodonebull kappa receptor effect
Opioids
bull lsquoLack of analgesic effect of opioids on neuropathic hellip painrsquo Pain 19883311
bull lsquohellip intravenous hellip morphine reduce the pain of Osteoarthritisrsquo Neurology
1991411024bull lsquoA call for more science not more
rhetoric regarding opioids and arthritic painrsquo Pain 2001471
bull lsquoEfficacy of oxycodone in neuropathic painhelliprsquo Neurology 1998501837
OPIOIDS FOR OA PAINbull Osteoarthritis guidelines provide limited guidance on opioid use bull The 1995 ACR guidelines for hip OA suggest opioids be avoided for
long term use but short term use may be helpful without reference to primary data15
bull The 1995 ACR knee OA guidelines do not discuss opioids directly16 bull The 1998 UK guidelines on degenerative arthritis suggest that if
relief is inadequate with 24 grams of ibuprofen and 40 grams of paracetamol a day other antiinflammatories or opioids may be considered18
bull The 2000 update of the ACR OA guidelines suggests that opioids might be used as a medication of last resort17
bull Opioids are effective in OA hip and knee pain and have predictable side effects
bull It would be unwise were physicians to discount an entire class of medications over unfounded fears and incomplete knowledge of their benefits44
USE OF ULTRACET IN OA KNEESbull The efficacy of tramadolacetaminophen combination tablets (Ultracetreg) as add-
on and maintenance therapy in knee osteoarthritis pain inadequately controlled by nonsteroidal anti-inflammatory drug (NSAID)
Park KS Choi JJ Kim WU Min JK Park SH Cho CS
bull TramadolAPAP add-on significantly improved knee OA pain which had been inadequately controlled by NSAIDs In those subjects who showed favorable response to tramadolAPAP and NSAID combination therapy both tramadolAPAP and NSAIDs were effective at maintaining the pain-reduced state and there was no significant difference in efficacy between tramadolAPAP and NSAIDs
Clinical Rheumatology 2011 3 Aug
Opioid Sparing Regimes
bull Multimodal analgesia (Kehlet et al 1999)
bull NSAIDs and COX-2 (Romsing Moiniche 2004)
bull Paracetamol (Romsing 2002)
bull Ketamine (Elia Tramer 2005)
bull Gabapentin and Pregabalin (Dahl et al 2004)
bull Gabapentin and Rofecoxib (Gilron et al 2005)
Opioid reduction 20 ndash 40 Reduction of PONV 30
Clinical effects
Single-modality treatment of a Multi- modality problem is
futile
ldquoTherersquos no pain thatrsquos so easy to bear than that of
someone elserdquo
ndashLeriche
Van Gogh ldquoOld Man in Sorrowrdquo
Central Sensitization May Have Contributed to OA Pain and Neuropathic
Pain Symptoms1
bull Focus group transcripts from participants with knee OA (N=80) were analyzed to determine the use of unprompted NP descriptors to characterize their pain (including burning tingling pins and needles and numbness) to determine whether people with chronic symptomatic knee OA use pain descriptors suggestive of underlying NP
bull The proportion of participants who used NP descriptors to characterize their pain was 34 (95 CI 24 to 45)
bull Participants using NP descriptors were younger than those who did not (mean age plusmn SD age 648 plusmn 97 years vs 720 plusmn 100 years respectively P=0003)
bull Characteristics that did not statistically distinguish participants who used NP descriptors from those who did included duration of OA pain intensity OA severity and gender
OA = osteoarthritis NP = neuropathic pain CI = confidence interval SD = standard deviation
1 Hochman JR et al Arthritis Care Res (Hoboken) 2010621019ndash1023
Central Sensitization in OA Expansion of Symptoms Beyond the
Joint
bull Quantitative sensory testing of PPTs in patients with knee OA pain (n=48) and matched controls without knee pain (n=24) revealed that subjects with OA pain exhibited sensitization in both OA-affected and unaffected areasndash Increasing pain intensity in
the OA-affected (knee) joint was associated with lower PPT in OA-unaffected areas (eg arm)1
PPT at arm (OA-unaffected area)
R = -032 Plt005
VAS at OA-affected Knee Joint
1500
1000
500
0 1 2 3 4 5 6 7 8 9 10PP
T k
Pa
Arendt-Nielsen L et al Pain 2010149573ndash581
OA = osteoarthritis PPT = pressure pain threshold VAS = visual analog scale
OA = osteoarthritis PPT = pressure pain threshold VAS = visual analog scale WOMAC = Western Ontario and McMaster Universities SF-36 = short form-36 health survey
Central Sensitization in OA Increased Pain Severity and Worse Pain-Associated
OutcomesImamura M et al Arthritis Rheum 2008591424ndash1431
Measure Spearmanrsquos rank correlation coefficient r P Value
VASPatellar tendon Sacral 2 subcutaneous dermatome levelAdductor longus muscle
-0545 -0546 -0561
lt0001 lt0001 lt0001
WOMAC painPatellar tendon Sacral 2 subcutaneous dermatome levelAdductor longus muscle
-0589-0601 -0540
lt0001 lt0001lt0001
WOMAC physical activityLumbar 2 subcutaneous dermatome level Sacral 2 subcutaneous dermatome level Peroneus longus muscle
-0550 -0509 -0571
lt0001lt0001 lt0001
SF-36 bodily painLumbar 1ndashLumbar 2 supraspinous ligamentLumbar 2 subcutaneous dermatome level Adductor longus muscle
0534 0606 0569
lt0001 lt0001 lt0001
A cross-sectional study that assessed hyperalgesia in patients with refractory OA-associated pain (n=62) reported significant correlations between PPT values at each listed site and VAS WOMAC pain and physical activity subscales and SF-36 bodily pain score
SKIN
SPINAL CORD
Dorsal horn
PRIMARY AFFERENT NERVE
Dorsal root ganglion
POSTSYNAPTIC PROCESSPRESYNAPTIC PROCESS
NMDA receptor
Ca2+ Second messengers
kinases (eg PKC) diacylglycerol cAMP
Gene transcription
P
CELL NUCLEUS
Long term changes
(receptor function transmitter production)
Glutamate release
C-fosoncogene
Cortical Reorganisation
I will show that my client is welltolerated amp effectivehelliphellip
I will showthat my clientis well tolerated and effective
bull For chronic pain most measures of treatment response involve patient- reported outcomes for which the patient is the most important judge of whether changes are important or meaningful12
ndash Determinations of statistical significance must be supplemented by consideration of the clinical importance of changes in outcome measures1
bull The IMMPACT consensus meeting proposed provisional benchmarks for identifying clinically important changes in the specific outcome measures for chronic pain clinical trials1
Using NNT Analyses in the Treatment of Pain IMMPACT Consensus Meeting Recommendations
NNT = number needed to treat IMMPACT = Initiative on Methods Measurement and Pain Assessment in Clinical Trials1 Dworkin RH et al J Pain 20089105ndash121 2 Acquadro C et al Value Health 20036522ndash531
10ndash20Reduction in pain intensity
ge50Reduction in pain intensity
ge30Reduction in pain intensity
Minimally Important Improvement
Moderately Important Improvement
Substantial Improvement
132
253
353638
4244
55788
1718
0 4 8 12 16 20
Oxycodone 5Codeine 60Tramadol 50Propoxyphene 65APAP 325Oxycodone 5ASA 650Codeine 60Tramadol 100APAP 650Propox 100APAP 1000APAP 600Cod 60Morphine 10APAP 1000Oxyc 10Ibuprofen 400Oxycodone 15
McQuay H BMJ 1997
Patients with 50 reduction Patients with 50 reduction in pain vs placeboin pain vs placebo
NNT
USE OF PARACETAMOL IN TREATMENT OF OA PAIN
22
How effective was paracetamol
How effective was paracetamol compared with NSAIDs
F Wolfe S Zhao N Lane Preference for nonsteroidal antiinflammatory drugs over acetaminophen by rheumatic disease patients Arthritis amp Rheumatism 2000 43 378-385
2007 League table of NNT for at least 50 pain relief over 4-6 hrs in patients with moderate to severe pain
(all oral analgesics except IM morphine )
[httpwwwmedicineoxacukbandolierboothpainpagacutrevanalgesicsleagtabhtml
ETORICOXIB IN ACUTE PAIN
bull Etoricoxib 120 mg has been approved for treating acute pain which includes post-operative pain and other acute pain such as primary dysmenorrhea and acute gouty arthritis
bull Efficacy of etoricoxib in the post-operative setting as evaluated by NNT bull COCHRANE REVIEW Five randomized placebo-controlled studies
with a total number of 880 patients were included -- Four studies on patients with dental pain following extraction of at least one impacted third molar
--One study on patients with pain following uncomplicated orthopaedic surgery
bull NNT were calculated to measure at least 50 pain relief over 4-6 hrs (substantial pain relief) based on TOPAR scores
Results 120 mg etoricoxib with a NNT of 19 for acute post-operative pain
1 Chang DJ Desjardins PJ King TR Erb T Geba GP The analgesic efficacy of etoricoxib compared with oxycodoneacetaminophen in an acute postoperative pain model a randomized double-blind clinical trial Anesthesia and Analgesia 200499(3)807ndash15
2 Malmstrom K Sapre A Couglin H Agrawal NG Mazenko RS Fricke JR Jr Etoricoxib in acute pain associated with dental surgery a randomized double-blind placebo- and active comparator-controlled dose-ranging study Clinical Therapeutics 200426(5)667ndash79
3 Malmstrom K Kotey P Coughlin H Desjardins PJ A randomized double-blind parallel-group study comparing the analgesic effect of etoricoxib to placebo naproxen sodium and acetaminophen with codeine using the dental impaction pain model Clinical Journal of Pain 200420(3)147ndash 55
4 Malmstrom K Ang J Fricke JR Shingo S Reicin A The analgesic effect of etoricoxib relative to that of cetaminophen analgesics a randomized controlled single-dose study in acute dental impaction pain Current Medical Research and Opinion 200521(1)141ndash9 Rasmussen 2005 published data only
5 Rasmussen GL Malmstrom K Bourne MH Jove M Rhondeau SM Kotey P Etoricoxib provides analgesic efficacy to patients after knee or hip replacement surgery a randomized double-blind placebo-controlled study Anaesthesia and Analgesia 2005101(4) 1104ndash11
Etoricoxib in acute pain bull Indirect comparisons of NNTs for at least 50 pain
relief over 4 to 6 hours in reviews of other analgesics using identical methods indicate that etoricoxib 120 mg
-- has slightly better efficacy than rofecoxib 50 mg (22 (19 to 24) Barden 2005)
-- is significantly better than lumiracoxib 400mg (27 (22 to 35) Roy 2007) or-- celecoxib 400 mg (25 (22 to 29) Derry 2008)
-- better than the non-selective NSAIDs ibuprofen 400 mg (27 (25 to 30) Collins 1999) naproxen 500 mg (27 (23 to 32 Derry 2009a) and diclofenac 50mg (24 (18 to 33Derry 2009b)
Placebo
Paracetamol 10007
Paracetamolcodeine 1000606
Ibuprofen 4005
Celecoxib 4004
Naproxen 5005503
Rofecoxib 502
Etoricoxib 1201
0 4 8 12 16 20 24Median remedication time (hr)
Each bar is from a Cochrane review
Acute pain Time for patients to Re-medication
The weighted median time to re-medication with ARCOXIA 120mg is about 24hrs
vs placebo at 18hrs
1 Clarke R et al Cochrane Database Syst Rev 2009 Apr 15(2)CD004309 2 Bulley S et al Cochrane Database Syst Rev 2009 Oct 7(4)CD0046043 Derry C et al Cochrane Database Syst Rev 2009 Jan 21(1)CD004234 4 Derry S Cochrane Database Syst Rev 2008 Oct 8(4)CD0042335 Derry C et al Cochrane Database Syst Rev 2009 Jul 8(3)CD0015486 Toms L et al Cochrane Database Syst Rev 2009 Jan 21(1)CD0015477 Toms L et al Cochrane Database Syst Rev 2008 Oct 8(4)CD004602
Placebo (n=56)
Etoricoxib 60 mg (n=224)
Naproxen 1000 mgc
(n=221)
a0-
to 100-mm VAS (0 = none to 100 = extreme)
b0-
to 100-mm VAS (0 = very well to 100 = very poor) c500 mg twice dailyPlt0001 vs placebo for both etoricoxib and naproxen P = NS etoricoxib vs naproxen
Leung AT et al Curr Med Res Opin 200218(2)49ndash58
LS M
ean
Cha
nge
plusmnSE
Weeks Postrandomization
Osteoarthritis Etoricoxib 60 mg vs Naproxen
Results Etoricoxib relieved pain and improved mobility and disease statuEtoricoxib relieved pain and improved mobility and disease statuss
ndash35
ndash25
ndash5
5
ndash15
WOMAC Pain Subscalea
S R 4 82 12
WOMAC Physical Function Subscalea PGADSb
ndash35
ndash25
ndash5
5
ndash15
S R 4 82 12ndash35
ndash25
ndash5
5
ndash15
S R 4 82 12Weeks Postrandomization Weeks Postrandomization
Adverse effects of NSAIDsAdverse effects of NSAIDs
BNF March 2002
Dose-dependent toxicityIntolerability dyspepsiaGI bleedingUlcers ndash bleeds perforations
Upper-GI
Renal
Contributes to blood loss
Fluid retention oedema hypertensionRenal dysfunction failure ndash acute chronicHeart failure
Anti-platelet effects
Angioedema bronchospasmHypersensitivity
No Short-Term Adverse GI Effects -
The Big Mistake
bull Study designed to evaluate short-term GI effects in elderly
bull Study planned to enrol 160 patientsbull Study terminated by investigator at 17 subjects
ndash 8 patients had ulcersndash 4 of 4 in ketorolac group
lsquo hellip because of the unexpectedly high incidence of gastroduodenal ulcers observedhelliprsquo
Harris et al ClinTher 2001231422
Class Effect of All NSAIDs
httpwwwfdagovcderdruginfopageCOX2NSAIDdecisionMemopdf
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
33
Cardiovascular Safetybull Arthritis patients often have concomitant CV
disease1
bull Pain is an important predictor of CV risk23
bull Randomized controlled trials and observational data demonstrate that CV risk of etoricoxib appears similar to that of traditional NSAIDs4-6
bull Recent data suggest that differential CV effects of NSAIDs (selective and nonselective) may be independent of COX-2 inhibition78
References 1 Singh G et al Am J Manag Care 20028(suppl)S383-S391 2
Sokka T Pincus T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 3
Pincus T Sokka T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 4
httpwwwfdagovohrmsdocketsac05slides2005-4090S1_06_01_Pfizer-celecoxibppt (accessed 14 February 2006) 5
White WB et al Am J Cardiol 200289425ndash430 6
Graham DJ et al Lancet 2005365475ndash481 7 Yang HM et al Circulation 2004110301ndash308 8 Steffel J et al Circulation 20051111685ndash1689
Events per 100 patient years
Coxib Coxib Placebo Coxib NSAID Percent naproxen
Rofecoxib 17 19 11 08 73
Celecoxib 13 15 11 11 20
Valdecoxib 13 12 13 20 about 50
Etoricoxib 13 12 12 08 67
Lumiracoxib 09 08 52
34
APTC endpoint (cardiovascular haemorrhagic and unknown death and nonfatal myocardial infarction and stroke)
1
MR Weir et al Selective COX-2 inhibition and cardiovascular effects a review of the rofecoxib development program American heart Journal 2003 146 591-604
2
WB White et al Cardiovascular thrombotic events in arthritis trials of the cyclooxygenase-2 inhibitor celecoxib American Journal of cardiology 2003 92 411-418
3
WB White et al Effects of the cyclooxygenase-2 specific inhibitor valdecoxib versus nonsteroidal anti-inflammatory agents and placebo on cardiovascular thrombotic events in patients with arthritis American Journal of Therapeutics 2004 11 244-250
4
S Curtis et al Cardiovascular safety summary associated with the etoricoxib development programme Arthritis amp Rheumatism 2003 48 Suppl S616
5
ME Farkouh et al Comparison of lumiracoxib with naproxen and ibuprofen in the therapeutic arthritis research and gastrointestinal event trial (TARGET) cardiovascular outcomes randomised controlled trial Lancet 2004 364 675-684
RECOMMENDATIONS
NSAIDs COXIBs
bull Use lowest effective dose shortest duration
bull Not for patients who have recently undergone coronary artery bypass graft (CABG) surgery and revascularisation procedures
bull Coxibs should not be prescribed for patients with established ischaemic heart disease stroke or congestive heart failure
bull Caution for Coxibs for patients who have hypertension hyperlipidaemia diabetes and smoking as well as peripheral arterial disease
bull Etoricoxib should not be prescribed for patients with hypertension whose blood pressure has not been adequately controlled
The EU Summit is supported by Pfizer
Tricyclic Agents
bull best documented analgesics here (NNT 22)bull amitriptyline best investigatedbull desipraminenortriptyline less AEs
bull start on low doses increases compliancebullOften adverse effects (NNH 28)bull effect needs timebull SSRIs not as effective (NNT 67)
bull noradrenergic effect necessarybull venlafaxine another option
Antidepressants Compared with Placebo
Condition Number of trials
Antidepressant improvedtotal
Placebo improvedtotal
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 13 180260 73205 19 (16 to
24)30 (24 to 40)
Postherpetic neuralgia 3 4377 868 48 (24 to
94)23 (17 to 33)
Atypical facial pain 2 6288 3085 20 (15 to
28)28 (20 to 47)
Central pain 1 1015 115 10 (15 to 69)
17 (11 to 30)
Bandolier
Anticonvulsants as Membrane Stabilisers
bull pregabalinbull gabapentin bull carbamazepinebull clonazepam pooled NNT 27bull valproatebull lamotriginebull baclofen
Anticonvulsants Compared with Placebo
Condition Number of trials
Anticonvulsant improvedtotal
Placebo improvedtot
al
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 3 5668 2668 19 (14 to 27) 25 (18
to 40)
Trigeminal neuralgia 3 178315 41224 31 (23 to 41) 26 (22
to 33)
Migraine prophylaxis 2 6374 1777 37 (24 to 59) 16 (13
to 20)
Other pain syndromes 1 514 115 54 (07 to 40)
not calculat ed
Bandolier
Relative Activity on Serotonin and Norepinephrine Reuptake Among
Antidepressants
CitalopramFluvoxamineSertralineParoxetineFluoxetine
VenlafaxineDuloxetine
MaprotilineDesipramineNortriptylineReboxetine
AmitriptylineMilnacipranImipramine
Serotonin Mixed Norepinephrine
Antidepressant Analgesic Antidepressant
Fishbain et al Pain Med 20001310-316
Opioidsbull In principle opioids are effective in nociceptive
and some neuropathic pain however not always and not necessarily completely for dynamic pain
bull Possibly preferable opioids here arendash tramadol
bull noradrenergic and serotoninergic effectndash morphine
bull Mu receptor anatagonistmonaminergic effect
ndash oxycodonebull kappa receptor effect
Opioids
bull lsquoLack of analgesic effect of opioids on neuropathic hellip painrsquo Pain 19883311
bull lsquohellip intravenous hellip morphine reduce the pain of Osteoarthritisrsquo Neurology
1991411024bull lsquoA call for more science not more
rhetoric regarding opioids and arthritic painrsquo Pain 2001471
bull lsquoEfficacy of oxycodone in neuropathic painhelliprsquo Neurology 1998501837
OPIOIDS FOR OA PAINbull Osteoarthritis guidelines provide limited guidance on opioid use bull The 1995 ACR guidelines for hip OA suggest opioids be avoided for
long term use but short term use may be helpful without reference to primary data15
bull The 1995 ACR knee OA guidelines do not discuss opioids directly16 bull The 1998 UK guidelines on degenerative arthritis suggest that if
relief is inadequate with 24 grams of ibuprofen and 40 grams of paracetamol a day other antiinflammatories or opioids may be considered18
bull The 2000 update of the ACR OA guidelines suggests that opioids might be used as a medication of last resort17
bull Opioids are effective in OA hip and knee pain and have predictable side effects
bull It would be unwise were physicians to discount an entire class of medications over unfounded fears and incomplete knowledge of their benefits44
USE OF ULTRACET IN OA KNEESbull The efficacy of tramadolacetaminophen combination tablets (Ultracetreg) as add-
on and maintenance therapy in knee osteoarthritis pain inadequately controlled by nonsteroidal anti-inflammatory drug (NSAID)
Park KS Choi JJ Kim WU Min JK Park SH Cho CS
bull TramadolAPAP add-on significantly improved knee OA pain which had been inadequately controlled by NSAIDs In those subjects who showed favorable response to tramadolAPAP and NSAID combination therapy both tramadolAPAP and NSAIDs were effective at maintaining the pain-reduced state and there was no significant difference in efficacy between tramadolAPAP and NSAIDs
Clinical Rheumatology 2011 3 Aug
Opioid Sparing Regimes
bull Multimodal analgesia (Kehlet et al 1999)
bull NSAIDs and COX-2 (Romsing Moiniche 2004)
bull Paracetamol (Romsing 2002)
bull Ketamine (Elia Tramer 2005)
bull Gabapentin and Pregabalin (Dahl et al 2004)
bull Gabapentin and Rofecoxib (Gilron et al 2005)
Opioid reduction 20 ndash 40 Reduction of PONV 30
Clinical effects
Single-modality treatment of a Multi- modality problem is
futile
ldquoTherersquos no pain thatrsquos so easy to bear than that of
someone elserdquo
ndashLeriche
Van Gogh ldquoOld Man in Sorrowrdquo
Central Sensitization in OA Expansion of Symptoms Beyond the
Joint
bull Quantitative sensory testing of PPTs in patients with knee OA pain (n=48) and matched controls without knee pain (n=24) revealed that subjects with OA pain exhibited sensitization in both OA-affected and unaffected areasndash Increasing pain intensity in
the OA-affected (knee) joint was associated with lower PPT in OA-unaffected areas (eg arm)1
PPT at arm (OA-unaffected area)
R = -032 Plt005
VAS at OA-affected Knee Joint
1500
1000
500
0 1 2 3 4 5 6 7 8 9 10PP
T k
Pa
Arendt-Nielsen L et al Pain 2010149573ndash581
OA = osteoarthritis PPT = pressure pain threshold VAS = visual analog scale
OA = osteoarthritis PPT = pressure pain threshold VAS = visual analog scale WOMAC = Western Ontario and McMaster Universities SF-36 = short form-36 health survey
Central Sensitization in OA Increased Pain Severity and Worse Pain-Associated
OutcomesImamura M et al Arthritis Rheum 2008591424ndash1431
Measure Spearmanrsquos rank correlation coefficient r P Value
VASPatellar tendon Sacral 2 subcutaneous dermatome levelAdductor longus muscle
-0545 -0546 -0561
lt0001 lt0001 lt0001
WOMAC painPatellar tendon Sacral 2 subcutaneous dermatome levelAdductor longus muscle
-0589-0601 -0540
lt0001 lt0001lt0001
WOMAC physical activityLumbar 2 subcutaneous dermatome level Sacral 2 subcutaneous dermatome level Peroneus longus muscle
-0550 -0509 -0571
lt0001lt0001 lt0001
SF-36 bodily painLumbar 1ndashLumbar 2 supraspinous ligamentLumbar 2 subcutaneous dermatome level Adductor longus muscle
0534 0606 0569
lt0001 lt0001 lt0001
A cross-sectional study that assessed hyperalgesia in patients with refractory OA-associated pain (n=62) reported significant correlations between PPT values at each listed site and VAS WOMAC pain and physical activity subscales and SF-36 bodily pain score
SKIN
SPINAL CORD
Dorsal horn
PRIMARY AFFERENT NERVE
Dorsal root ganglion
POSTSYNAPTIC PROCESSPRESYNAPTIC PROCESS
NMDA receptor
Ca2+ Second messengers
kinases (eg PKC) diacylglycerol cAMP
Gene transcription
P
CELL NUCLEUS
Long term changes
(receptor function transmitter production)
Glutamate release
C-fosoncogene
Cortical Reorganisation
I will show that my client is welltolerated amp effectivehelliphellip
I will showthat my clientis well tolerated and effective
bull For chronic pain most measures of treatment response involve patient- reported outcomes for which the patient is the most important judge of whether changes are important or meaningful12
ndash Determinations of statistical significance must be supplemented by consideration of the clinical importance of changes in outcome measures1
bull The IMMPACT consensus meeting proposed provisional benchmarks for identifying clinically important changes in the specific outcome measures for chronic pain clinical trials1
Using NNT Analyses in the Treatment of Pain IMMPACT Consensus Meeting Recommendations
NNT = number needed to treat IMMPACT = Initiative on Methods Measurement and Pain Assessment in Clinical Trials1 Dworkin RH et al J Pain 20089105ndash121 2 Acquadro C et al Value Health 20036522ndash531
10ndash20Reduction in pain intensity
ge50Reduction in pain intensity
ge30Reduction in pain intensity
Minimally Important Improvement
Moderately Important Improvement
Substantial Improvement
132
253
353638
4244
55788
1718
0 4 8 12 16 20
Oxycodone 5Codeine 60Tramadol 50Propoxyphene 65APAP 325Oxycodone 5ASA 650Codeine 60Tramadol 100APAP 650Propox 100APAP 1000APAP 600Cod 60Morphine 10APAP 1000Oxyc 10Ibuprofen 400Oxycodone 15
McQuay H BMJ 1997
Patients with 50 reduction Patients with 50 reduction in pain vs placeboin pain vs placebo
NNT
USE OF PARACETAMOL IN TREATMENT OF OA PAIN
22
How effective was paracetamol
How effective was paracetamol compared with NSAIDs
F Wolfe S Zhao N Lane Preference for nonsteroidal antiinflammatory drugs over acetaminophen by rheumatic disease patients Arthritis amp Rheumatism 2000 43 378-385
2007 League table of NNT for at least 50 pain relief over 4-6 hrs in patients with moderate to severe pain
(all oral analgesics except IM morphine )
[httpwwwmedicineoxacukbandolierboothpainpagacutrevanalgesicsleagtabhtml
ETORICOXIB IN ACUTE PAIN
bull Etoricoxib 120 mg has been approved for treating acute pain which includes post-operative pain and other acute pain such as primary dysmenorrhea and acute gouty arthritis
bull Efficacy of etoricoxib in the post-operative setting as evaluated by NNT bull COCHRANE REVIEW Five randomized placebo-controlled studies
with a total number of 880 patients were included -- Four studies on patients with dental pain following extraction of at least one impacted third molar
--One study on patients with pain following uncomplicated orthopaedic surgery
bull NNT were calculated to measure at least 50 pain relief over 4-6 hrs (substantial pain relief) based on TOPAR scores
Results 120 mg etoricoxib with a NNT of 19 for acute post-operative pain
1 Chang DJ Desjardins PJ King TR Erb T Geba GP The analgesic efficacy of etoricoxib compared with oxycodoneacetaminophen in an acute postoperative pain model a randomized double-blind clinical trial Anesthesia and Analgesia 200499(3)807ndash15
2 Malmstrom K Sapre A Couglin H Agrawal NG Mazenko RS Fricke JR Jr Etoricoxib in acute pain associated with dental surgery a randomized double-blind placebo- and active comparator-controlled dose-ranging study Clinical Therapeutics 200426(5)667ndash79
3 Malmstrom K Kotey P Coughlin H Desjardins PJ A randomized double-blind parallel-group study comparing the analgesic effect of etoricoxib to placebo naproxen sodium and acetaminophen with codeine using the dental impaction pain model Clinical Journal of Pain 200420(3)147ndash 55
4 Malmstrom K Ang J Fricke JR Shingo S Reicin A The analgesic effect of etoricoxib relative to that of cetaminophen analgesics a randomized controlled single-dose study in acute dental impaction pain Current Medical Research and Opinion 200521(1)141ndash9 Rasmussen 2005 published data only
5 Rasmussen GL Malmstrom K Bourne MH Jove M Rhondeau SM Kotey P Etoricoxib provides analgesic efficacy to patients after knee or hip replacement surgery a randomized double-blind placebo-controlled study Anaesthesia and Analgesia 2005101(4) 1104ndash11
Etoricoxib in acute pain bull Indirect comparisons of NNTs for at least 50 pain
relief over 4 to 6 hours in reviews of other analgesics using identical methods indicate that etoricoxib 120 mg
-- has slightly better efficacy than rofecoxib 50 mg (22 (19 to 24) Barden 2005)
-- is significantly better than lumiracoxib 400mg (27 (22 to 35) Roy 2007) or-- celecoxib 400 mg (25 (22 to 29) Derry 2008)
-- better than the non-selective NSAIDs ibuprofen 400 mg (27 (25 to 30) Collins 1999) naproxen 500 mg (27 (23 to 32 Derry 2009a) and diclofenac 50mg (24 (18 to 33Derry 2009b)
Placebo
Paracetamol 10007
Paracetamolcodeine 1000606
Ibuprofen 4005
Celecoxib 4004
Naproxen 5005503
Rofecoxib 502
Etoricoxib 1201
0 4 8 12 16 20 24Median remedication time (hr)
Each bar is from a Cochrane review
Acute pain Time for patients to Re-medication
The weighted median time to re-medication with ARCOXIA 120mg is about 24hrs
vs placebo at 18hrs
1 Clarke R et al Cochrane Database Syst Rev 2009 Apr 15(2)CD004309 2 Bulley S et al Cochrane Database Syst Rev 2009 Oct 7(4)CD0046043 Derry C et al Cochrane Database Syst Rev 2009 Jan 21(1)CD004234 4 Derry S Cochrane Database Syst Rev 2008 Oct 8(4)CD0042335 Derry C et al Cochrane Database Syst Rev 2009 Jul 8(3)CD0015486 Toms L et al Cochrane Database Syst Rev 2009 Jan 21(1)CD0015477 Toms L et al Cochrane Database Syst Rev 2008 Oct 8(4)CD004602
Placebo (n=56)
Etoricoxib 60 mg (n=224)
Naproxen 1000 mgc
(n=221)
a0-
to 100-mm VAS (0 = none to 100 = extreme)
b0-
to 100-mm VAS (0 = very well to 100 = very poor) c500 mg twice dailyPlt0001 vs placebo for both etoricoxib and naproxen P = NS etoricoxib vs naproxen
Leung AT et al Curr Med Res Opin 200218(2)49ndash58
LS M
ean
Cha
nge
plusmnSE
Weeks Postrandomization
Osteoarthritis Etoricoxib 60 mg vs Naproxen
Results Etoricoxib relieved pain and improved mobility and disease statuEtoricoxib relieved pain and improved mobility and disease statuss
ndash35
ndash25
ndash5
5
ndash15
WOMAC Pain Subscalea
S R 4 82 12
WOMAC Physical Function Subscalea PGADSb
ndash35
ndash25
ndash5
5
ndash15
S R 4 82 12ndash35
ndash25
ndash5
5
ndash15
S R 4 82 12Weeks Postrandomization Weeks Postrandomization
Adverse effects of NSAIDsAdverse effects of NSAIDs
BNF March 2002
Dose-dependent toxicityIntolerability dyspepsiaGI bleedingUlcers ndash bleeds perforations
Upper-GI
Renal
Contributes to blood loss
Fluid retention oedema hypertensionRenal dysfunction failure ndash acute chronicHeart failure
Anti-platelet effects
Angioedema bronchospasmHypersensitivity
No Short-Term Adverse GI Effects -
The Big Mistake
bull Study designed to evaluate short-term GI effects in elderly
bull Study planned to enrol 160 patientsbull Study terminated by investigator at 17 subjects
ndash 8 patients had ulcersndash 4 of 4 in ketorolac group
lsquo hellip because of the unexpectedly high incidence of gastroduodenal ulcers observedhelliprsquo
Harris et al ClinTher 2001231422
Class Effect of All NSAIDs
httpwwwfdagovcderdruginfopageCOX2NSAIDdecisionMemopdf
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
33
Cardiovascular Safetybull Arthritis patients often have concomitant CV
disease1
bull Pain is an important predictor of CV risk23
bull Randomized controlled trials and observational data demonstrate that CV risk of etoricoxib appears similar to that of traditional NSAIDs4-6
bull Recent data suggest that differential CV effects of NSAIDs (selective and nonselective) may be independent of COX-2 inhibition78
References 1 Singh G et al Am J Manag Care 20028(suppl)S383-S391 2
Sokka T Pincus T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 3
Pincus T Sokka T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 4
httpwwwfdagovohrmsdocketsac05slides2005-4090S1_06_01_Pfizer-celecoxibppt (accessed 14 February 2006) 5
White WB et al Am J Cardiol 200289425ndash430 6
Graham DJ et al Lancet 2005365475ndash481 7 Yang HM et al Circulation 2004110301ndash308 8 Steffel J et al Circulation 20051111685ndash1689
Events per 100 patient years
Coxib Coxib Placebo Coxib NSAID Percent naproxen
Rofecoxib 17 19 11 08 73
Celecoxib 13 15 11 11 20
Valdecoxib 13 12 13 20 about 50
Etoricoxib 13 12 12 08 67
Lumiracoxib 09 08 52
34
APTC endpoint (cardiovascular haemorrhagic and unknown death and nonfatal myocardial infarction and stroke)
1
MR Weir et al Selective COX-2 inhibition and cardiovascular effects a review of the rofecoxib development program American heart Journal 2003 146 591-604
2
WB White et al Cardiovascular thrombotic events in arthritis trials of the cyclooxygenase-2 inhibitor celecoxib American Journal of cardiology 2003 92 411-418
3
WB White et al Effects of the cyclooxygenase-2 specific inhibitor valdecoxib versus nonsteroidal anti-inflammatory agents and placebo on cardiovascular thrombotic events in patients with arthritis American Journal of Therapeutics 2004 11 244-250
4
S Curtis et al Cardiovascular safety summary associated with the etoricoxib development programme Arthritis amp Rheumatism 2003 48 Suppl S616
5
ME Farkouh et al Comparison of lumiracoxib with naproxen and ibuprofen in the therapeutic arthritis research and gastrointestinal event trial (TARGET) cardiovascular outcomes randomised controlled trial Lancet 2004 364 675-684
RECOMMENDATIONS
NSAIDs COXIBs
bull Use lowest effective dose shortest duration
bull Not for patients who have recently undergone coronary artery bypass graft (CABG) surgery and revascularisation procedures
bull Coxibs should not be prescribed for patients with established ischaemic heart disease stroke or congestive heart failure
bull Caution for Coxibs for patients who have hypertension hyperlipidaemia diabetes and smoking as well as peripheral arterial disease
bull Etoricoxib should not be prescribed for patients with hypertension whose blood pressure has not been adequately controlled
The EU Summit is supported by Pfizer
Tricyclic Agents
bull best documented analgesics here (NNT 22)bull amitriptyline best investigatedbull desipraminenortriptyline less AEs
bull start on low doses increases compliancebullOften adverse effects (NNH 28)bull effect needs timebull SSRIs not as effective (NNT 67)
bull noradrenergic effect necessarybull venlafaxine another option
Antidepressants Compared with Placebo
Condition Number of trials
Antidepressant improvedtotal
Placebo improvedtotal
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 13 180260 73205 19 (16 to
24)30 (24 to 40)
Postherpetic neuralgia 3 4377 868 48 (24 to
94)23 (17 to 33)
Atypical facial pain 2 6288 3085 20 (15 to
28)28 (20 to 47)
Central pain 1 1015 115 10 (15 to 69)
17 (11 to 30)
Bandolier
Anticonvulsants as Membrane Stabilisers
bull pregabalinbull gabapentin bull carbamazepinebull clonazepam pooled NNT 27bull valproatebull lamotriginebull baclofen
Anticonvulsants Compared with Placebo
Condition Number of trials
Anticonvulsant improvedtotal
Placebo improvedtot
al
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 3 5668 2668 19 (14 to 27) 25 (18
to 40)
Trigeminal neuralgia 3 178315 41224 31 (23 to 41) 26 (22
to 33)
Migraine prophylaxis 2 6374 1777 37 (24 to 59) 16 (13
to 20)
Other pain syndromes 1 514 115 54 (07 to 40)
not calculat ed
Bandolier
Relative Activity on Serotonin and Norepinephrine Reuptake Among
Antidepressants
CitalopramFluvoxamineSertralineParoxetineFluoxetine
VenlafaxineDuloxetine
MaprotilineDesipramineNortriptylineReboxetine
AmitriptylineMilnacipranImipramine
Serotonin Mixed Norepinephrine
Antidepressant Analgesic Antidepressant
Fishbain et al Pain Med 20001310-316
Opioidsbull In principle opioids are effective in nociceptive
and some neuropathic pain however not always and not necessarily completely for dynamic pain
bull Possibly preferable opioids here arendash tramadol
bull noradrenergic and serotoninergic effectndash morphine
bull Mu receptor anatagonistmonaminergic effect
ndash oxycodonebull kappa receptor effect
Opioids
bull lsquoLack of analgesic effect of opioids on neuropathic hellip painrsquo Pain 19883311
bull lsquohellip intravenous hellip morphine reduce the pain of Osteoarthritisrsquo Neurology
1991411024bull lsquoA call for more science not more
rhetoric regarding opioids and arthritic painrsquo Pain 2001471
bull lsquoEfficacy of oxycodone in neuropathic painhelliprsquo Neurology 1998501837
OPIOIDS FOR OA PAINbull Osteoarthritis guidelines provide limited guidance on opioid use bull The 1995 ACR guidelines for hip OA suggest opioids be avoided for
long term use but short term use may be helpful without reference to primary data15
bull The 1995 ACR knee OA guidelines do not discuss opioids directly16 bull The 1998 UK guidelines on degenerative arthritis suggest that if
relief is inadequate with 24 grams of ibuprofen and 40 grams of paracetamol a day other antiinflammatories or opioids may be considered18
bull The 2000 update of the ACR OA guidelines suggests that opioids might be used as a medication of last resort17
bull Opioids are effective in OA hip and knee pain and have predictable side effects
bull It would be unwise were physicians to discount an entire class of medications over unfounded fears and incomplete knowledge of their benefits44
USE OF ULTRACET IN OA KNEESbull The efficacy of tramadolacetaminophen combination tablets (Ultracetreg) as add-
on and maintenance therapy in knee osteoarthritis pain inadequately controlled by nonsteroidal anti-inflammatory drug (NSAID)
Park KS Choi JJ Kim WU Min JK Park SH Cho CS
bull TramadolAPAP add-on significantly improved knee OA pain which had been inadequately controlled by NSAIDs In those subjects who showed favorable response to tramadolAPAP and NSAID combination therapy both tramadolAPAP and NSAIDs were effective at maintaining the pain-reduced state and there was no significant difference in efficacy between tramadolAPAP and NSAIDs
Clinical Rheumatology 2011 3 Aug
Opioid Sparing Regimes
bull Multimodal analgesia (Kehlet et al 1999)
bull NSAIDs and COX-2 (Romsing Moiniche 2004)
bull Paracetamol (Romsing 2002)
bull Ketamine (Elia Tramer 2005)
bull Gabapentin and Pregabalin (Dahl et al 2004)
bull Gabapentin and Rofecoxib (Gilron et al 2005)
Opioid reduction 20 ndash 40 Reduction of PONV 30
Clinical effects
Single-modality treatment of a Multi- modality problem is
futile
ldquoTherersquos no pain thatrsquos so easy to bear than that of
someone elserdquo
ndashLeriche
Van Gogh ldquoOld Man in Sorrowrdquo
OA = osteoarthritis PPT = pressure pain threshold VAS = visual analog scale WOMAC = Western Ontario and McMaster Universities SF-36 = short form-36 health survey
Central Sensitization in OA Increased Pain Severity and Worse Pain-Associated
OutcomesImamura M et al Arthritis Rheum 2008591424ndash1431
Measure Spearmanrsquos rank correlation coefficient r P Value
VASPatellar tendon Sacral 2 subcutaneous dermatome levelAdductor longus muscle
-0545 -0546 -0561
lt0001 lt0001 lt0001
WOMAC painPatellar tendon Sacral 2 subcutaneous dermatome levelAdductor longus muscle
-0589-0601 -0540
lt0001 lt0001lt0001
WOMAC physical activityLumbar 2 subcutaneous dermatome level Sacral 2 subcutaneous dermatome level Peroneus longus muscle
-0550 -0509 -0571
lt0001lt0001 lt0001
SF-36 bodily painLumbar 1ndashLumbar 2 supraspinous ligamentLumbar 2 subcutaneous dermatome level Adductor longus muscle
0534 0606 0569
lt0001 lt0001 lt0001
A cross-sectional study that assessed hyperalgesia in patients with refractory OA-associated pain (n=62) reported significant correlations between PPT values at each listed site and VAS WOMAC pain and physical activity subscales and SF-36 bodily pain score
SKIN
SPINAL CORD
Dorsal horn
PRIMARY AFFERENT NERVE
Dorsal root ganglion
POSTSYNAPTIC PROCESSPRESYNAPTIC PROCESS
NMDA receptor
Ca2+ Second messengers
kinases (eg PKC) diacylglycerol cAMP
Gene transcription
P
CELL NUCLEUS
Long term changes
(receptor function transmitter production)
Glutamate release
C-fosoncogene
Cortical Reorganisation
I will show that my client is welltolerated amp effectivehelliphellip
I will showthat my clientis well tolerated and effective
bull For chronic pain most measures of treatment response involve patient- reported outcomes for which the patient is the most important judge of whether changes are important or meaningful12
ndash Determinations of statistical significance must be supplemented by consideration of the clinical importance of changes in outcome measures1
bull The IMMPACT consensus meeting proposed provisional benchmarks for identifying clinically important changes in the specific outcome measures for chronic pain clinical trials1
Using NNT Analyses in the Treatment of Pain IMMPACT Consensus Meeting Recommendations
NNT = number needed to treat IMMPACT = Initiative on Methods Measurement and Pain Assessment in Clinical Trials1 Dworkin RH et al J Pain 20089105ndash121 2 Acquadro C et al Value Health 20036522ndash531
10ndash20Reduction in pain intensity
ge50Reduction in pain intensity
ge30Reduction in pain intensity
Minimally Important Improvement
Moderately Important Improvement
Substantial Improvement
132
253
353638
4244
55788
1718
0 4 8 12 16 20
Oxycodone 5Codeine 60Tramadol 50Propoxyphene 65APAP 325Oxycodone 5ASA 650Codeine 60Tramadol 100APAP 650Propox 100APAP 1000APAP 600Cod 60Morphine 10APAP 1000Oxyc 10Ibuprofen 400Oxycodone 15
McQuay H BMJ 1997
Patients with 50 reduction Patients with 50 reduction in pain vs placeboin pain vs placebo
NNT
USE OF PARACETAMOL IN TREATMENT OF OA PAIN
22
How effective was paracetamol
How effective was paracetamol compared with NSAIDs
F Wolfe S Zhao N Lane Preference for nonsteroidal antiinflammatory drugs over acetaminophen by rheumatic disease patients Arthritis amp Rheumatism 2000 43 378-385
2007 League table of NNT for at least 50 pain relief over 4-6 hrs in patients with moderate to severe pain
(all oral analgesics except IM morphine )
[httpwwwmedicineoxacukbandolierboothpainpagacutrevanalgesicsleagtabhtml
ETORICOXIB IN ACUTE PAIN
bull Etoricoxib 120 mg has been approved for treating acute pain which includes post-operative pain and other acute pain such as primary dysmenorrhea and acute gouty arthritis
bull Efficacy of etoricoxib in the post-operative setting as evaluated by NNT bull COCHRANE REVIEW Five randomized placebo-controlled studies
with a total number of 880 patients were included -- Four studies on patients with dental pain following extraction of at least one impacted third molar
--One study on patients with pain following uncomplicated orthopaedic surgery
bull NNT were calculated to measure at least 50 pain relief over 4-6 hrs (substantial pain relief) based on TOPAR scores
Results 120 mg etoricoxib with a NNT of 19 for acute post-operative pain
1 Chang DJ Desjardins PJ King TR Erb T Geba GP The analgesic efficacy of etoricoxib compared with oxycodoneacetaminophen in an acute postoperative pain model a randomized double-blind clinical trial Anesthesia and Analgesia 200499(3)807ndash15
2 Malmstrom K Sapre A Couglin H Agrawal NG Mazenko RS Fricke JR Jr Etoricoxib in acute pain associated with dental surgery a randomized double-blind placebo- and active comparator-controlled dose-ranging study Clinical Therapeutics 200426(5)667ndash79
3 Malmstrom K Kotey P Coughlin H Desjardins PJ A randomized double-blind parallel-group study comparing the analgesic effect of etoricoxib to placebo naproxen sodium and acetaminophen with codeine using the dental impaction pain model Clinical Journal of Pain 200420(3)147ndash 55
4 Malmstrom K Ang J Fricke JR Shingo S Reicin A The analgesic effect of etoricoxib relative to that of cetaminophen analgesics a randomized controlled single-dose study in acute dental impaction pain Current Medical Research and Opinion 200521(1)141ndash9 Rasmussen 2005 published data only
5 Rasmussen GL Malmstrom K Bourne MH Jove M Rhondeau SM Kotey P Etoricoxib provides analgesic efficacy to patients after knee or hip replacement surgery a randomized double-blind placebo-controlled study Anaesthesia and Analgesia 2005101(4) 1104ndash11
Etoricoxib in acute pain bull Indirect comparisons of NNTs for at least 50 pain
relief over 4 to 6 hours in reviews of other analgesics using identical methods indicate that etoricoxib 120 mg
-- has slightly better efficacy than rofecoxib 50 mg (22 (19 to 24) Barden 2005)
-- is significantly better than lumiracoxib 400mg (27 (22 to 35) Roy 2007) or-- celecoxib 400 mg (25 (22 to 29) Derry 2008)
-- better than the non-selective NSAIDs ibuprofen 400 mg (27 (25 to 30) Collins 1999) naproxen 500 mg (27 (23 to 32 Derry 2009a) and diclofenac 50mg (24 (18 to 33Derry 2009b)
Placebo
Paracetamol 10007
Paracetamolcodeine 1000606
Ibuprofen 4005
Celecoxib 4004
Naproxen 5005503
Rofecoxib 502
Etoricoxib 1201
0 4 8 12 16 20 24Median remedication time (hr)
Each bar is from a Cochrane review
Acute pain Time for patients to Re-medication
The weighted median time to re-medication with ARCOXIA 120mg is about 24hrs
vs placebo at 18hrs
1 Clarke R et al Cochrane Database Syst Rev 2009 Apr 15(2)CD004309 2 Bulley S et al Cochrane Database Syst Rev 2009 Oct 7(4)CD0046043 Derry C et al Cochrane Database Syst Rev 2009 Jan 21(1)CD004234 4 Derry S Cochrane Database Syst Rev 2008 Oct 8(4)CD0042335 Derry C et al Cochrane Database Syst Rev 2009 Jul 8(3)CD0015486 Toms L et al Cochrane Database Syst Rev 2009 Jan 21(1)CD0015477 Toms L et al Cochrane Database Syst Rev 2008 Oct 8(4)CD004602
Placebo (n=56)
Etoricoxib 60 mg (n=224)
Naproxen 1000 mgc
(n=221)
a0-
to 100-mm VAS (0 = none to 100 = extreme)
b0-
to 100-mm VAS (0 = very well to 100 = very poor) c500 mg twice dailyPlt0001 vs placebo for both etoricoxib and naproxen P = NS etoricoxib vs naproxen
Leung AT et al Curr Med Res Opin 200218(2)49ndash58
LS M
ean
Cha
nge
plusmnSE
Weeks Postrandomization
Osteoarthritis Etoricoxib 60 mg vs Naproxen
Results Etoricoxib relieved pain and improved mobility and disease statuEtoricoxib relieved pain and improved mobility and disease statuss
ndash35
ndash25
ndash5
5
ndash15
WOMAC Pain Subscalea
S R 4 82 12
WOMAC Physical Function Subscalea PGADSb
ndash35
ndash25
ndash5
5
ndash15
S R 4 82 12ndash35
ndash25
ndash5
5
ndash15
S R 4 82 12Weeks Postrandomization Weeks Postrandomization
Adverse effects of NSAIDsAdverse effects of NSAIDs
BNF March 2002
Dose-dependent toxicityIntolerability dyspepsiaGI bleedingUlcers ndash bleeds perforations
Upper-GI
Renal
Contributes to blood loss
Fluid retention oedema hypertensionRenal dysfunction failure ndash acute chronicHeart failure
Anti-platelet effects
Angioedema bronchospasmHypersensitivity
No Short-Term Adverse GI Effects -
The Big Mistake
bull Study designed to evaluate short-term GI effects in elderly
bull Study planned to enrol 160 patientsbull Study terminated by investigator at 17 subjects
ndash 8 patients had ulcersndash 4 of 4 in ketorolac group
lsquo hellip because of the unexpectedly high incidence of gastroduodenal ulcers observedhelliprsquo
Harris et al ClinTher 2001231422
Class Effect of All NSAIDs
httpwwwfdagovcderdruginfopageCOX2NSAIDdecisionMemopdf
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
33
Cardiovascular Safetybull Arthritis patients often have concomitant CV
disease1
bull Pain is an important predictor of CV risk23
bull Randomized controlled trials and observational data demonstrate that CV risk of etoricoxib appears similar to that of traditional NSAIDs4-6
bull Recent data suggest that differential CV effects of NSAIDs (selective and nonselective) may be independent of COX-2 inhibition78
References 1 Singh G et al Am J Manag Care 20028(suppl)S383-S391 2
Sokka T Pincus T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 3
Pincus T Sokka T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 4
httpwwwfdagovohrmsdocketsac05slides2005-4090S1_06_01_Pfizer-celecoxibppt (accessed 14 February 2006) 5
White WB et al Am J Cardiol 200289425ndash430 6
Graham DJ et al Lancet 2005365475ndash481 7 Yang HM et al Circulation 2004110301ndash308 8 Steffel J et al Circulation 20051111685ndash1689
Events per 100 patient years
Coxib Coxib Placebo Coxib NSAID Percent naproxen
Rofecoxib 17 19 11 08 73
Celecoxib 13 15 11 11 20
Valdecoxib 13 12 13 20 about 50
Etoricoxib 13 12 12 08 67
Lumiracoxib 09 08 52
34
APTC endpoint (cardiovascular haemorrhagic and unknown death and nonfatal myocardial infarction and stroke)
1
MR Weir et al Selective COX-2 inhibition and cardiovascular effects a review of the rofecoxib development program American heart Journal 2003 146 591-604
2
WB White et al Cardiovascular thrombotic events in arthritis trials of the cyclooxygenase-2 inhibitor celecoxib American Journal of cardiology 2003 92 411-418
3
WB White et al Effects of the cyclooxygenase-2 specific inhibitor valdecoxib versus nonsteroidal anti-inflammatory agents and placebo on cardiovascular thrombotic events in patients with arthritis American Journal of Therapeutics 2004 11 244-250
4
S Curtis et al Cardiovascular safety summary associated with the etoricoxib development programme Arthritis amp Rheumatism 2003 48 Suppl S616
5
ME Farkouh et al Comparison of lumiracoxib with naproxen and ibuprofen in the therapeutic arthritis research and gastrointestinal event trial (TARGET) cardiovascular outcomes randomised controlled trial Lancet 2004 364 675-684
RECOMMENDATIONS
NSAIDs COXIBs
bull Use lowest effective dose shortest duration
bull Not for patients who have recently undergone coronary artery bypass graft (CABG) surgery and revascularisation procedures
bull Coxibs should not be prescribed for patients with established ischaemic heart disease stroke or congestive heart failure
bull Caution for Coxibs for patients who have hypertension hyperlipidaemia diabetes and smoking as well as peripheral arterial disease
bull Etoricoxib should not be prescribed for patients with hypertension whose blood pressure has not been adequately controlled
The EU Summit is supported by Pfizer
Tricyclic Agents
bull best documented analgesics here (NNT 22)bull amitriptyline best investigatedbull desipraminenortriptyline less AEs
bull start on low doses increases compliancebullOften adverse effects (NNH 28)bull effect needs timebull SSRIs not as effective (NNT 67)
bull noradrenergic effect necessarybull venlafaxine another option
Antidepressants Compared with Placebo
Condition Number of trials
Antidepressant improvedtotal
Placebo improvedtotal
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 13 180260 73205 19 (16 to
24)30 (24 to 40)
Postherpetic neuralgia 3 4377 868 48 (24 to
94)23 (17 to 33)
Atypical facial pain 2 6288 3085 20 (15 to
28)28 (20 to 47)
Central pain 1 1015 115 10 (15 to 69)
17 (11 to 30)
Bandolier
Anticonvulsants as Membrane Stabilisers
bull pregabalinbull gabapentin bull carbamazepinebull clonazepam pooled NNT 27bull valproatebull lamotriginebull baclofen
Anticonvulsants Compared with Placebo
Condition Number of trials
Anticonvulsant improvedtotal
Placebo improvedtot
al
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 3 5668 2668 19 (14 to 27) 25 (18
to 40)
Trigeminal neuralgia 3 178315 41224 31 (23 to 41) 26 (22
to 33)
Migraine prophylaxis 2 6374 1777 37 (24 to 59) 16 (13
to 20)
Other pain syndromes 1 514 115 54 (07 to 40)
not calculat ed
Bandolier
Relative Activity on Serotonin and Norepinephrine Reuptake Among
Antidepressants
CitalopramFluvoxamineSertralineParoxetineFluoxetine
VenlafaxineDuloxetine
MaprotilineDesipramineNortriptylineReboxetine
AmitriptylineMilnacipranImipramine
Serotonin Mixed Norepinephrine
Antidepressant Analgesic Antidepressant
Fishbain et al Pain Med 20001310-316
Opioidsbull In principle opioids are effective in nociceptive
and some neuropathic pain however not always and not necessarily completely for dynamic pain
bull Possibly preferable opioids here arendash tramadol
bull noradrenergic and serotoninergic effectndash morphine
bull Mu receptor anatagonistmonaminergic effect
ndash oxycodonebull kappa receptor effect
Opioids
bull lsquoLack of analgesic effect of opioids on neuropathic hellip painrsquo Pain 19883311
bull lsquohellip intravenous hellip morphine reduce the pain of Osteoarthritisrsquo Neurology
1991411024bull lsquoA call for more science not more
rhetoric regarding opioids and arthritic painrsquo Pain 2001471
bull lsquoEfficacy of oxycodone in neuropathic painhelliprsquo Neurology 1998501837
OPIOIDS FOR OA PAINbull Osteoarthritis guidelines provide limited guidance on opioid use bull The 1995 ACR guidelines for hip OA suggest opioids be avoided for
long term use but short term use may be helpful without reference to primary data15
bull The 1995 ACR knee OA guidelines do not discuss opioids directly16 bull The 1998 UK guidelines on degenerative arthritis suggest that if
relief is inadequate with 24 grams of ibuprofen and 40 grams of paracetamol a day other antiinflammatories or opioids may be considered18
bull The 2000 update of the ACR OA guidelines suggests that opioids might be used as a medication of last resort17
bull Opioids are effective in OA hip and knee pain and have predictable side effects
bull It would be unwise were physicians to discount an entire class of medications over unfounded fears and incomplete knowledge of their benefits44
USE OF ULTRACET IN OA KNEESbull The efficacy of tramadolacetaminophen combination tablets (Ultracetreg) as add-
on and maintenance therapy in knee osteoarthritis pain inadequately controlled by nonsteroidal anti-inflammatory drug (NSAID)
Park KS Choi JJ Kim WU Min JK Park SH Cho CS
bull TramadolAPAP add-on significantly improved knee OA pain which had been inadequately controlled by NSAIDs In those subjects who showed favorable response to tramadolAPAP and NSAID combination therapy both tramadolAPAP and NSAIDs were effective at maintaining the pain-reduced state and there was no significant difference in efficacy between tramadolAPAP and NSAIDs
Clinical Rheumatology 2011 3 Aug
Opioid Sparing Regimes
bull Multimodal analgesia (Kehlet et al 1999)
bull NSAIDs and COX-2 (Romsing Moiniche 2004)
bull Paracetamol (Romsing 2002)
bull Ketamine (Elia Tramer 2005)
bull Gabapentin and Pregabalin (Dahl et al 2004)
bull Gabapentin and Rofecoxib (Gilron et al 2005)
Opioid reduction 20 ndash 40 Reduction of PONV 30
Clinical effects
Single-modality treatment of a Multi- modality problem is
futile
ldquoTherersquos no pain thatrsquos so easy to bear than that of
someone elserdquo
ndashLeriche
Van Gogh ldquoOld Man in Sorrowrdquo
SKIN
SPINAL CORD
Dorsal horn
PRIMARY AFFERENT NERVE
Dorsal root ganglion
POSTSYNAPTIC PROCESSPRESYNAPTIC PROCESS
NMDA receptor
Ca2+ Second messengers
kinases (eg PKC) diacylglycerol cAMP
Gene transcription
P
CELL NUCLEUS
Long term changes
(receptor function transmitter production)
Glutamate release
C-fosoncogene
Cortical Reorganisation
I will show that my client is welltolerated amp effectivehelliphellip
I will showthat my clientis well tolerated and effective
bull For chronic pain most measures of treatment response involve patient- reported outcomes for which the patient is the most important judge of whether changes are important or meaningful12
ndash Determinations of statistical significance must be supplemented by consideration of the clinical importance of changes in outcome measures1
bull The IMMPACT consensus meeting proposed provisional benchmarks for identifying clinically important changes in the specific outcome measures for chronic pain clinical trials1
Using NNT Analyses in the Treatment of Pain IMMPACT Consensus Meeting Recommendations
NNT = number needed to treat IMMPACT = Initiative on Methods Measurement and Pain Assessment in Clinical Trials1 Dworkin RH et al J Pain 20089105ndash121 2 Acquadro C et al Value Health 20036522ndash531
10ndash20Reduction in pain intensity
ge50Reduction in pain intensity
ge30Reduction in pain intensity
Minimally Important Improvement
Moderately Important Improvement
Substantial Improvement
132
253
353638
4244
55788
1718
0 4 8 12 16 20
Oxycodone 5Codeine 60Tramadol 50Propoxyphene 65APAP 325Oxycodone 5ASA 650Codeine 60Tramadol 100APAP 650Propox 100APAP 1000APAP 600Cod 60Morphine 10APAP 1000Oxyc 10Ibuprofen 400Oxycodone 15
McQuay H BMJ 1997
Patients with 50 reduction Patients with 50 reduction in pain vs placeboin pain vs placebo
NNT
USE OF PARACETAMOL IN TREATMENT OF OA PAIN
22
How effective was paracetamol
How effective was paracetamol compared with NSAIDs
F Wolfe S Zhao N Lane Preference for nonsteroidal antiinflammatory drugs over acetaminophen by rheumatic disease patients Arthritis amp Rheumatism 2000 43 378-385
2007 League table of NNT for at least 50 pain relief over 4-6 hrs in patients with moderate to severe pain
(all oral analgesics except IM morphine )
[httpwwwmedicineoxacukbandolierboothpainpagacutrevanalgesicsleagtabhtml
ETORICOXIB IN ACUTE PAIN
bull Etoricoxib 120 mg has been approved for treating acute pain which includes post-operative pain and other acute pain such as primary dysmenorrhea and acute gouty arthritis
bull Efficacy of etoricoxib in the post-operative setting as evaluated by NNT bull COCHRANE REVIEW Five randomized placebo-controlled studies
with a total number of 880 patients were included -- Four studies on patients with dental pain following extraction of at least one impacted third molar
--One study on patients with pain following uncomplicated orthopaedic surgery
bull NNT were calculated to measure at least 50 pain relief over 4-6 hrs (substantial pain relief) based on TOPAR scores
Results 120 mg etoricoxib with a NNT of 19 for acute post-operative pain
1 Chang DJ Desjardins PJ King TR Erb T Geba GP The analgesic efficacy of etoricoxib compared with oxycodoneacetaminophen in an acute postoperative pain model a randomized double-blind clinical trial Anesthesia and Analgesia 200499(3)807ndash15
2 Malmstrom K Sapre A Couglin H Agrawal NG Mazenko RS Fricke JR Jr Etoricoxib in acute pain associated with dental surgery a randomized double-blind placebo- and active comparator-controlled dose-ranging study Clinical Therapeutics 200426(5)667ndash79
3 Malmstrom K Kotey P Coughlin H Desjardins PJ A randomized double-blind parallel-group study comparing the analgesic effect of etoricoxib to placebo naproxen sodium and acetaminophen with codeine using the dental impaction pain model Clinical Journal of Pain 200420(3)147ndash 55
4 Malmstrom K Ang J Fricke JR Shingo S Reicin A The analgesic effect of etoricoxib relative to that of cetaminophen analgesics a randomized controlled single-dose study in acute dental impaction pain Current Medical Research and Opinion 200521(1)141ndash9 Rasmussen 2005 published data only
5 Rasmussen GL Malmstrom K Bourne MH Jove M Rhondeau SM Kotey P Etoricoxib provides analgesic efficacy to patients after knee or hip replacement surgery a randomized double-blind placebo-controlled study Anaesthesia and Analgesia 2005101(4) 1104ndash11
Etoricoxib in acute pain bull Indirect comparisons of NNTs for at least 50 pain
relief over 4 to 6 hours in reviews of other analgesics using identical methods indicate that etoricoxib 120 mg
-- has slightly better efficacy than rofecoxib 50 mg (22 (19 to 24) Barden 2005)
-- is significantly better than lumiracoxib 400mg (27 (22 to 35) Roy 2007) or-- celecoxib 400 mg (25 (22 to 29) Derry 2008)
-- better than the non-selective NSAIDs ibuprofen 400 mg (27 (25 to 30) Collins 1999) naproxen 500 mg (27 (23 to 32 Derry 2009a) and diclofenac 50mg (24 (18 to 33Derry 2009b)
Placebo
Paracetamol 10007
Paracetamolcodeine 1000606
Ibuprofen 4005
Celecoxib 4004
Naproxen 5005503
Rofecoxib 502
Etoricoxib 1201
0 4 8 12 16 20 24Median remedication time (hr)
Each bar is from a Cochrane review
Acute pain Time for patients to Re-medication
The weighted median time to re-medication with ARCOXIA 120mg is about 24hrs
vs placebo at 18hrs
1 Clarke R et al Cochrane Database Syst Rev 2009 Apr 15(2)CD004309 2 Bulley S et al Cochrane Database Syst Rev 2009 Oct 7(4)CD0046043 Derry C et al Cochrane Database Syst Rev 2009 Jan 21(1)CD004234 4 Derry S Cochrane Database Syst Rev 2008 Oct 8(4)CD0042335 Derry C et al Cochrane Database Syst Rev 2009 Jul 8(3)CD0015486 Toms L et al Cochrane Database Syst Rev 2009 Jan 21(1)CD0015477 Toms L et al Cochrane Database Syst Rev 2008 Oct 8(4)CD004602
Placebo (n=56)
Etoricoxib 60 mg (n=224)
Naproxen 1000 mgc
(n=221)
a0-
to 100-mm VAS (0 = none to 100 = extreme)
b0-
to 100-mm VAS (0 = very well to 100 = very poor) c500 mg twice dailyPlt0001 vs placebo for both etoricoxib and naproxen P = NS etoricoxib vs naproxen
Leung AT et al Curr Med Res Opin 200218(2)49ndash58
LS M
ean
Cha
nge
plusmnSE
Weeks Postrandomization
Osteoarthritis Etoricoxib 60 mg vs Naproxen
Results Etoricoxib relieved pain and improved mobility and disease statuEtoricoxib relieved pain and improved mobility and disease statuss
ndash35
ndash25
ndash5
5
ndash15
WOMAC Pain Subscalea
S R 4 82 12
WOMAC Physical Function Subscalea PGADSb
ndash35
ndash25
ndash5
5
ndash15
S R 4 82 12ndash35
ndash25
ndash5
5
ndash15
S R 4 82 12Weeks Postrandomization Weeks Postrandomization
Adverse effects of NSAIDsAdverse effects of NSAIDs
BNF March 2002
Dose-dependent toxicityIntolerability dyspepsiaGI bleedingUlcers ndash bleeds perforations
Upper-GI
Renal
Contributes to blood loss
Fluid retention oedema hypertensionRenal dysfunction failure ndash acute chronicHeart failure
Anti-platelet effects
Angioedema bronchospasmHypersensitivity
No Short-Term Adverse GI Effects -
The Big Mistake
bull Study designed to evaluate short-term GI effects in elderly
bull Study planned to enrol 160 patientsbull Study terminated by investigator at 17 subjects
ndash 8 patients had ulcersndash 4 of 4 in ketorolac group
lsquo hellip because of the unexpectedly high incidence of gastroduodenal ulcers observedhelliprsquo
Harris et al ClinTher 2001231422
Class Effect of All NSAIDs
httpwwwfdagovcderdruginfopageCOX2NSAIDdecisionMemopdf
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
33
Cardiovascular Safetybull Arthritis patients often have concomitant CV
disease1
bull Pain is an important predictor of CV risk23
bull Randomized controlled trials and observational data demonstrate that CV risk of etoricoxib appears similar to that of traditional NSAIDs4-6
bull Recent data suggest that differential CV effects of NSAIDs (selective and nonselective) may be independent of COX-2 inhibition78
References 1 Singh G et al Am J Manag Care 20028(suppl)S383-S391 2
Sokka T Pincus T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 3
Pincus T Sokka T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 4
httpwwwfdagovohrmsdocketsac05slides2005-4090S1_06_01_Pfizer-celecoxibppt (accessed 14 February 2006) 5
White WB et al Am J Cardiol 200289425ndash430 6
Graham DJ et al Lancet 2005365475ndash481 7 Yang HM et al Circulation 2004110301ndash308 8 Steffel J et al Circulation 20051111685ndash1689
Events per 100 patient years
Coxib Coxib Placebo Coxib NSAID Percent naproxen
Rofecoxib 17 19 11 08 73
Celecoxib 13 15 11 11 20
Valdecoxib 13 12 13 20 about 50
Etoricoxib 13 12 12 08 67
Lumiracoxib 09 08 52
34
APTC endpoint (cardiovascular haemorrhagic and unknown death and nonfatal myocardial infarction and stroke)
1
MR Weir et al Selective COX-2 inhibition and cardiovascular effects a review of the rofecoxib development program American heart Journal 2003 146 591-604
2
WB White et al Cardiovascular thrombotic events in arthritis trials of the cyclooxygenase-2 inhibitor celecoxib American Journal of cardiology 2003 92 411-418
3
WB White et al Effects of the cyclooxygenase-2 specific inhibitor valdecoxib versus nonsteroidal anti-inflammatory agents and placebo on cardiovascular thrombotic events in patients with arthritis American Journal of Therapeutics 2004 11 244-250
4
S Curtis et al Cardiovascular safety summary associated with the etoricoxib development programme Arthritis amp Rheumatism 2003 48 Suppl S616
5
ME Farkouh et al Comparison of lumiracoxib with naproxen and ibuprofen in the therapeutic arthritis research and gastrointestinal event trial (TARGET) cardiovascular outcomes randomised controlled trial Lancet 2004 364 675-684
RECOMMENDATIONS
NSAIDs COXIBs
bull Use lowest effective dose shortest duration
bull Not for patients who have recently undergone coronary artery bypass graft (CABG) surgery and revascularisation procedures
bull Coxibs should not be prescribed for patients with established ischaemic heart disease stroke or congestive heart failure
bull Caution for Coxibs for patients who have hypertension hyperlipidaemia diabetes and smoking as well as peripheral arterial disease
bull Etoricoxib should not be prescribed for patients with hypertension whose blood pressure has not been adequately controlled
The EU Summit is supported by Pfizer
Tricyclic Agents
bull best documented analgesics here (NNT 22)bull amitriptyline best investigatedbull desipraminenortriptyline less AEs
bull start on low doses increases compliancebullOften adverse effects (NNH 28)bull effect needs timebull SSRIs not as effective (NNT 67)
bull noradrenergic effect necessarybull venlafaxine another option
Antidepressants Compared with Placebo
Condition Number of trials
Antidepressant improvedtotal
Placebo improvedtotal
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 13 180260 73205 19 (16 to
24)30 (24 to 40)
Postherpetic neuralgia 3 4377 868 48 (24 to
94)23 (17 to 33)
Atypical facial pain 2 6288 3085 20 (15 to
28)28 (20 to 47)
Central pain 1 1015 115 10 (15 to 69)
17 (11 to 30)
Bandolier
Anticonvulsants as Membrane Stabilisers
bull pregabalinbull gabapentin bull carbamazepinebull clonazepam pooled NNT 27bull valproatebull lamotriginebull baclofen
Anticonvulsants Compared with Placebo
Condition Number of trials
Anticonvulsant improvedtotal
Placebo improvedtot
al
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 3 5668 2668 19 (14 to 27) 25 (18
to 40)
Trigeminal neuralgia 3 178315 41224 31 (23 to 41) 26 (22
to 33)
Migraine prophylaxis 2 6374 1777 37 (24 to 59) 16 (13
to 20)
Other pain syndromes 1 514 115 54 (07 to 40)
not calculat ed
Bandolier
Relative Activity on Serotonin and Norepinephrine Reuptake Among
Antidepressants
CitalopramFluvoxamineSertralineParoxetineFluoxetine
VenlafaxineDuloxetine
MaprotilineDesipramineNortriptylineReboxetine
AmitriptylineMilnacipranImipramine
Serotonin Mixed Norepinephrine
Antidepressant Analgesic Antidepressant
Fishbain et al Pain Med 20001310-316
Opioidsbull In principle opioids are effective in nociceptive
and some neuropathic pain however not always and not necessarily completely for dynamic pain
bull Possibly preferable opioids here arendash tramadol
bull noradrenergic and serotoninergic effectndash morphine
bull Mu receptor anatagonistmonaminergic effect
ndash oxycodonebull kappa receptor effect
Opioids
bull lsquoLack of analgesic effect of opioids on neuropathic hellip painrsquo Pain 19883311
bull lsquohellip intravenous hellip morphine reduce the pain of Osteoarthritisrsquo Neurology
1991411024bull lsquoA call for more science not more
rhetoric regarding opioids and arthritic painrsquo Pain 2001471
bull lsquoEfficacy of oxycodone in neuropathic painhelliprsquo Neurology 1998501837
OPIOIDS FOR OA PAINbull Osteoarthritis guidelines provide limited guidance on opioid use bull The 1995 ACR guidelines for hip OA suggest opioids be avoided for
long term use but short term use may be helpful without reference to primary data15
bull The 1995 ACR knee OA guidelines do not discuss opioids directly16 bull The 1998 UK guidelines on degenerative arthritis suggest that if
relief is inadequate with 24 grams of ibuprofen and 40 grams of paracetamol a day other antiinflammatories or opioids may be considered18
bull The 2000 update of the ACR OA guidelines suggests that opioids might be used as a medication of last resort17
bull Opioids are effective in OA hip and knee pain and have predictable side effects
bull It would be unwise were physicians to discount an entire class of medications over unfounded fears and incomplete knowledge of their benefits44
USE OF ULTRACET IN OA KNEESbull The efficacy of tramadolacetaminophen combination tablets (Ultracetreg) as add-
on and maintenance therapy in knee osteoarthritis pain inadequately controlled by nonsteroidal anti-inflammatory drug (NSAID)
Park KS Choi JJ Kim WU Min JK Park SH Cho CS
bull TramadolAPAP add-on significantly improved knee OA pain which had been inadequately controlled by NSAIDs In those subjects who showed favorable response to tramadolAPAP and NSAID combination therapy both tramadolAPAP and NSAIDs were effective at maintaining the pain-reduced state and there was no significant difference in efficacy between tramadolAPAP and NSAIDs
Clinical Rheumatology 2011 3 Aug
Opioid Sparing Regimes
bull Multimodal analgesia (Kehlet et al 1999)
bull NSAIDs and COX-2 (Romsing Moiniche 2004)
bull Paracetamol (Romsing 2002)
bull Ketamine (Elia Tramer 2005)
bull Gabapentin and Pregabalin (Dahl et al 2004)
bull Gabapentin and Rofecoxib (Gilron et al 2005)
Opioid reduction 20 ndash 40 Reduction of PONV 30
Clinical effects
Single-modality treatment of a Multi- modality problem is
futile
ldquoTherersquos no pain thatrsquos so easy to bear than that of
someone elserdquo
ndashLeriche
Van Gogh ldquoOld Man in Sorrowrdquo
POSTSYNAPTIC PROCESSPRESYNAPTIC PROCESS
NMDA receptor
Ca2+ Second messengers
kinases (eg PKC) diacylglycerol cAMP
Gene transcription
P
CELL NUCLEUS
Long term changes
(receptor function transmitter production)
Glutamate release
C-fosoncogene
Cortical Reorganisation
I will show that my client is welltolerated amp effectivehelliphellip
I will showthat my clientis well tolerated and effective
bull For chronic pain most measures of treatment response involve patient- reported outcomes for which the patient is the most important judge of whether changes are important or meaningful12
ndash Determinations of statistical significance must be supplemented by consideration of the clinical importance of changes in outcome measures1
bull The IMMPACT consensus meeting proposed provisional benchmarks for identifying clinically important changes in the specific outcome measures for chronic pain clinical trials1
Using NNT Analyses in the Treatment of Pain IMMPACT Consensus Meeting Recommendations
NNT = number needed to treat IMMPACT = Initiative on Methods Measurement and Pain Assessment in Clinical Trials1 Dworkin RH et al J Pain 20089105ndash121 2 Acquadro C et al Value Health 20036522ndash531
10ndash20Reduction in pain intensity
ge50Reduction in pain intensity
ge30Reduction in pain intensity
Minimally Important Improvement
Moderately Important Improvement
Substantial Improvement
132
253
353638
4244
55788
1718
0 4 8 12 16 20
Oxycodone 5Codeine 60Tramadol 50Propoxyphene 65APAP 325Oxycodone 5ASA 650Codeine 60Tramadol 100APAP 650Propox 100APAP 1000APAP 600Cod 60Morphine 10APAP 1000Oxyc 10Ibuprofen 400Oxycodone 15
McQuay H BMJ 1997
Patients with 50 reduction Patients with 50 reduction in pain vs placeboin pain vs placebo
NNT
USE OF PARACETAMOL IN TREATMENT OF OA PAIN
22
How effective was paracetamol
How effective was paracetamol compared with NSAIDs
F Wolfe S Zhao N Lane Preference for nonsteroidal antiinflammatory drugs over acetaminophen by rheumatic disease patients Arthritis amp Rheumatism 2000 43 378-385
2007 League table of NNT for at least 50 pain relief over 4-6 hrs in patients with moderate to severe pain
(all oral analgesics except IM morphine )
[httpwwwmedicineoxacukbandolierboothpainpagacutrevanalgesicsleagtabhtml
ETORICOXIB IN ACUTE PAIN
bull Etoricoxib 120 mg has been approved for treating acute pain which includes post-operative pain and other acute pain such as primary dysmenorrhea and acute gouty arthritis
bull Efficacy of etoricoxib in the post-operative setting as evaluated by NNT bull COCHRANE REVIEW Five randomized placebo-controlled studies
with a total number of 880 patients were included -- Four studies on patients with dental pain following extraction of at least one impacted third molar
--One study on patients with pain following uncomplicated orthopaedic surgery
bull NNT were calculated to measure at least 50 pain relief over 4-6 hrs (substantial pain relief) based on TOPAR scores
Results 120 mg etoricoxib with a NNT of 19 for acute post-operative pain
1 Chang DJ Desjardins PJ King TR Erb T Geba GP The analgesic efficacy of etoricoxib compared with oxycodoneacetaminophen in an acute postoperative pain model a randomized double-blind clinical trial Anesthesia and Analgesia 200499(3)807ndash15
2 Malmstrom K Sapre A Couglin H Agrawal NG Mazenko RS Fricke JR Jr Etoricoxib in acute pain associated with dental surgery a randomized double-blind placebo- and active comparator-controlled dose-ranging study Clinical Therapeutics 200426(5)667ndash79
3 Malmstrom K Kotey P Coughlin H Desjardins PJ A randomized double-blind parallel-group study comparing the analgesic effect of etoricoxib to placebo naproxen sodium and acetaminophen with codeine using the dental impaction pain model Clinical Journal of Pain 200420(3)147ndash 55
4 Malmstrom K Ang J Fricke JR Shingo S Reicin A The analgesic effect of etoricoxib relative to that of cetaminophen analgesics a randomized controlled single-dose study in acute dental impaction pain Current Medical Research and Opinion 200521(1)141ndash9 Rasmussen 2005 published data only
5 Rasmussen GL Malmstrom K Bourne MH Jove M Rhondeau SM Kotey P Etoricoxib provides analgesic efficacy to patients after knee or hip replacement surgery a randomized double-blind placebo-controlled study Anaesthesia and Analgesia 2005101(4) 1104ndash11
Etoricoxib in acute pain bull Indirect comparisons of NNTs for at least 50 pain
relief over 4 to 6 hours in reviews of other analgesics using identical methods indicate that etoricoxib 120 mg
-- has slightly better efficacy than rofecoxib 50 mg (22 (19 to 24) Barden 2005)
-- is significantly better than lumiracoxib 400mg (27 (22 to 35) Roy 2007) or-- celecoxib 400 mg (25 (22 to 29) Derry 2008)
-- better than the non-selective NSAIDs ibuprofen 400 mg (27 (25 to 30) Collins 1999) naproxen 500 mg (27 (23 to 32 Derry 2009a) and diclofenac 50mg (24 (18 to 33Derry 2009b)
Placebo
Paracetamol 10007
Paracetamolcodeine 1000606
Ibuprofen 4005
Celecoxib 4004
Naproxen 5005503
Rofecoxib 502
Etoricoxib 1201
0 4 8 12 16 20 24Median remedication time (hr)
Each bar is from a Cochrane review
Acute pain Time for patients to Re-medication
The weighted median time to re-medication with ARCOXIA 120mg is about 24hrs
vs placebo at 18hrs
1 Clarke R et al Cochrane Database Syst Rev 2009 Apr 15(2)CD004309 2 Bulley S et al Cochrane Database Syst Rev 2009 Oct 7(4)CD0046043 Derry C et al Cochrane Database Syst Rev 2009 Jan 21(1)CD004234 4 Derry S Cochrane Database Syst Rev 2008 Oct 8(4)CD0042335 Derry C et al Cochrane Database Syst Rev 2009 Jul 8(3)CD0015486 Toms L et al Cochrane Database Syst Rev 2009 Jan 21(1)CD0015477 Toms L et al Cochrane Database Syst Rev 2008 Oct 8(4)CD004602
Placebo (n=56)
Etoricoxib 60 mg (n=224)
Naproxen 1000 mgc
(n=221)
a0-
to 100-mm VAS (0 = none to 100 = extreme)
b0-
to 100-mm VAS (0 = very well to 100 = very poor) c500 mg twice dailyPlt0001 vs placebo for both etoricoxib and naproxen P = NS etoricoxib vs naproxen
Leung AT et al Curr Med Res Opin 200218(2)49ndash58
LS M
ean
Cha
nge
plusmnSE
Weeks Postrandomization
Osteoarthritis Etoricoxib 60 mg vs Naproxen
Results Etoricoxib relieved pain and improved mobility and disease statuEtoricoxib relieved pain and improved mobility and disease statuss
ndash35
ndash25
ndash5
5
ndash15
WOMAC Pain Subscalea
S R 4 82 12
WOMAC Physical Function Subscalea PGADSb
ndash35
ndash25
ndash5
5
ndash15
S R 4 82 12ndash35
ndash25
ndash5
5
ndash15
S R 4 82 12Weeks Postrandomization Weeks Postrandomization
Adverse effects of NSAIDsAdverse effects of NSAIDs
BNF March 2002
Dose-dependent toxicityIntolerability dyspepsiaGI bleedingUlcers ndash bleeds perforations
Upper-GI
Renal
Contributes to blood loss
Fluid retention oedema hypertensionRenal dysfunction failure ndash acute chronicHeart failure
Anti-platelet effects
Angioedema bronchospasmHypersensitivity
No Short-Term Adverse GI Effects -
The Big Mistake
bull Study designed to evaluate short-term GI effects in elderly
bull Study planned to enrol 160 patientsbull Study terminated by investigator at 17 subjects
ndash 8 patients had ulcersndash 4 of 4 in ketorolac group
lsquo hellip because of the unexpectedly high incidence of gastroduodenal ulcers observedhelliprsquo
Harris et al ClinTher 2001231422
Class Effect of All NSAIDs
httpwwwfdagovcderdruginfopageCOX2NSAIDdecisionMemopdf
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
33
Cardiovascular Safetybull Arthritis patients often have concomitant CV
disease1
bull Pain is an important predictor of CV risk23
bull Randomized controlled trials and observational data demonstrate that CV risk of etoricoxib appears similar to that of traditional NSAIDs4-6
bull Recent data suggest that differential CV effects of NSAIDs (selective and nonselective) may be independent of COX-2 inhibition78
References 1 Singh G et al Am J Manag Care 20028(suppl)S383-S391 2
Sokka T Pincus T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 3
Pincus T Sokka T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 4
httpwwwfdagovohrmsdocketsac05slides2005-4090S1_06_01_Pfizer-celecoxibppt (accessed 14 February 2006) 5
White WB et al Am J Cardiol 200289425ndash430 6
Graham DJ et al Lancet 2005365475ndash481 7 Yang HM et al Circulation 2004110301ndash308 8 Steffel J et al Circulation 20051111685ndash1689
Events per 100 patient years
Coxib Coxib Placebo Coxib NSAID Percent naproxen
Rofecoxib 17 19 11 08 73
Celecoxib 13 15 11 11 20
Valdecoxib 13 12 13 20 about 50
Etoricoxib 13 12 12 08 67
Lumiracoxib 09 08 52
34
APTC endpoint (cardiovascular haemorrhagic and unknown death and nonfatal myocardial infarction and stroke)
1
MR Weir et al Selective COX-2 inhibition and cardiovascular effects a review of the rofecoxib development program American heart Journal 2003 146 591-604
2
WB White et al Cardiovascular thrombotic events in arthritis trials of the cyclooxygenase-2 inhibitor celecoxib American Journal of cardiology 2003 92 411-418
3
WB White et al Effects of the cyclooxygenase-2 specific inhibitor valdecoxib versus nonsteroidal anti-inflammatory agents and placebo on cardiovascular thrombotic events in patients with arthritis American Journal of Therapeutics 2004 11 244-250
4
S Curtis et al Cardiovascular safety summary associated with the etoricoxib development programme Arthritis amp Rheumatism 2003 48 Suppl S616
5
ME Farkouh et al Comparison of lumiracoxib with naproxen and ibuprofen in the therapeutic arthritis research and gastrointestinal event trial (TARGET) cardiovascular outcomes randomised controlled trial Lancet 2004 364 675-684
RECOMMENDATIONS
NSAIDs COXIBs
bull Use lowest effective dose shortest duration
bull Not for patients who have recently undergone coronary artery bypass graft (CABG) surgery and revascularisation procedures
bull Coxibs should not be prescribed for patients with established ischaemic heart disease stroke or congestive heart failure
bull Caution for Coxibs for patients who have hypertension hyperlipidaemia diabetes and smoking as well as peripheral arterial disease
bull Etoricoxib should not be prescribed for patients with hypertension whose blood pressure has not been adequately controlled
The EU Summit is supported by Pfizer
Tricyclic Agents
bull best documented analgesics here (NNT 22)bull amitriptyline best investigatedbull desipraminenortriptyline less AEs
bull start on low doses increases compliancebullOften adverse effects (NNH 28)bull effect needs timebull SSRIs not as effective (NNT 67)
bull noradrenergic effect necessarybull venlafaxine another option
Antidepressants Compared with Placebo
Condition Number of trials
Antidepressant improvedtotal
Placebo improvedtotal
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 13 180260 73205 19 (16 to
24)30 (24 to 40)
Postherpetic neuralgia 3 4377 868 48 (24 to
94)23 (17 to 33)
Atypical facial pain 2 6288 3085 20 (15 to
28)28 (20 to 47)
Central pain 1 1015 115 10 (15 to 69)
17 (11 to 30)
Bandolier
Anticonvulsants as Membrane Stabilisers
bull pregabalinbull gabapentin bull carbamazepinebull clonazepam pooled NNT 27bull valproatebull lamotriginebull baclofen
Anticonvulsants Compared with Placebo
Condition Number of trials
Anticonvulsant improvedtotal
Placebo improvedtot
al
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 3 5668 2668 19 (14 to 27) 25 (18
to 40)
Trigeminal neuralgia 3 178315 41224 31 (23 to 41) 26 (22
to 33)
Migraine prophylaxis 2 6374 1777 37 (24 to 59) 16 (13
to 20)
Other pain syndromes 1 514 115 54 (07 to 40)
not calculat ed
Bandolier
Relative Activity on Serotonin and Norepinephrine Reuptake Among
Antidepressants
CitalopramFluvoxamineSertralineParoxetineFluoxetine
VenlafaxineDuloxetine
MaprotilineDesipramineNortriptylineReboxetine
AmitriptylineMilnacipranImipramine
Serotonin Mixed Norepinephrine
Antidepressant Analgesic Antidepressant
Fishbain et al Pain Med 20001310-316
Opioidsbull In principle opioids are effective in nociceptive
and some neuropathic pain however not always and not necessarily completely for dynamic pain
bull Possibly preferable opioids here arendash tramadol
bull noradrenergic and serotoninergic effectndash morphine
bull Mu receptor anatagonistmonaminergic effect
ndash oxycodonebull kappa receptor effect
Opioids
bull lsquoLack of analgesic effect of opioids on neuropathic hellip painrsquo Pain 19883311
bull lsquohellip intravenous hellip morphine reduce the pain of Osteoarthritisrsquo Neurology
1991411024bull lsquoA call for more science not more
rhetoric regarding opioids and arthritic painrsquo Pain 2001471
bull lsquoEfficacy of oxycodone in neuropathic painhelliprsquo Neurology 1998501837
OPIOIDS FOR OA PAINbull Osteoarthritis guidelines provide limited guidance on opioid use bull The 1995 ACR guidelines for hip OA suggest opioids be avoided for
long term use but short term use may be helpful without reference to primary data15
bull The 1995 ACR knee OA guidelines do not discuss opioids directly16 bull The 1998 UK guidelines on degenerative arthritis suggest that if
relief is inadequate with 24 grams of ibuprofen and 40 grams of paracetamol a day other antiinflammatories or opioids may be considered18
bull The 2000 update of the ACR OA guidelines suggests that opioids might be used as a medication of last resort17
bull Opioids are effective in OA hip and knee pain and have predictable side effects
bull It would be unwise were physicians to discount an entire class of medications over unfounded fears and incomplete knowledge of their benefits44
USE OF ULTRACET IN OA KNEESbull The efficacy of tramadolacetaminophen combination tablets (Ultracetreg) as add-
on and maintenance therapy in knee osteoarthritis pain inadequately controlled by nonsteroidal anti-inflammatory drug (NSAID)
Park KS Choi JJ Kim WU Min JK Park SH Cho CS
bull TramadolAPAP add-on significantly improved knee OA pain which had been inadequately controlled by NSAIDs In those subjects who showed favorable response to tramadolAPAP and NSAID combination therapy both tramadolAPAP and NSAIDs were effective at maintaining the pain-reduced state and there was no significant difference in efficacy between tramadolAPAP and NSAIDs
Clinical Rheumatology 2011 3 Aug
Opioid Sparing Regimes
bull Multimodal analgesia (Kehlet et al 1999)
bull NSAIDs and COX-2 (Romsing Moiniche 2004)
bull Paracetamol (Romsing 2002)
bull Ketamine (Elia Tramer 2005)
bull Gabapentin and Pregabalin (Dahl et al 2004)
bull Gabapentin and Rofecoxib (Gilron et al 2005)
Opioid reduction 20 ndash 40 Reduction of PONV 30
Clinical effects
Single-modality treatment of a Multi- modality problem is
futile
ldquoTherersquos no pain thatrsquos so easy to bear than that of
someone elserdquo
ndashLeriche
Van Gogh ldquoOld Man in Sorrowrdquo
Cortical Reorganisation
I will show that my client is welltolerated amp effectivehelliphellip
I will showthat my clientis well tolerated and effective
bull For chronic pain most measures of treatment response involve patient- reported outcomes for which the patient is the most important judge of whether changes are important or meaningful12
ndash Determinations of statistical significance must be supplemented by consideration of the clinical importance of changes in outcome measures1
bull The IMMPACT consensus meeting proposed provisional benchmarks for identifying clinically important changes in the specific outcome measures for chronic pain clinical trials1
Using NNT Analyses in the Treatment of Pain IMMPACT Consensus Meeting Recommendations
NNT = number needed to treat IMMPACT = Initiative on Methods Measurement and Pain Assessment in Clinical Trials1 Dworkin RH et al J Pain 20089105ndash121 2 Acquadro C et al Value Health 20036522ndash531
10ndash20Reduction in pain intensity
ge50Reduction in pain intensity
ge30Reduction in pain intensity
Minimally Important Improvement
Moderately Important Improvement
Substantial Improvement
132
253
353638
4244
55788
1718
0 4 8 12 16 20
Oxycodone 5Codeine 60Tramadol 50Propoxyphene 65APAP 325Oxycodone 5ASA 650Codeine 60Tramadol 100APAP 650Propox 100APAP 1000APAP 600Cod 60Morphine 10APAP 1000Oxyc 10Ibuprofen 400Oxycodone 15
McQuay H BMJ 1997
Patients with 50 reduction Patients with 50 reduction in pain vs placeboin pain vs placebo
NNT
USE OF PARACETAMOL IN TREATMENT OF OA PAIN
22
How effective was paracetamol
How effective was paracetamol compared with NSAIDs
F Wolfe S Zhao N Lane Preference for nonsteroidal antiinflammatory drugs over acetaminophen by rheumatic disease patients Arthritis amp Rheumatism 2000 43 378-385
2007 League table of NNT for at least 50 pain relief over 4-6 hrs in patients with moderate to severe pain
(all oral analgesics except IM morphine )
[httpwwwmedicineoxacukbandolierboothpainpagacutrevanalgesicsleagtabhtml
ETORICOXIB IN ACUTE PAIN
bull Etoricoxib 120 mg has been approved for treating acute pain which includes post-operative pain and other acute pain such as primary dysmenorrhea and acute gouty arthritis
bull Efficacy of etoricoxib in the post-operative setting as evaluated by NNT bull COCHRANE REVIEW Five randomized placebo-controlled studies
with a total number of 880 patients were included -- Four studies on patients with dental pain following extraction of at least one impacted third molar
--One study on patients with pain following uncomplicated orthopaedic surgery
bull NNT were calculated to measure at least 50 pain relief over 4-6 hrs (substantial pain relief) based on TOPAR scores
Results 120 mg etoricoxib with a NNT of 19 for acute post-operative pain
1 Chang DJ Desjardins PJ King TR Erb T Geba GP The analgesic efficacy of etoricoxib compared with oxycodoneacetaminophen in an acute postoperative pain model a randomized double-blind clinical trial Anesthesia and Analgesia 200499(3)807ndash15
2 Malmstrom K Sapre A Couglin H Agrawal NG Mazenko RS Fricke JR Jr Etoricoxib in acute pain associated with dental surgery a randomized double-blind placebo- and active comparator-controlled dose-ranging study Clinical Therapeutics 200426(5)667ndash79
3 Malmstrom K Kotey P Coughlin H Desjardins PJ A randomized double-blind parallel-group study comparing the analgesic effect of etoricoxib to placebo naproxen sodium and acetaminophen with codeine using the dental impaction pain model Clinical Journal of Pain 200420(3)147ndash 55
4 Malmstrom K Ang J Fricke JR Shingo S Reicin A The analgesic effect of etoricoxib relative to that of cetaminophen analgesics a randomized controlled single-dose study in acute dental impaction pain Current Medical Research and Opinion 200521(1)141ndash9 Rasmussen 2005 published data only
5 Rasmussen GL Malmstrom K Bourne MH Jove M Rhondeau SM Kotey P Etoricoxib provides analgesic efficacy to patients after knee or hip replacement surgery a randomized double-blind placebo-controlled study Anaesthesia and Analgesia 2005101(4) 1104ndash11
Etoricoxib in acute pain bull Indirect comparisons of NNTs for at least 50 pain
relief over 4 to 6 hours in reviews of other analgesics using identical methods indicate that etoricoxib 120 mg
-- has slightly better efficacy than rofecoxib 50 mg (22 (19 to 24) Barden 2005)
-- is significantly better than lumiracoxib 400mg (27 (22 to 35) Roy 2007) or-- celecoxib 400 mg (25 (22 to 29) Derry 2008)
-- better than the non-selective NSAIDs ibuprofen 400 mg (27 (25 to 30) Collins 1999) naproxen 500 mg (27 (23 to 32 Derry 2009a) and diclofenac 50mg (24 (18 to 33Derry 2009b)
Placebo
Paracetamol 10007
Paracetamolcodeine 1000606
Ibuprofen 4005
Celecoxib 4004
Naproxen 5005503
Rofecoxib 502
Etoricoxib 1201
0 4 8 12 16 20 24Median remedication time (hr)
Each bar is from a Cochrane review
Acute pain Time for patients to Re-medication
The weighted median time to re-medication with ARCOXIA 120mg is about 24hrs
vs placebo at 18hrs
1 Clarke R et al Cochrane Database Syst Rev 2009 Apr 15(2)CD004309 2 Bulley S et al Cochrane Database Syst Rev 2009 Oct 7(4)CD0046043 Derry C et al Cochrane Database Syst Rev 2009 Jan 21(1)CD004234 4 Derry S Cochrane Database Syst Rev 2008 Oct 8(4)CD0042335 Derry C et al Cochrane Database Syst Rev 2009 Jul 8(3)CD0015486 Toms L et al Cochrane Database Syst Rev 2009 Jan 21(1)CD0015477 Toms L et al Cochrane Database Syst Rev 2008 Oct 8(4)CD004602
Placebo (n=56)
Etoricoxib 60 mg (n=224)
Naproxen 1000 mgc
(n=221)
a0-
to 100-mm VAS (0 = none to 100 = extreme)
b0-
to 100-mm VAS (0 = very well to 100 = very poor) c500 mg twice dailyPlt0001 vs placebo for both etoricoxib and naproxen P = NS etoricoxib vs naproxen
Leung AT et al Curr Med Res Opin 200218(2)49ndash58
LS M
ean
Cha
nge
plusmnSE
Weeks Postrandomization
Osteoarthritis Etoricoxib 60 mg vs Naproxen
Results Etoricoxib relieved pain and improved mobility and disease statuEtoricoxib relieved pain and improved mobility and disease statuss
ndash35
ndash25
ndash5
5
ndash15
WOMAC Pain Subscalea
S R 4 82 12
WOMAC Physical Function Subscalea PGADSb
ndash35
ndash25
ndash5
5
ndash15
S R 4 82 12ndash35
ndash25
ndash5
5
ndash15
S R 4 82 12Weeks Postrandomization Weeks Postrandomization
Adverse effects of NSAIDsAdverse effects of NSAIDs
BNF March 2002
Dose-dependent toxicityIntolerability dyspepsiaGI bleedingUlcers ndash bleeds perforations
Upper-GI
Renal
Contributes to blood loss
Fluid retention oedema hypertensionRenal dysfunction failure ndash acute chronicHeart failure
Anti-platelet effects
Angioedema bronchospasmHypersensitivity
No Short-Term Adverse GI Effects -
The Big Mistake
bull Study designed to evaluate short-term GI effects in elderly
bull Study planned to enrol 160 patientsbull Study terminated by investigator at 17 subjects
ndash 8 patients had ulcersndash 4 of 4 in ketorolac group
lsquo hellip because of the unexpectedly high incidence of gastroduodenal ulcers observedhelliprsquo
Harris et al ClinTher 2001231422
Class Effect of All NSAIDs
httpwwwfdagovcderdruginfopageCOX2NSAIDdecisionMemopdf
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
33
Cardiovascular Safetybull Arthritis patients often have concomitant CV
disease1
bull Pain is an important predictor of CV risk23
bull Randomized controlled trials and observational data demonstrate that CV risk of etoricoxib appears similar to that of traditional NSAIDs4-6
bull Recent data suggest that differential CV effects of NSAIDs (selective and nonselective) may be independent of COX-2 inhibition78
References 1 Singh G et al Am J Manag Care 20028(suppl)S383-S391 2
Sokka T Pincus T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 3
Pincus T Sokka T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 4
httpwwwfdagovohrmsdocketsac05slides2005-4090S1_06_01_Pfizer-celecoxibppt (accessed 14 February 2006) 5
White WB et al Am J Cardiol 200289425ndash430 6
Graham DJ et al Lancet 2005365475ndash481 7 Yang HM et al Circulation 2004110301ndash308 8 Steffel J et al Circulation 20051111685ndash1689
Events per 100 patient years
Coxib Coxib Placebo Coxib NSAID Percent naproxen
Rofecoxib 17 19 11 08 73
Celecoxib 13 15 11 11 20
Valdecoxib 13 12 13 20 about 50
Etoricoxib 13 12 12 08 67
Lumiracoxib 09 08 52
34
APTC endpoint (cardiovascular haemorrhagic and unknown death and nonfatal myocardial infarction and stroke)
1
MR Weir et al Selective COX-2 inhibition and cardiovascular effects a review of the rofecoxib development program American heart Journal 2003 146 591-604
2
WB White et al Cardiovascular thrombotic events in arthritis trials of the cyclooxygenase-2 inhibitor celecoxib American Journal of cardiology 2003 92 411-418
3
WB White et al Effects of the cyclooxygenase-2 specific inhibitor valdecoxib versus nonsteroidal anti-inflammatory agents and placebo on cardiovascular thrombotic events in patients with arthritis American Journal of Therapeutics 2004 11 244-250
4
S Curtis et al Cardiovascular safety summary associated with the etoricoxib development programme Arthritis amp Rheumatism 2003 48 Suppl S616
5
ME Farkouh et al Comparison of lumiracoxib with naproxen and ibuprofen in the therapeutic arthritis research and gastrointestinal event trial (TARGET) cardiovascular outcomes randomised controlled trial Lancet 2004 364 675-684
RECOMMENDATIONS
NSAIDs COXIBs
bull Use lowest effective dose shortest duration
bull Not for patients who have recently undergone coronary artery bypass graft (CABG) surgery and revascularisation procedures
bull Coxibs should not be prescribed for patients with established ischaemic heart disease stroke or congestive heart failure
bull Caution for Coxibs for patients who have hypertension hyperlipidaemia diabetes and smoking as well as peripheral arterial disease
bull Etoricoxib should not be prescribed for patients with hypertension whose blood pressure has not been adequately controlled
The EU Summit is supported by Pfizer
Tricyclic Agents
bull best documented analgesics here (NNT 22)bull amitriptyline best investigatedbull desipraminenortriptyline less AEs
bull start on low doses increases compliancebullOften adverse effects (NNH 28)bull effect needs timebull SSRIs not as effective (NNT 67)
bull noradrenergic effect necessarybull venlafaxine another option
Antidepressants Compared with Placebo
Condition Number of trials
Antidepressant improvedtotal
Placebo improvedtotal
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 13 180260 73205 19 (16 to
24)30 (24 to 40)
Postherpetic neuralgia 3 4377 868 48 (24 to
94)23 (17 to 33)
Atypical facial pain 2 6288 3085 20 (15 to
28)28 (20 to 47)
Central pain 1 1015 115 10 (15 to 69)
17 (11 to 30)
Bandolier
Anticonvulsants as Membrane Stabilisers
bull pregabalinbull gabapentin bull carbamazepinebull clonazepam pooled NNT 27bull valproatebull lamotriginebull baclofen
Anticonvulsants Compared with Placebo
Condition Number of trials
Anticonvulsant improvedtotal
Placebo improvedtot
al
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 3 5668 2668 19 (14 to 27) 25 (18
to 40)
Trigeminal neuralgia 3 178315 41224 31 (23 to 41) 26 (22
to 33)
Migraine prophylaxis 2 6374 1777 37 (24 to 59) 16 (13
to 20)
Other pain syndromes 1 514 115 54 (07 to 40)
not calculat ed
Bandolier
Relative Activity on Serotonin and Norepinephrine Reuptake Among
Antidepressants
CitalopramFluvoxamineSertralineParoxetineFluoxetine
VenlafaxineDuloxetine
MaprotilineDesipramineNortriptylineReboxetine
AmitriptylineMilnacipranImipramine
Serotonin Mixed Norepinephrine
Antidepressant Analgesic Antidepressant
Fishbain et al Pain Med 20001310-316
Opioidsbull In principle opioids are effective in nociceptive
and some neuropathic pain however not always and not necessarily completely for dynamic pain
bull Possibly preferable opioids here arendash tramadol
bull noradrenergic and serotoninergic effectndash morphine
bull Mu receptor anatagonistmonaminergic effect
ndash oxycodonebull kappa receptor effect
Opioids
bull lsquoLack of analgesic effect of opioids on neuropathic hellip painrsquo Pain 19883311
bull lsquohellip intravenous hellip morphine reduce the pain of Osteoarthritisrsquo Neurology
1991411024bull lsquoA call for more science not more
rhetoric regarding opioids and arthritic painrsquo Pain 2001471
bull lsquoEfficacy of oxycodone in neuropathic painhelliprsquo Neurology 1998501837
OPIOIDS FOR OA PAINbull Osteoarthritis guidelines provide limited guidance on opioid use bull The 1995 ACR guidelines for hip OA suggest opioids be avoided for
long term use but short term use may be helpful without reference to primary data15
bull The 1995 ACR knee OA guidelines do not discuss opioids directly16 bull The 1998 UK guidelines on degenerative arthritis suggest that if
relief is inadequate with 24 grams of ibuprofen and 40 grams of paracetamol a day other antiinflammatories or opioids may be considered18
bull The 2000 update of the ACR OA guidelines suggests that opioids might be used as a medication of last resort17
bull Opioids are effective in OA hip and knee pain and have predictable side effects
bull It would be unwise were physicians to discount an entire class of medications over unfounded fears and incomplete knowledge of their benefits44
USE OF ULTRACET IN OA KNEESbull The efficacy of tramadolacetaminophen combination tablets (Ultracetreg) as add-
on and maintenance therapy in knee osteoarthritis pain inadequately controlled by nonsteroidal anti-inflammatory drug (NSAID)
Park KS Choi JJ Kim WU Min JK Park SH Cho CS
bull TramadolAPAP add-on significantly improved knee OA pain which had been inadequately controlled by NSAIDs In those subjects who showed favorable response to tramadolAPAP and NSAID combination therapy both tramadolAPAP and NSAIDs were effective at maintaining the pain-reduced state and there was no significant difference in efficacy between tramadolAPAP and NSAIDs
Clinical Rheumatology 2011 3 Aug
Opioid Sparing Regimes
bull Multimodal analgesia (Kehlet et al 1999)
bull NSAIDs and COX-2 (Romsing Moiniche 2004)
bull Paracetamol (Romsing 2002)
bull Ketamine (Elia Tramer 2005)
bull Gabapentin and Pregabalin (Dahl et al 2004)
bull Gabapentin and Rofecoxib (Gilron et al 2005)
Opioid reduction 20 ndash 40 Reduction of PONV 30
Clinical effects
Single-modality treatment of a Multi- modality problem is
futile
ldquoTherersquos no pain thatrsquos so easy to bear than that of
someone elserdquo
ndashLeriche
Van Gogh ldquoOld Man in Sorrowrdquo
I will show that my client is welltolerated amp effectivehelliphellip
I will showthat my clientis well tolerated and effective
bull For chronic pain most measures of treatment response involve patient- reported outcomes for which the patient is the most important judge of whether changes are important or meaningful12
ndash Determinations of statistical significance must be supplemented by consideration of the clinical importance of changes in outcome measures1
bull The IMMPACT consensus meeting proposed provisional benchmarks for identifying clinically important changes in the specific outcome measures for chronic pain clinical trials1
Using NNT Analyses in the Treatment of Pain IMMPACT Consensus Meeting Recommendations
NNT = number needed to treat IMMPACT = Initiative on Methods Measurement and Pain Assessment in Clinical Trials1 Dworkin RH et al J Pain 20089105ndash121 2 Acquadro C et al Value Health 20036522ndash531
10ndash20Reduction in pain intensity
ge50Reduction in pain intensity
ge30Reduction in pain intensity
Minimally Important Improvement
Moderately Important Improvement
Substantial Improvement
132
253
353638
4244
55788
1718
0 4 8 12 16 20
Oxycodone 5Codeine 60Tramadol 50Propoxyphene 65APAP 325Oxycodone 5ASA 650Codeine 60Tramadol 100APAP 650Propox 100APAP 1000APAP 600Cod 60Morphine 10APAP 1000Oxyc 10Ibuprofen 400Oxycodone 15
McQuay H BMJ 1997
Patients with 50 reduction Patients with 50 reduction in pain vs placeboin pain vs placebo
NNT
USE OF PARACETAMOL IN TREATMENT OF OA PAIN
22
How effective was paracetamol
How effective was paracetamol compared with NSAIDs
F Wolfe S Zhao N Lane Preference for nonsteroidal antiinflammatory drugs over acetaminophen by rheumatic disease patients Arthritis amp Rheumatism 2000 43 378-385
2007 League table of NNT for at least 50 pain relief over 4-6 hrs in patients with moderate to severe pain
(all oral analgesics except IM morphine )
[httpwwwmedicineoxacukbandolierboothpainpagacutrevanalgesicsleagtabhtml
ETORICOXIB IN ACUTE PAIN
bull Etoricoxib 120 mg has been approved for treating acute pain which includes post-operative pain and other acute pain such as primary dysmenorrhea and acute gouty arthritis
bull Efficacy of etoricoxib in the post-operative setting as evaluated by NNT bull COCHRANE REVIEW Five randomized placebo-controlled studies
with a total number of 880 patients were included -- Four studies on patients with dental pain following extraction of at least one impacted third molar
--One study on patients with pain following uncomplicated orthopaedic surgery
bull NNT were calculated to measure at least 50 pain relief over 4-6 hrs (substantial pain relief) based on TOPAR scores
Results 120 mg etoricoxib with a NNT of 19 for acute post-operative pain
1 Chang DJ Desjardins PJ King TR Erb T Geba GP The analgesic efficacy of etoricoxib compared with oxycodoneacetaminophen in an acute postoperative pain model a randomized double-blind clinical trial Anesthesia and Analgesia 200499(3)807ndash15
2 Malmstrom K Sapre A Couglin H Agrawal NG Mazenko RS Fricke JR Jr Etoricoxib in acute pain associated with dental surgery a randomized double-blind placebo- and active comparator-controlled dose-ranging study Clinical Therapeutics 200426(5)667ndash79
3 Malmstrom K Kotey P Coughlin H Desjardins PJ A randomized double-blind parallel-group study comparing the analgesic effect of etoricoxib to placebo naproxen sodium and acetaminophen with codeine using the dental impaction pain model Clinical Journal of Pain 200420(3)147ndash 55
4 Malmstrom K Ang J Fricke JR Shingo S Reicin A The analgesic effect of etoricoxib relative to that of cetaminophen analgesics a randomized controlled single-dose study in acute dental impaction pain Current Medical Research and Opinion 200521(1)141ndash9 Rasmussen 2005 published data only
5 Rasmussen GL Malmstrom K Bourne MH Jove M Rhondeau SM Kotey P Etoricoxib provides analgesic efficacy to patients after knee or hip replacement surgery a randomized double-blind placebo-controlled study Anaesthesia and Analgesia 2005101(4) 1104ndash11
Etoricoxib in acute pain bull Indirect comparisons of NNTs for at least 50 pain
relief over 4 to 6 hours in reviews of other analgesics using identical methods indicate that etoricoxib 120 mg
-- has slightly better efficacy than rofecoxib 50 mg (22 (19 to 24) Barden 2005)
-- is significantly better than lumiracoxib 400mg (27 (22 to 35) Roy 2007) or-- celecoxib 400 mg (25 (22 to 29) Derry 2008)
-- better than the non-selective NSAIDs ibuprofen 400 mg (27 (25 to 30) Collins 1999) naproxen 500 mg (27 (23 to 32 Derry 2009a) and diclofenac 50mg (24 (18 to 33Derry 2009b)
Placebo
Paracetamol 10007
Paracetamolcodeine 1000606
Ibuprofen 4005
Celecoxib 4004
Naproxen 5005503
Rofecoxib 502
Etoricoxib 1201
0 4 8 12 16 20 24Median remedication time (hr)
Each bar is from a Cochrane review
Acute pain Time for patients to Re-medication
The weighted median time to re-medication with ARCOXIA 120mg is about 24hrs
vs placebo at 18hrs
1 Clarke R et al Cochrane Database Syst Rev 2009 Apr 15(2)CD004309 2 Bulley S et al Cochrane Database Syst Rev 2009 Oct 7(4)CD0046043 Derry C et al Cochrane Database Syst Rev 2009 Jan 21(1)CD004234 4 Derry S Cochrane Database Syst Rev 2008 Oct 8(4)CD0042335 Derry C et al Cochrane Database Syst Rev 2009 Jul 8(3)CD0015486 Toms L et al Cochrane Database Syst Rev 2009 Jan 21(1)CD0015477 Toms L et al Cochrane Database Syst Rev 2008 Oct 8(4)CD004602
Placebo (n=56)
Etoricoxib 60 mg (n=224)
Naproxen 1000 mgc
(n=221)
a0-
to 100-mm VAS (0 = none to 100 = extreme)
b0-
to 100-mm VAS (0 = very well to 100 = very poor) c500 mg twice dailyPlt0001 vs placebo for both etoricoxib and naproxen P = NS etoricoxib vs naproxen
Leung AT et al Curr Med Res Opin 200218(2)49ndash58
LS M
ean
Cha
nge
plusmnSE
Weeks Postrandomization
Osteoarthritis Etoricoxib 60 mg vs Naproxen
Results Etoricoxib relieved pain and improved mobility and disease statuEtoricoxib relieved pain and improved mobility and disease statuss
ndash35
ndash25
ndash5
5
ndash15
WOMAC Pain Subscalea
S R 4 82 12
WOMAC Physical Function Subscalea PGADSb
ndash35
ndash25
ndash5
5
ndash15
S R 4 82 12ndash35
ndash25
ndash5
5
ndash15
S R 4 82 12Weeks Postrandomization Weeks Postrandomization
Adverse effects of NSAIDsAdverse effects of NSAIDs
BNF March 2002
Dose-dependent toxicityIntolerability dyspepsiaGI bleedingUlcers ndash bleeds perforations
Upper-GI
Renal
Contributes to blood loss
Fluid retention oedema hypertensionRenal dysfunction failure ndash acute chronicHeart failure
Anti-platelet effects
Angioedema bronchospasmHypersensitivity
No Short-Term Adverse GI Effects -
The Big Mistake
bull Study designed to evaluate short-term GI effects in elderly
bull Study planned to enrol 160 patientsbull Study terminated by investigator at 17 subjects
ndash 8 patients had ulcersndash 4 of 4 in ketorolac group
lsquo hellip because of the unexpectedly high incidence of gastroduodenal ulcers observedhelliprsquo
Harris et al ClinTher 2001231422
Class Effect of All NSAIDs
httpwwwfdagovcderdruginfopageCOX2NSAIDdecisionMemopdf
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
33
Cardiovascular Safetybull Arthritis patients often have concomitant CV
disease1
bull Pain is an important predictor of CV risk23
bull Randomized controlled trials and observational data demonstrate that CV risk of etoricoxib appears similar to that of traditional NSAIDs4-6
bull Recent data suggest that differential CV effects of NSAIDs (selective and nonselective) may be independent of COX-2 inhibition78
References 1 Singh G et al Am J Manag Care 20028(suppl)S383-S391 2
Sokka T Pincus T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 3
Pincus T Sokka T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 4
httpwwwfdagovohrmsdocketsac05slides2005-4090S1_06_01_Pfizer-celecoxibppt (accessed 14 February 2006) 5
White WB et al Am J Cardiol 200289425ndash430 6
Graham DJ et al Lancet 2005365475ndash481 7 Yang HM et al Circulation 2004110301ndash308 8 Steffel J et al Circulation 20051111685ndash1689
Events per 100 patient years
Coxib Coxib Placebo Coxib NSAID Percent naproxen
Rofecoxib 17 19 11 08 73
Celecoxib 13 15 11 11 20
Valdecoxib 13 12 13 20 about 50
Etoricoxib 13 12 12 08 67
Lumiracoxib 09 08 52
34
APTC endpoint (cardiovascular haemorrhagic and unknown death and nonfatal myocardial infarction and stroke)
1
MR Weir et al Selective COX-2 inhibition and cardiovascular effects a review of the rofecoxib development program American heart Journal 2003 146 591-604
2
WB White et al Cardiovascular thrombotic events in arthritis trials of the cyclooxygenase-2 inhibitor celecoxib American Journal of cardiology 2003 92 411-418
3
WB White et al Effects of the cyclooxygenase-2 specific inhibitor valdecoxib versus nonsteroidal anti-inflammatory agents and placebo on cardiovascular thrombotic events in patients with arthritis American Journal of Therapeutics 2004 11 244-250
4
S Curtis et al Cardiovascular safety summary associated with the etoricoxib development programme Arthritis amp Rheumatism 2003 48 Suppl S616
5
ME Farkouh et al Comparison of lumiracoxib with naproxen and ibuprofen in the therapeutic arthritis research and gastrointestinal event trial (TARGET) cardiovascular outcomes randomised controlled trial Lancet 2004 364 675-684
RECOMMENDATIONS
NSAIDs COXIBs
bull Use lowest effective dose shortest duration
bull Not for patients who have recently undergone coronary artery bypass graft (CABG) surgery and revascularisation procedures
bull Coxibs should not be prescribed for patients with established ischaemic heart disease stroke or congestive heart failure
bull Caution for Coxibs for patients who have hypertension hyperlipidaemia diabetes and smoking as well as peripheral arterial disease
bull Etoricoxib should not be prescribed for patients with hypertension whose blood pressure has not been adequately controlled
The EU Summit is supported by Pfizer
Tricyclic Agents
bull best documented analgesics here (NNT 22)bull amitriptyline best investigatedbull desipraminenortriptyline less AEs
bull start on low doses increases compliancebullOften adverse effects (NNH 28)bull effect needs timebull SSRIs not as effective (NNT 67)
bull noradrenergic effect necessarybull venlafaxine another option
Antidepressants Compared with Placebo
Condition Number of trials
Antidepressant improvedtotal
Placebo improvedtotal
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 13 180260 73205 19 (16 to
24)30 (24 to 40)
Postherpetic neuralgia 3 4377 868 48 (24 to
94)23 (17 to 33)
Atypical facial pain 2 6288 3085 20 (15 to
28)28 (20 to 47)
Central pain 1 1015 115 10 (15 to 69)
17 (11 to 30)
Bandolier
Anticonvulsants as Membrane Stabilisers
bull pregabalinbull gabapentin bull carbamazepinebull clonazepam pooled NNT 27bull valproatebull lamotriginebull baclofen
Anticonvulsants Compared with Placebo
Condition Number of trials
Anticonvulsant improvedtotal
Placebo improvedtot
al
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 3 5668 2668 19 (14 to 27) 25 (18
to 40)
Trigeminal neuralgia 3 178315 41224 31 (23 to 41) 26 (22
to 33)
Migraine prophylaxis 2 6374 1777 37 (24 to 59) 16 (13
to 20)
Other pain syndromes 1 514 115 54 (07 to 40)
not calculat ed
Bandolier
Relative Activity on Serotonin and Norepinephrine Reuptake Among
Antidepressants
CitalopramFluvoxamineSertralineParoxetineFluoxetine
VenlafaxineDuloxetine
MaprotilineDesipramineNortriptylineReboxetine
AmitriptylineMilnacipranImipramine
Serotonin Mixed Norepinephrine
Antidepressant Analgesic Antidepressant
Fishbain et al Pain Med 20001310-316
Opioidsbull In principle opioids are effective in nociceptive
and some neuropathic pain however not always and not necessarily completely for dynamic pain
bull Possibly preferable opioids here arendash tramadol
bull noradrenergic and serotoninergic effectndash morphine
bull Mu receptor anatagonistmonaminergic effect
ndash oxycodonebull kappa receptor effect
Opioids
bull lsquoLack of analgesic effect of opioids on neuropathic hellip painrsquo Pain 19883311
bull lsquohellip intravenous hellip morphine reduce the pain of Osteoarthritisrsquo Neurology
1991411024bull lsquoA call for more science not more
rhetoric regarding opioids and arthritic painrsquo Pain 2001471
bull lsquoEfficacy of oxycodone in neuropathic painhelliprsquo Neurology 1998501837
OPIOIDS FOR OA PAINbull Osteoarthritis guidelines provide limited guidance on opioid use bull The 1995 ACR guidelines for hip OA suggest opioids be avoided for
long term use but short term use may be helpful without reference to primary data15
bull The 1995 ACR knee OA guidelines do not discuss opioids directly16 bull The 1998 UK guidelines on degenerative arthritis suggest that if
relief is inadequate with 24 grams of ibuprofen and 40 grams of paracetamol a day other antiinflammatories or opioids may be considered18
bull The 2000 update of the ACR OA guidelines suggests that opioids might be used as a medication of last resort17
bull Opioids are effective in OA hip and knee pain and have predictable side effects
bull It would be unwise were physicians to discount an entire class of medications over unfounded fears and incomplete knowledge of their benefits44
USE OF ULTRACET IN OA KNEESbull The efficacy of tramadolacetaminophen combination tablets (Ultracetreg) as add-
on and maintenance therapy in knee osteoarthritis pain inadequately controlled by nonsteroidal anti-inflammatory drug (NSAID)
Park KS Choi JJ Kim WU Min JK Park SH Cho CS
bull TramadolAPAP add-on significantly improved knee OA pain which had been inadequately controlled by NSAIDs In those subjects who showed favorable response to tramadolAPAP and NSAID combination therapy both tramadolAPAP and NSAIDs were effective at maintaining the pain-reduced state and there was no significant difference in efficacy between tramadolAPAP and NSAIDs
Clinical Rheumatology 2011 3 Aug
Opioid Sparing Regimes
bull Multimodal analgesia (Kehlet et al 1999)
bull NSAIDs and COX-2 (Romsing Moiniche 2004)
bull Paracetamol (Romsing 2002)
bull Ketamine (Elia Tramer 2005)
bull Gabapentin and Pregabalin (Dahl et al 2004)
bull Gabapentin and Rofecoxib (Gilron et al 2005)
Opioid reduction 20 ndash 40 Reduction of PONV 30
Clinical effects
Single-modality treatment of a Multi- modality problem is
futile
ldquoTherersquos no pain thatrsquos so easy to bear than that of
someone elserdquo
ndashLeriche
Van Gogh ldquoOld Man in Sorrowrdquo
bull For chronic pain most measures of treatment response involve patient- reported outcomes for which the patient is the most important judge of whether changes are important or meaningful12
ndash Determinations of statistical significance must be supplemented by consideration of the clinical importance of changes in outcome measures1
bull The IMMPACT consensus meeting proposed provisional benchmarks for identifying clinically important changes in the specific outcome measures for chronic pain clinical trials1
Using NNT Analyses in the Treatment of Pain IMMPACT Consensus Meeting Recommendations
NNT = number needed to treat IMMPACT = Initiative on Methods Measurement and Pain Assessment in Clinical Trials1 Dworkin RH et al J Pain 20089105ndash121 2 Acquadro C et al Value Health 20036522ndash531
10ndash20Reduction in pain intensity
ge50Reduction in pain intensity
ge30Reduction in pain intensity
Minimally Important Improvement
Moderately Important Improvement
Substantial Improvement
132
253
353638
4244
55788
1718
0 4 8 12 16 20
Oxycodone 5Codeine 60Tramadol 50Propoxyphene 65APAP 325Oxycodone 5ASA 650Codeine 60Tramadol 100APAP 650Propox 100APAP 1000APAP 600Cod 60Morphine 10APAP 1000Oxyc 10Ibuprofen 400Oxycodone 15
McQuay H BMJ 1997
Patients with 50 reduction Patients with 50 reduction in pain vs placeboin pain vs placebo
NNT
USE OF PARACETAMOL IN TREATMENT OF OA PAIN
22
How effective was paracetamol
How effective was paracetamol compared with NSAIDs
F Wolfe S Zhao N Lane Preference for nonsteroidal antiinflammatory drugs over acetaminophen by rheumatic disease patients Arthritis amp Rheumatism 2000 43 378-385
2007 League table of NNT for at least 50 pain relief over 4-6 hrs in patients with moderate to severe pain
(all oral analgesics except IM morphine )
[httpwwwmedicineoxacukbandolierboothpainpagacutrevanalgesicsleagtabhtml
ETORICOXIB IN ACUTE PAIN
bull Etoricoxib 120 mg has been approved for treating acute pain which includes post-operative pain and other acute pain such as primary dysmenorrhea and acute gouty arthritis
bull Efficacy of etoricoxib in the post-operative setting as evaluated by NNT bull COCHRANE REVIEW Five randomized placebo-controlled studies
with a total number of 880 patients were included -- Four studies on patients with dental pain following extraction of at least one impacted third molar
--One study on patients with pain following uncomplicated orthopaedic surgery
bull NNT were calculated to measure at least 50 pain relief over 4-6 hrs (substantial pain relief) based on TOPAR scores
Results 120 mg etoricoxib with a NNT of 19 for acute post-operative pain
1 Chang DJ Desjardins PJ King TR Erb T Geba GP The analgesic efficacy of etoricoxib compared with oxycodoneacetaminophen in an acute postoperative pain model a randomized double-blind clinical trial Anesthesia and Analgesia 200499(3)807ndash15
2 Malmstrom K Sapre A Couglin H Agrawal NG Mazenko RS Fricke JR Jr Etoricoxib in acute pain associated with dental surgery a randomized double-blind placebo- and active comparator-controlled dose-ranging study Clinical Therapeutics 200426(5)667ndash79
3 Malmstrom K Kotey P Coughlin H Desjardins PJ A randomized double-blind parallel-group study comparing the analgesic effect of etoricoxib to placebo naproxen sodium and acetaminophen with codeine using the dental impaction pain model Clinical Journal of Pain 200420(3)147ndash 55
4 Malmstrom K Ang J Fricke JR Shingo S Reicin A The analgesic effect of etoricoxib relative to that of cetaminophen analgesics a randomized controlled single-dose study in acute dental impaction pain Current Medical Research and Opinion 200521(1)141ndash9 Rasmussen 2005 published data only
5 Rasmussen GL Malmstrom K Bourne MH Jove M Rhondeau SM Kotey P Etoricoxib provides analgesic efficacy to patients after knee or hip replacement surgery a randomized double-blind placebo-controlled study Anaesthesia and Analgesia 2005101(4) 1104ndash11
Etoricoxib in acute pain bull Indirect comparisons of NNTs for at least 50 pain
relief over 4 to 6 hours in reviews of other analgesics using identical methods indicate that etoricoxib 120 mg
-- has slightly better efficacy than rofecoxib 50 mg (22 (19 to 24) Barden 2005)
-- is significantly better than lumiracoxib 400mg (27 (22 to 35) Roy 2007) or-- celecoxib 400 mg (25 (22 to 29) Derry 2008)
-- better than the non-selective NSAIDs ibuprofen 400 mg (27 (25 to 30) Collins 1999) naproxen 500 mg (27 (23 to 32 Derry 2009a) and diclofenac 50mg (24 (18 to 33Derry 2009b)
Placebo
Paracetamol 10007
Paracetamolcodeine 1000606
Ibuprofen 4005
Celecoxib 4004
Naproxen 5005503
Rofecoxib 502
Etoricoxib 1201
0 4 8 12 16 20 24Median remedication time (hr)
Each bar is from a Cochrane review
Acute pain Time for patients to Re-medication
The weighted median time to re-medication with ARCOXIA 120mg is about 24hrs
vs placebo at 18hrs
1 Clarke R et al Cochrane Database Syst Rev 2009 Apr 15(2)CD004309 2 Bulley S et al Cochrane Database Syst Rev 2009 Oct 7(4)CD0046043 Derry C et al Cochrane Database Syst Rev 2009 Jan 21(1)CD004234 4 Derry S Cochrane Database Syst Rev 2008 Oct 8(4)CD0042335 Derry C et al Cochrane Database Syst Rev 2009 Jul 8(3)CD0015486 Toms L et al Cochrane Database Syst Rev 2009 Jan 21(1)CD0015477 Toms L et al Cochrane Database Syst Rev 2008 Oct 8(4)CD004602
Placebo (n=56)
Etoricoxib 60 mg (n=224)
Naproxen 1000 mgc
(n=221)
a0-
to 100-mm VAS (0 = none to 100 = extreme)
b0-
to 100-mm VAS (0 = very well to 100 = very poor) c500 mg twice dailyPlt0001 vs placebo for both etoricoxib and naproxen P = NS etoricoxib vs naproxen
Leung AT et al Curr Med Res Opin 200218(2)49ndash58
LS M
ean
Cha
nge
plusmnSE
Weeks Postrandomization
Osteoarthritis Etoricoxib 60 mg vs Naproxen
Results Etoricoxib relieved pain and improved mobility and disease statuEtoricoxib relieved pain and improved mobility and disease statuss
ndash35
ndash25
ndash5
5
ndash15
WOMAC Pain Subscalea
S R 4 82 12
WOMAC Physical Function Subscalea PGADSb
ndash35
ndash25
ndash5
5
ndash15
S R 4 82 12ndash35
ndash25
ndash5
5
ndash15
S R 4 82 12Weeks Postrandomization Weeks Postrandomization
Adverse effects of NSAIDsAdverse effects of NSAIDs
BNF March 2002
Dose-dependent toxicityIntolerability dyspepsiaGI bleedingUlcers ndash bleeds perforations
Upper-GI
Renal
Contributes to blood loss
Fluid retention oedema hypertensionRenal dysfunction failure ndash acute chronicHeart failure
Anti-platelet effects
Angioedema bronchospasmHypersensitivity
No Short-Term Adverse GI Effects -
The Big Mistake
bull Study designed to evaluate short-term GI effects in elderly
bull Study planned to enrol 160 patientsbull Study terminated by investigator at 17 subjects
ndash 8 patients had ulcersndash 4 of 4 in ketorolac group
lsquo hellip because of the unexpectedly high incidence of gastroduodenal ulcers observedhelliprsquo
Harris et al ClinTher 2001231422
Class Effect of All NSAIDs
httpwwwfdagovcderdruginfopageCOX2NSAIDdecisionMemopdf
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
33
Cardiovascular Safetybull Arthritis patients often have concomitant CV
disease1
bull Pain is an important predictor of CV risk23
bull Randomized controlled trials and observational data demonstrate that CV risk of etoricoxib appears similar to that of traditional NSAIDs4-6
bull Recent data suggest that differential CV effects of NSAIDs (selective and nonselective) may be independent of COX-2 inhibition78
References 1 Singh G et al Am J Manag Care 20028(suppl)S383-S391 2
Sokka T Pincus T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 3
Pincus T Sokka T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 4
httpwwwfdagovohrmsdocketsac05slides2005-4090S1_06_01_Pfizer-celecoxibppt (accessed 14 February 2006) 5
White WB et al Am J Cardiol 200289425ndash430 6
Graham DJ et al Lancet 2005365475ndash481 7 Yang HM et al Circulation 2004110301ndash308 8 Steffel J et al Circulation 20051111685ndash1689
Events per 100 patient years
Coxib Coxib Placebo Coxib NSAID Percent naproxen
Rofecoxib 17 19 11 08 73
Celecoxib 13 15 11 11 20
Valdecoxib 13 12 13 20 about 50
Etoricoxib 13 12 12 08 67
Lumiracoxib 09 08 52
34
APTC endpoint (cardiovascular haemorrhagic and unknown death and nonfatal myocardial infarction and stroke)
1
MR Weir et al Selective COX-2 inhibition and cardiovascular effects a review of the rofecoxib development program American heart Journal 2003 146 591-604
2
WB White et al Cardiovascular thrombotic events in arthritis trials of the cyclooxygenase-2 inhibitor celecoxib American Journal of cardiology 2003 92 411-418
3
WB White et al Effects of the cyclooxygenase-2 specific inhibitor valdecoxib versus nonsteroidal anti-inflammatory agents and placebo on cardiovascular thrombotic events in patients with arthritis American Journal of Therapeutics 2004 11 244-250
4
S Curtis et al Cardiovascular safety summary associated with the etoricoxib development programme Arthritis amp Rheumatism 2003 48 Suppl S616
5
ME Farkouh et al Comparison of lumiracoxib with naproxen and ibuprofen in the therapeutic arthritis research and gastrointestinal event trial (TARGET) cardiovascular outcomes randomised controlled trial Lancet 2004 364 675-684
RECOMMENDATIONS
NSAIDs COXIBs
bull Use lowest effective dose shortest duration
bull Not for patients who have recently undergone coronary artery bypass graft (CABG) surgery and revascularisation procedures
bull Coxibs should not be prescribed for patients with established ischaemic heart disease stroke or congestive heart failure
bull Caution for Coxibs for patients who have hypertension hyperlipidaemia diabetes and smoking as well as peripheral arterial disease
bull Etoricoxib should not be prescribed for patients with hypertension whose blood pressure has not been adequately controlled
The EU Summit is supported by Pfizer
Tricyclic Agents
bull best documented analgesics here (NNT 22)bull amitriptyline best investigatedbull desipraminenortriptyline less AEs
bull start on low doses increases compliancebullOften adverse effects (NNH 28)bull effect needs timebull SSRIs not as effective (NNT 67)
bull noradrenergic effect necessarybull venlafaxine another option
Antidepressants Compared with Placebo
Condition Number of trials
Antidepressant improvedtotal
Placebo improvedtotal
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 13 180260 73205 19 (16 to
24)30 (24 to 40)
Postherpetic neuralgia 3 4377 868 48 (24 to
94)23 (17 to 33)
Atypical facial pain 2 6288 3085 20 (15 to
28)28 (20 to 47)
Central pain 1 1015 115 10 (15 to 69)
17 (11 to 30)
Bandolier
Anticonvulsants as Membrane Stabilisers
bull pregabalinbull gabapentin bull carbamazepinebull clonazepam pooled NNT 27bull valproatebull lamotriginebull baclofen
Anticonvulsants Compared with Placebo
Condition Number of trials
Anticonvulsant improvedtotal
Placebo improvedtot
al
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 3 5668 2668 19 (14 to 27) 25 (18
to 40)
Trigeminal neuralgia 3 178315 41224 31 (23 to 41) 26 (22
to 33)
Migraine prophylaxis 2 6374 1777 37 (24 to 59) 16 (13
to 20)
Other pain syndromes 1 514 115 54 (07 to 40)
not calculat ed
Bandolier
Relative Activity on Serotonin and Norepinephrine Reuptake Among
Antidepressants
CitalopramFluvoxamineSertralineParoxetineFluoxetine
VenlafaxineDuloxetine
MaprotilineDesipramineNortriptylineReboxetine
AmitriptylineMilnacipranImipramine
Serotonin Mixed Norepinephrine
Antidepressant Analgesic Antidepressant
Fishbain et al Pain Med 20001310-316
Opioidsbull In principle opioids are effective in nociceptive
and some neuropathic pain however not always and not necessarily completely for dynamic pain
bull Possibly preferable opioids here arendash tramadol
bull noradrenergic and serotoninergic effectndash morphine
bull Mu receptor anatagonistmonaminergic effect
ndash oxycodonebull kappa receptor effect
Opioids
bull lsquoLack of analgesic effect of opioids on neuropathic hellip painrsquo Pain 19883311
bull lsquohellip intravenous hellip morphine reduce the pain of Osteoarthritisrsquo Neurology
1991411024bull lsquoA call for more science not more
rhetoric regarding opioids and arthritic painrsquo Pain 2001471
bull lsquoEfficacy of oxycodone in neuropathic painhelliprsquo Neurology 1998501837
OPIOIDS FOR OA PAINbull Osteoarthritis guidelines provide limited guidance on opioid use bull The 1995 ACR guidelines for hip OA suggest opioids be avoided for
long term use but short term use may be helpful without reference to primary data15
bull The 1995 ACR knee OA guidelines do not discuss opioids directly16 bull The 1998 UK guidelines on degenerative arthritis suggest that if
relief is inadequate with 24 grams of ibuprofen and 40 grams of paracetamol a day other antiinflammatories or opioids may be considered18
bull The 2000 update of the ACR OA guidelines suggests that opioids might be used as a medication of last resort17
bull Opioids are effective in OA hip and knee pain and have predictable side effects
bull It would be unwise were physicians to discount an entire class of medications over unfounded fears and incomplete knowledge of their benefits44
USE OF ULTRACET IN OA KNEESbull The efficacy of tramadolacetaminophen combination tablets (Ultracetreg) as add-
on and maintenance therapy in knee osteoarthritis pain inadequately controlled by nonsteroidal anti-inflammatory drug (NSAID)
Park KS Choi JJ Kim WU Min JK Park SH Cho CS
bull TramadolAPAP add-on significantly improved knee OA pain which had been inadequately controlled by NSAIDs In those subjects who showed favorable response to tramadolAPAP and NSAID combination therapy both tramadolAPAP and NSAIDs were effective at maintaining the pain-reduced state and there was no significant difference in efficacy between tramadolAPAP and NSAIDs
Clinical Rheumatology 2011 3 Aug
Opioid Sparing Regimes
bull Multimodal analgesia (Kehlet et al 1999)
bull NSAIDs and COX-2 (Romsing Moiniche 2004)
bull Paracetamol (Romsing 2002)
bull Ketamine (Elia Tramer 2005)
bull Gabapentin and Pregabalin (Dahl et al 2004)
bull Gabapentin and Rofecoxib (Gilron et al 2005)
Opioid reduction 20 ndash 40 Reduction of PONV 30
Clinical effects
Single-modality treatment of a Multi- modality problem is
futile
ldquoTherersquos no pain thatrsquos so easy to bear than that of
someone elserdquo
ndashLeriche
Van Gogh ldquoOld Man in Sorrowrdquo
132
253
353638
4244
55788
1718
0 4 8 12 16 20
Oxycodone 5Codeine 60Tramadol 50Propoxyphene 65APAP 325Oxycodone 5ASA 650Codeine 60Tramadol 100APAP 650Propox 100APAP 1000APAP 600Cod 60Morphine 10APAP 1000Oxyc 10Ibuprofen 400Oxycodone 15
McQuay H BMJ 1997
Patients with 50 reduction Patients with 50 reduction in pain vs placeboin pain vs placebo
NNT
USE OF PARACETAMOL IN TREATMENT OF OA PAIN
22
How effective was paracetamol
How effective was paracetamol compared with NSAIDs
F Wolfe S Zhao N Lane Preference for nonsteroidal antiinflammatory drugs over acetaminophen by rheumatic disease patients Arthritis amp Rheumatism 2000 43 378-385
2007 League table of NNT for at least 50 pain relief over 4-6 hrs in patients with moderate to severe pain
(all oral analgesics except IM morphine )
[httpwwwmedicineoxacukbandolierboothpainpagacutrevanalgesicsleagtabhtml
ETORICOXIB IN ACUTE PAIN
bull Etoricoxib 120 mg has been approved for treating acute pain which includes post-operative pain and other acute pain such as primary dysmenorrhea and acute gouty arthritis
bull Efficacy of etoricoxib in the post-operative setting as evaluated by NNT bull COCHRANE REVIEW Five randomized placebo-controlled studies
with a total number of 880 patients were included -- Four studies on patients with dental pain following extraction of at least one impacted third molar
--One study on patients with pain following uncomplicated orthopaedic surgery
bull NNT were calculated to measure at least 50 pain relief over 4-6 hrs (substantial pain relief) based on TOPAR scores
Results 120 mg etoricoxib with a NNT of 19 for acute post-operative pain
1 Chang DJ Desjardins PJ King TR Erb T Geba GP The analgesic efficacy of etoricoxib compared with oxycodoneacetaminophen in an acute postoperative pain model a randomized double-blind clinical trial Anesthesia and Analgesia 200499(3)807ndash15
2 Malmstrom K Sapre A Couglin H Agrawal NG Mazenko RS Fricke JR Jr Etoricoxib in acute pain associated with dental surgery a randomized double-blind placebo- and active comparator-controlled dose-ranging study Clinical Therapeutics 200426(5)667ndash79
3 Malmstrom K Kotey P Coughlin H Desjardins PJ A randomized double-blind parallel-group study comparing the analgesic effect of etoricoxib to placebo naproxen sodium and acetaminophen with codeine using the dental impaction pain model Clinical Journal of Pain 200420(3)147ndash 55
4 Malmstrom K Ang J Fricke JR Shingo S Reicin A The analgesic effect of etoricoxib relative to that of cetaminophen analgesics a randomized controlled single-dose study in acute dental impaction pain Current Medical Research and Opinion 200521(1)141ndash9 Rasmussen 2005 published data only
5 Rasmussen GL Malmstrom K Bourne MH Jove M Rhondeau SM Kotey P Etoricoxib provides analgesic efficacy to patients after knee or hip replacement surgery a randomized double-blind placebo-controlled study Anaesthesia and Analgesia 2005101(4) 1104ndash11
Etoricoxib in acute pain bull Indirect comparisons of NNTs for at least 50 pain
relief over 4 to 6 hours in reviews of other analgesics using identical methods indicate that etoricoxib 120 mg
-- has slightly better efficacy than rofecoxib 50 mg (22 (19 to 24) Barden 2005)
-- is significantly better than lumiracoxib 400mg (27 (22 to 35) Roy 2007) or-- celecoxib 400 mg (25 (22 to 29) Derry 2008)
-- better than the non-selective NSAIDs ibuprofen 400 mg (27 (25 to 30) Collins 1999) naproxen 500 mg (27 (23 to 32 Derry 2009a) and diclofenac 50mg (24 (18 to 33Derry 2009b)
Placebo
Paracetamol 10007
Paracetamolcodeine 1000606
Ibuprofen 4005
Celecoxib 4004
Naproxen 5005503
Rofecoxib 502
Etoricoxib 1201
0 4 8 12 16 20 24Median remedication time (hr)
Each bar is from a Cochrane review
Acute pain Time for patients to Re-medication
The weighted median time to re-medication with ARCOXIA 120mg is about 24hrs
vs placebo at 18hrs
1 Clarke R et al Cochrane Database Syst Rev 2009 Apr 15(2)CD004309 2 Bulley S et al Cochrane Database Syst Rev 2009 Oct 7(4)CD0046043 Derry C et al Cochrane Database Syst Rev 2009 Jan 21(1)CD004234 4 Derry S Cochrane Database Syst Rev 2008 Oct 8(4)CD0042335 Derry C et al Cochrane Database Syst Rev 2009 Jul 8(3)CD0015486 Toms L et al Cochrane Database Syst Rev 2009 Jan 21(1)CD0015477 Toms L et al Cochrane Database Syst Rev 2008 Oct 8(4)CD004602
Placebo (n=56)
Etoricoxib 60 mg (n=224)
Naproxen 1000 mgc
(n=221)
a0-
to 100-mm VAS (0 = none to 100 = extreme)
b0-
to 100-mm VAS (0 = very well to 100 = very poor) c500 mg twice dailyPlt0001 vs placebo for both etoricoxib and naproxen P = NS etoricoxib vs naproxen
Leung AT et al Curr Med Res Opin 200218(2)49ndash58
LS M
ean
Cha
nge
plusmnSE
Weeks Postrandomization
Osteoarthritis Etoricoxib 60 mg vs Naproxen
Results Etoricoxib relieved pain and improved mobility and disease statuEtoricoxib relieved pain and improved mobility and disease statuss
ndash35
ndash25
ndash5
5
ndash15
WOMAC Pain Subscalea
S R 4 82 12
WOMAC Physical Function Subscalea PGADSb
ndash35
ndash25
ndash5
5
ndash15
S R 4 82 12ndash35
ndash25
ndash5
5
ndash15
S R 4 82 12Weeks Postrandomization Weeks Postrandomization
Adverse effects of NSAIDsAdverse effects of NSAIDs
BNF March 2002
Dose-dependent toxicityIntolerability dyspepsiaGI bleedingUlcers ndash bleeds perforations
Upper-GI
Renal
Contributes to blood loss
Fluid retention oedema hypertensionRenal dysfunction failure ndash acute chronicHeart failure
Anti-platelet effects
Angioedema bronchospasmHypersensitivity
No Short-Term Adverse GI Effects -
The Big Mistake
bull Study designed to evaluate short-term GI effects in elderly
bull Study planned to enrol 160 patientsbull Study terminated by investigator at 17 subjects
ndash 8 patients had ulcersndash 4 of 4 in ketorolac group
lsquo hellip because of the unexpectedly high incidence of gastroduodenal ulcers observedhelliprsquo
Harris et al ClinTher 2001231422
Class Effect of All NSAIDs
httpwwwfdagovcderdruginfopageCOX2NSAIDdecisionMemopdf
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
33
Cardiovascular Safetybull Arthritis patients often have concomitant CV
disease1
bull Pain is an important predictor of CV risk23
bull Randomized controlled trials and observational data demonstrate that CV risk of etoricoxib appears similar to that of traditional NSAIDs4-6
bull Recent data suggest that differential CV effects of NSAIDs (selective and nonselective) may be independent of COX-2 inhibition78
References 1 Singh G et al Am J Manag Care 20028(suppl)S383-S391 2
Sokka T Pincus T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 3
Pincus T Sokka T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 4
httpwwwfdagovohrmsdocketsac05slides2005-4090S1_06_01_Pfizer-celecoxibppt (accessed 14 February 2006) 5
White WB et al Am J Cardiol 200289425ndash430 6
Graham DJ et al Lancet 2005365475ndash481 7 Yang HM et al Circulation 2004110301ndash308 8 Steffel J et al Circulation 20051111685ndash1689
Events per 100 patient years
Coxib Coxib Placebo Coxib NSAID Percent naproxen
Rofecoxib 17 19 11 08 73
Celecoxib 13 15 11 11 20
Valdecoxib 13 12 13 20 about 50
Etoricoxib 13 12 12 08 67
Lumiracoxib 09 08 52
34
APTC endpoint (cardiovascular haemorrhagic and unknown death and nonfatal myocardial infarction and stroke)
1
MR Weir et al Selective COX-2 inhibition and cardiovascular effects a review of the rofecoxib development program American heart Journal 2003 146 591-604
2
WB White et al Cardiovascular thrombotic events in arthritis trials of the cyclooxygenase-2 inhibitor celecoxib American Journal of cardiology 2003 92 411-418
3
WB White et al Effects of the cyclooxygenase-2 specific inhibitor valdecoxib versus nonsteroidal anti-inflammatory agents and placebo on cardiovascular thrombotic events in patients with arthritis American Journal of Therapeutics 2004 11 244-250
4
S Curtis et al Cardiovascular safety summary associated with the etoricoxib development programme Arthritis amp Rheumatism 2003 48 Suppl S616
5
ME Farkouh et al Comparison of lumiracoxib with naproxen and ibuprofen in the therapeutic arthritis research and gastrointestinal event trial (TARGET) cardiovascular outcomes randomised controlled trial Lancet 2004 364 675-684
RECOMMENDATIONS
NSAIDs COXIBs
bull Use lowest effective dose shortest duration
bull Not for patients who have recently undergone coronary artery bypass graft (CABG) surgery and revascularisation procedures
bull Coxibs should not be prescribed for patients with established ischaemic heart disease stroke or congestive heart failure
bull Caution for Coxibs for patients who have hypertension hyperlipidaemia diabetes and smoking as well as peripheral arterial disease
bull Etoricoxib should not be prescribed for patients with hypertension whose blood pressure has not been adequately controlled
The EU Summit is supported by Pfizer
Tricyclic Agents
bull best documented analgesics here (NNT 22)bull amitriptyline best investigatedbull desipraminenortriptyline less AEs
bull start on low doses increases compliancebullOften adverse effects (NNH 28)bull effect needs timebull SSRIs not as effective (NNT 67)
bull noradrenergic effect necessarybull venlafaxine another option
Antidepressants Compared with Placebo
Condition Number of trials
Antidepressant improvedtotal
Placebo improvedtotal
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 13 180260 73205 19 (16 to
24)30 (24 to 40)
Postherpetic neuralgia 3 4377 868 48 (24 to
94)23 (17 to 33)
Atypical facial pain 2 6288 3085 20 (15 to
28)28 (20 to 47)
Central pain 1 1015 115 10 (15 to 69)
17 (11 to 30)
Bandolier
Anticonvulsants as Membrane Stabilisers
bull pregabalinbull gabapentin bull carbamazepinebull clonazepam pooled NNT 27bull valproatebull lamotriginebull baclofen
Anticonvulsants Compared with Placebo
Condition Number of trials
Anticonvulsant improvedtotal
Placebo improvedtot
al
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 3 5668 2668 19 (14 to 27) 25 (18
to 40)
Trigeminal neuralgia 3 178315 41224 31 (23 to 41) 26 (22
to 33)
Migraine prophylaxis 2 6374 1777 37 (24 to 59) 16 (13
to 20)
Other pain syndromes 1 514 115 54 (07 to 40)
not calculat ed
Bandolier
Relative Activity on Serotonin and Norepinephrine Reuptake Among
Antidepressants
CitalopramFluvoxamineSertralineParoxetineFluoxetine
VenlafaxineDuloxetine
MaprotilineDesipramineNortriptylineReboxetine
AmitriptylineMilnacipranImipramine
Serotonin Mixed Norepinephrine
Antidepressant Analgesic Antidepressant
Fishbain et al Pain Med 20001310-316
Opioidsbull In principle opioids are effective in nociceptive
and some neuropathic pain however not always and not necessarily completely for dynamic pain
bull Possibly preferable opioids here arendash tramadol
bull noradrenergic and serotoninergic effectndash morphine
bull Mu receptor anatagonistmonaminergic effect
ndash oxycodonebull kappa receptor effect
Opioids
bull lsquoLack of analgesic effect of opioids on neuropathic hellip painrsquo Pain 19883311
bull lsquohellip intravenous hellip morphine reduce the pain of Osteoarthritisrsquo Neurology
1991411024bull lsquoA call for more science not more
rhetoric regarding opioids and arthritic painrsquo Pain 2001471
bull lsquoEfficacy of oxycodone in neuropathic painhelliprsquo Neurology 1998501837
OPIOIDS FOR OA PAINbull Osteoarthritis guidelines provide limited guidance on opioid use bull The 1995 ACR guidelines for hip OA suggest opioids be avoided for
long term use but short term use may be helpful without reference to primary data15
bull The 1995 ACR knee OA guidelines do not discuss opioids directly16 bull The 1998 UK guidelines on degenerative arthritis suggest that if
relief is inadequate with 24 grams of ibuprofen and 40 grams of paracetamol a day other antiinflammatories or opioids may be considered18
bull The 2000 update of the ACR OA guidelines suggests that opioids might be used as a medication of last resort17
bull Opioids are effective in OA hip and knee pain and have predictable side effects
bull It would be unwise were physicians to discount an entire class of medications over unfounded fears and incomplete knowledge of their benefits44
USE OF ULTRACET IN OA KNEESbull The efficacy of tramadolacetaminophen combination tablets (Ultracetreg) as add-
on and maintenance therapy in knee osteoarthritis pain inadequately controlled by nonsteroidal anti-inflammatory drug (NSAID)
Park KS Choi JJ Kim WU Min JK Park SH Cho CS
bull TramadolAPAP add-on significantly improved knee OA pain which had been inadequately controlled by NSAIDs In those subjects who showed favorable response to tramadolAPAP and NSAID combination therapy both tramadolAPAP and NSAIDs were effective at maintaining the pain-reduced state and there was no significant difference in efficacy between tramadolAPAP and NSAIDs
Clinical Rheumatology 2011 3 Aug
Opioid Sparing Regimes
bull Multimodal analgesia (Kehlet et al 1999)
bull NSAIDs and COX-2 (Romsing Moiniche 2004)
bull Paracetamol (Romsing 2002)
bull Ketamine (Elia Tramer 2005)
bull Gabapentin and Pregabalin (Dahl et al 2004)
bull Gabapentin and Rofecoxib (Gilron et al 2005)
Opioid reduction 20 ndash 40 Reduction of PONV 30
Clinical effects
Single-modality treatment of a Multi- modality problem is
futile
ldquoTherersquos no pain thatrsquos so easy to bear than that of
someone elserdquo
ndashLeriche
Van Gogh ldquoOld Man in Sorrowrdquo
USE OF PARACETAMOL IN TREATMENT OF OA PAIN
22
How effective was paracetamol
How effective was paracetamol compared with NSAIDs
F Wolfe S Zhao N Lane Preference for nonsteroidal antiinflammatory drugs over acetaminophen by rheumatic disease patients Arthritis amp Rheumatism 2000 43 378-385
2007 League table of NNT for at least 50 pain relief over 4-6 hrs in patients with moderate to severe pain
(all oral analgesics except IM morphine )
[httpwwwmedicineoxacukbandolierboothpainpagacutrevanalgesicsleagtabhtml
ETORICOXIB IN ACUTE PAIN
bull Etoricoxib 120 mg has been approved for treating acute pain which includes post-operative pain and other acute pain such as primary dysmenorrhea and acute gouty arthritis
bull Efficacy of etoricoxib in the post-operative setting as evaluated by NNT bull COCHRANE REVIEW Five randomized placebo-controlled studies
with a total number of 880 patients were included -- Four studies on patients with dental pain following extraction of at least one impacted third molar
--One study on patients with pain following uncomplicated orthopaedic surgery
bull NNT were calculated to measure at least 50 pain relief over 4-6 hrs (substantial pain relief) based on TOPAR scores
Results 120 mg etoricoxib with a NNT of 19 for acute post-operative pain
1 Chang DJ Desjardins PJ King TR Erb T Geba GP The analgesic efficacy of etoricoxib compared with oxycodoneacetaminophen in an acute postoperative pain model a randomized double-blind clinical trial Anesthesia and Analgesia 200499(3)807ndash15
2 Malmstrom K Sapre A Couglin H Agrawal NG Mazenko RS Fricke JR Jr Etoricoxib in acute pain associated with dental surgery a randomized double-blind placebo- and active comparator-controlled dose-ranging study Clinical Therapeutics 200426(5)667ndash79
3 Malmstrom K Kotey P Coughlin H Desjardins PJ A randomized double-blind parallel-group study comparing the analgesic effect of etoricoxib to placebo naproxen sodium and acetaminophen with codeine using the dental impaction pain model Clinical Journal of Pain 200420(3)147ndash 55
4 Malmstrom K Ang J Fricke JR Shingo S Reicin A The analgesic effect of etoricoxib relative to that of cetaminophen analgesics a randomized controlled single-dose study in acute dental impaction pain Current Medical Research and Opinion 200521(1)141ndash9 Rasmussen 2005 published data only
5 Rasmussen GL Malmstrom K Bourne MH Jove M Rhondeau SM Kotey P Etoricoxib provides analgesic efficacy to patients after knee or hip replacement surgery a randomized double-blind placebo-controlled study Anaesthesia and Analgesia 2005101(4) 1104ndash11
Etoricoxib in acute pain bull Indirect comparisons of NNTs for at least 50 pain
relief over 4 to 6 hours in reviews of other analgesics using identical methods indicate that etoricoxib 120 mg
-- has slightly better efficacy than rofecoxib 50 mg (22 (19 to 24) Barden 2005)
-- is significantly better than lumiracoxib 400mg (27 (22 to 35) Roy 2007) or-- celecoxib 400 mg (25 (22 to 29) Derry 2008)
-- better than the non-selective NSAIDs ibuprofen 400 mg (27 (25 to 30) Collins 1999) naproxen 500 mg (27 (23 to 32 Derry 2009a) and diclofenac 50mg (24 (18 to 33Derry 2009b)
Placebo
Paracetamol 10007
Paracetamolcodeine 1000606
Ibuprofen 4005
Celecoxib 4004
Naproxen 5005503
Rofecoxib 502
Etoricoxib 1201
0 4 8 12 16 20 24Median remedication time (hr)
Each bar is from a Cochrane review
Acute pain Time for patients to Re-medication
The weighted median time to re-medication with ARCOXIA 120mg is about 24hrs
vs placebo at 18hrs
1 Clarke R et al Cochrane Database Syst Rev 2009 Apr 15(2)CD004309 2 Bulley S et al Cochrane Database Syst Rev 2009 Oct 7(4)CD0046043 Derry C et al Cochrane Database Syst Rev 2009 Jan 21(1)CD004234 4 Derry S Cochrane Database Syst Rev 2008 Oct 8(4)CD0042335 Derry C et al Cochrane Database Syst Rev 2009 Jul 8(3)CD0015486 Toms L et al Cochrane Database Syst Rev 2009 Jan 21(1)CD0015477 Toms L et al Cochrane Database Syst Rev 2008 Oct 8(4)CD004602
Placebo (n=56)
Etoricoxib 60 mg (n=224)
Naproxen 1000 mgc
(n=221)
a0-
to 100-mm VAS (0 = none to 100 = extreme)
b0-
to 100-mm VAS (0 = very well to 100 = very poor) c500 mg twice dailyPlt0001 vs placebo for both etoricoxib and naproxen P = NS etoricoxib vs naproxen
Leung AT et al Curr Med Res Opin 200218(2)49ndash58
LS M
ean
Cha
nge
plusmnSE
Weeks Postrandomization
Osteoarthritis Etoricoxib 60 mg vs Naproxen
Results Etoricoxib relieved pain and improved mobility and disease statuEtoricoxib relieved pain and improved mobility and disease statuss
ndash35
ndash25
ndash5
5
ndash15
WOMAC Pain Subscalea
S R 4 82 12
WOMAC Physical Function Subscalea PGADSb
ndash35
ndash25
ndash5
5
ndash15
S R 4 82 12ndash35
ndash25
ndash5
5
ndash15
S R 4 82 12Weeks Postrandomization Weeks Postrandomization
Adverse effects of NSAIDsAdverse effects of NSAIDs
BNF March 2002
Dose-dependent toxicityIntolerability dyspepsiaGI bleedingUlcers ndash bleeds perforations
Upper-GI
Renal
Contributes to blood loss
Fluid retention oedema hypertensionRenal dysfunction failure ndash acute chronicHeart failure
Anti-platelet effects
Angioedema bronchospasmHypersensitivity
No Short-Term Adverse GI Effects -
The Big Mistake
bull Study designed to evaluate short-term GI effects in elderly
bull Study planned to enrol 160 patientsbull Study terminated by investigator at 17 subjects
ndash 8 patients had ulcersndash 4 of 4 in ketorolac group
lsquo hellip because of the unexpectedly high incidence of gastroduodenal ulcers observedhelliprsquo
Harris et al ClinTher 2001231422
Class Effect of All NSAIDs
httpwwwfdagovcderdruginfopageCOX2NSAIDdecisionMemopdf
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
33
Cardiovascular Safetybull Arthritis patients often have concomitant CV
disease1
bull Pain is an important predictor of CV risk23
bull Randomized controlled trials and observational data demonstrate that CV risk of etoricoxib appears similar to that of traditional NSAIDs4-6
bull Recent data suggest that differential CV effects of NSAIDs (selective and nonselective) may be independent of COX-2 inhibition78
References 1 Singh G et al Am J Manag Care 20028(suppl)S383-S391 2
Sokka T Pincus T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 3
Pincus T Sokka T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 4
httpwwwfdagovohrmsdocketsac05slides2005-4090S1_06_01_Pfizer-celecoxibppt (accessed 14 February 2006) 5
White WB et al Am J Cardiol 200289425ndash430 6
Graham DJ et al Lancet 2005365475ndash481 7 Yang HM et al Circulation 2004110301ndash308 8 Steffel J et al Circulation 20051111685ndash1689
Events per 100 patient years
Coxib Coxib Placebo Coxib NSAID Percent naproxen
Rofecoxib 17 19 11 08 73
Celecoxib 13 15 11 11 20
Valdecoxib 13 12 13 20 about 50
Etoricoxib 13 12 12 08 67
Lumiracoxib 09 08 52
34
APTC endpoint (cardiovascular haemorrhagic and unknown death and nonfatal myocardial infarction and stroke)
1
MR Weir et al Selective COX-2 inhibition and cardiovascular effects a review of the rofecoxib development program American heart Journal 2003 146 591-604
2
WB White et al Cardiovascular thrombotic events in arthritis trials of the cyclooxygenase-2 inhibitor celecoxib American Journal of cardiology 2003 92 411-418
3
WB White et al Effects of the cyclooxygenase-2 specific inhibitor valdecoxib versus nonsteroidal anti-inflammatory agents and placebo on cardiovascular thrombotic events in patients with arthritis American Journal of Therapeutics 2004 11 244-250
4
S Curtis et al Cardiovascular safety summary associated with the etoricoxib development programme Arthritis amp Rheumatism 2003 48 Suppl S616
5
ME Farkouh et al Comparison of lumiracoxib with naproxen and ibuprofen in the therapeutic arthritis research and gastrointestinal event trial (TARGET) cardiovascular outcomes randomised controlled trial Lancet 2004 364 675-684
RECOMMENDATIONS
NSAIDs COXIBs
bull Use lowest effective dose shortest duration
bull Not for patients who have recently undergone coronary artery bypass graft (CABG) surgery and revascularisation procedures
bull Coxibs should not be prescribed for patients with established ischaemic heart disease stroke or congestive heart failure
bull Caution for Coxibs for patients who have hypertension hyperlipidaemia diabetes and smoking as well as peripheral arterial disease
bull Etoricoxib should not be prescribed for patients with hypertension whose blood pressure has not been adequately controlled
The EU Summit is supported by Pfizer
Tricyclic Agents
bull best documented analgesics here (NNT 22)bull amitriptyline best investigatedbull desipraminenortriptyline less AEs
bull start on low doses increases compliancebullOften adverse effects (NNH 28)bull effect needs timebull SSRIs not as effective (NNT 67)
bull noradrenergic effect necessarybull venlafaxine another option
Antidepressants Compared with Placebo
Condition Number of trials
Antidepressant improvedtotal
Placebo improvedtotal
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 13 180260 73205 19 (16 to
24)30 (24 to 40)
Postherpetic neuralgia 3 4377 868 48 (24 to
94)23 (17 to 33)
Atypical facial pain 2 6288 3085 20 (15 to
28)28 (20 to 47)
Central pain 1 1015 115 10 (15 to 69)
17 (11 to 30)
Bandolier
Anticonvulsants as Membrane Stabilisers
bull pregabalinbull gabapentin bull carbamazepinebull clonazepam pooled NNT 27bull valproatebull lamotriginebull baclofen
Anticonvulsants Compared with Placebo
Condition Number of trials
Anticonvulsant improvedtotal
Placebo improvedtot
al
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 3 5668 2668 19 (14 to 27) 25 (18
to 40)
Trigeminal neuralgia 3 178315 41224 31 (23 to 41) 26 (22
to 33)
Migraine prophylaxis 2 6374 1777 37 (24 to 59) 16 (13
to 20)
Other pain syndromes 1 514 115 54 (07 to 40)
not calculat ed
Bandolier
Relative Activity on Serotonin and Norepinephrine Reuptake Among
Antidepressants
CitalopramFluvoxamineSertralineParoxetineFluoxetine
VenlafaxineDuloxetine
MaprotilineDesipramineNortriptylineReboxetine
AmitriptylineMilnacipranImipramine
Serotonin Mixed Norepinephrine
Antidepressant Analgesic Antidepressant
Fishbain et al Pain Med 20001310-316
Opioidsbull In principle opioids are effective in nociceptive
and some neuropathic pain however not always and not necessarily completely for dynamic pain
bull Possibly preferable opioids here arendash tramadol
bull noradrenergic and serotoninergic effectndash morphine
bull Mu receptor anatagonistmonaminergic effect
ndash oxycodonebull kappa receptor effect
Opioids
bull lsquoLack of analgesic effect of opioids on neuropathic hellip painrsquo Pain 19883311
bull lsquohellip intravenous hellip morphine reduce the pain of Osteoarthritisrsquo Neurology
1991411024bull lsquoA call for more science not more
rhetoric regarding opioids and arthritic painrsquo Pain 2001471
bull lsquoEfficacy of oxycodone in neuropathic painhelliprsquo Neurology 1998501837
OPIOIDS FOR OA PAINbull Osteoarthritis guidelines provide limited guidance on opioid use bull The 1995 ACR guidelines for hip OA suggest opioids be avoided for
long term use but short term use may be helpful without reference to primary data15
bull The 1995 ACR knee OA guidelines do not discuss opioids directly16 bull The 1998 UK guidelines on degenerative arthritis suggest that if
relief is inadequate with 24 grams of ibuprofen and 40 grams of paracetamol a day other antiinflammatories or opioids may be considered18
bull The 2000 update of the ACR OA guidelines suggests that opioids might be used as a medication of last resort17
bull Opioids are effective in OA hip and knee pain and have predictable side effects
bull It would be unwise were physicians to discount an entire class of medications over unfounded fears and incomplete knowledge of their benefits44
USE OF ULTRACET IN OA KNEESbull The efficacy of tramadolacetaminophen combination tablets (Ultracetreg) as add-
on and maintenance therapy in knee osteoarthritis pain inadequately controlled by nonsteroidal anti-inflammatory drug (NSAID)
Park KS Choi JJ Kim WU Min JK Park SH Cho CS
bull TramadolAPAP add-on significantly improved knee OA pain which had been inadequately controlled by NSAIDs In those subjects who showed favorable response to tramadolAPAP and NSAID combination therapy both tramadolAPAP and NSAIDs were effective at maintaining the pain-reduced state and there was no significant difference in efficacy between tramadolAPAP and NSAIDs
Clinical Rheumatology 2011 3 Aug
Opioid Sparing Regimes
bull Multimodal analgesia (Kehlet et al 1999)
bull NSAIDs and COX-2 (Romsing Moiniche 2004)
bull Paracetamol (Romsing 2002)
bull Ketamine (Elia Tramer 2005)
bull Gabapentin and Pregabalin (Dahl et al 2004)
bull Gabapentin and Rofecoxib (Gilron et al 2005)
Opioid reduction 20 ndash 40 Reduction of PONV 30
Clinical effects
Single-modality treatment of a Multi- modality problem is
futile
ldquoTherersquos no pain thatrsquos so easy to bear than that of
someone elserdquo
ndashLeriche
Van Gogh ldquoOld Man in Sorrowrdquo
2007 League table of NNT for at least 50 pain relief over 4-6 hrs in patients with moderate to severe pain
(all oral analgesics except IM morphine )
[httpwwwmedicineoxacukbandolierboothpainpagacutrevanalgesicsleagtabhtml
ETORICOXIB IN ACUTE PAIN
bull Etoricoxib 120 mg has been approved for treating acute pain which includes post-operative pain and other acute pain such as primary dysmenorrhea and acute gouty arthritis
bull Efficacy of etoricoxib in the post-operative setting as evaluated by NNT bull COCHRANE REVIEW Five randomized placebo-controlled studies
with a total number of 880 patients were included -- Four studies on patients with dental pain following extraction of at least one impacted third molar
--One study on patients with pain following uncomplicated orthopaedic surgery
bull NNT were calculated to measure at least 50 pain relief over 4-6 hrs (substantial pain relief) based on TOPAR scores
Results 120 mg etoricoxib with a NNT of 19 for acute post-operative pain
1 Chang DJ Desjardins PJ King TR Erb T Geba GP The analgesic efficacy of etoricoxib compared with oxycodoneacetaminophen in an acute postoperative pain model a randomized double-blind clinical trial Anesthesia and Analgesia 200499(3)807ndash15
2 Malmstrom K Sapre A Couglin H Agrawal NG Mazenko RS Fricke JR Jr Etoricoxib in acute pain associated with dental surgery a randomized double-blind placebo- and active comparator-controlled dose-ranging study Clinical Therapeutics 200426(5)667ndash79
3 Malmstrom K Kotey P Coughlin H Desjardins PJ A randomized double-blind parallel-group study comparing the analgesic effect of etoricoxib to placebo naproxen sodium and acetaminophen with codeine using the dental impaction pain model Clinical Journal of Pain 200420(3)147ndash 55
4 Malmstrom K Ang J Fricke JR Shingo S Reicin A The analgesic effect of etoricoxib relative to that of cetaminophen analgesics a randomized controlled single-dose study in acute dental impaction pain Current Medical Research and Opinion 200521(1)141ndash9 Rasmussen 2005 published data only
5 Rasmussen GL Malmstrom K Bourne MH Jove M Rhondeau SM Kotey P Etoricoxib provides analgesic efficacy to patients after knee or hip replacement surgery a randomized double-blind placebo-controlled study Anaesthesia and Analgesia 2005101(4) 1104ndash11
Etoricoxib in acute pain bull Indirect comparisons of NNTs for at least 50 pain
relief over 4 to 6 hours in reviews of other analgesics using identical methods indicate that etoricoxib 120 mg
-- has slightly better efficacy than rofecoxib 50 mg (22 (19 to 24) Barden 2005)
-- is significantly better than lumiracoxib 400mg (27 (22 to 35) Roy 2007) or-- celecoxib 400 mg (25 (22 to 29) Derry 2008)
-- better than the non-selective NSAIDs ibuprofen 400 mg (27 (25 to 30) Collins 1999) naproxen 500 mg (27 (23 to 32 Derry 2009a) and diclofenac 50mg (24 (18 to 33Derry 2009b)
Placebo
Paracetamol 10007
Paracetamolcodeine 1000606
Ibuprofen 4005
Celecoxib 4004
Naproxen 5005503
Rofecoxib 502
Etoricoxib 1201
0 4 8 12 16 20 24Median remedication time (hr)
Each bar is from a Cochrane review
Acute pain Time for patients to Re-medication
The weighted median time to re-medication with ARCOXIA 120mg is about 24hrs
vs placebo at 18hrs
1 Clarke R et al Cochrane Database Syst Rev 2009 Apr 15(2)CD004309 2 Bulley S et al Cochrane Database Syst Rev 2009 Oct 7(4)CD0046043 Derry C et al Cochrane Database Syst Rev 2009 Jan 21(1)CD004234 4 Derry S Cochrane Database Syst Rev 2008 Oct 8(4)CD0042335 Derry C et al Cochrane Database Syst Rev 2009 Jul 8(3)CD0015486 Toms L et al Cochrane Database Syst Rev 2009 Jan 21(1)CD0015477 Toms L et al Cochrane Database Syst Rev 2008 Oct 8(4)CD004602
Placebo (n=56)
Etoricoxib 60 mg (n=224)
Naproxen 1000 mgc
(n=221)
a0-
to 100-mm VAS (0 = none to 100 = extreme)
b0-
to 100-mm VAS (0 = very well to 100 = very poor) c500 mg twice dailyPlt0001 vs placebo for both etoricoxib and naproxen P = NS etoricoxib vs naproxen
Leung AT et al Curr Med Res Opin 200218(2)49ndash58
LS M
ean
Cha
nge
plusmnSE
Weeks Postrandomization
Osteoarthritis Etoricoxib 60 mg vs Naproxen
Results Etoricoxib relieved pain and improved mobility and disease statuEtoricoxib relieved pain and improved mobility and disease statuss
ndash35
ndash25
ndash5
5
ndash15
WOMAC Pain Subscalea
S R 4 82 12
WOMAC Physical Function Subscalea PGADSb
ndash35
ndash25
ndash5
5
ndash15
S R 4 82 12ndash35
ndash25
ndash5
5
ndash15
S R 4 82 12Weeks Postrandomization Weeks Postrandomization
Adverse effects of NSAIDsAdverse effects of NSAIDs
BNF March 2002
Dose-dependent toxicityIntolerability dyspepsiaGI bleedingUlcers ndash bleeds perforations
Upper-GI
Renal
Contributes to blood loss
Fluid retention oedema hypertensionRenal dysfunction failure ndash acute chronicHeart failure
Anti-platelet effects
Angioedema bronchospasmHypersensitivity
No Short-Term Adverse GI Effects -
The Big Mistake
bull Study designed to evaluate short-term GI effects in elderly
bull Study planned to enrol 160 patientsbull Study terminated by investigator at 17 subjects
ndash 8 patients had ulcersndash 4 of 4 in ketorolac group
lsquo hellip because of the unexpectedly high incidence of gastroduodenal ulcers observedhelliprsquo
Harris et al ClinTher 2001231422
Class Effect of All NSAIDs
httpwwwfdagovcderdruginfopageCOX2NSAIDdecisionMemopdf
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
33
Cardiovascular Safetybull Arthritis patients often have concomitant CV
disease1
bull Pain is an important predictor of CV risk23
bull Randomized controlled trials and observational data demonstrate that CV risk of etoricoxib appears similar to that of traditional NSAIDs4-6
bull Recent data suggest that differential CV effects of NSAIDs (selective and nonselective) may be independent of COX-2 inhibition78
References 1 Singh G et al Am J Manag Care 20028(suppl)S383-S391 2
Sokka T Pincus T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 3
Pincus T Sokka T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 4
httpwwwfdagovohrmsdocketsac05slides2005-4090S1_06_01_Pfizer-celecoxibppt (accessed 14 February 2006) 5
White WB et al Am J Cardiol 200289425ndash430 6
Graham DJ et al Lancet 2005365475ndash481 7 Yang HM et al Circulation 2004110301ndash308 8 Steffel J et al Circulation 20051111685ndash1689
Events per 100 patient years
Coxib Coxib Placebo Coxib NSAID Percent naproxen
Rofecoxib 17 19 11 08 73
Celecoxib 13 15 11 11 20
Valdecoxib 13 12 13 20 about 50
Etoricoxib 13 12 12 08 67
Lumiracoxib 09 08 52
34
APTC endpoint (cardiovascular haemorrhagic and unknown death and nonfatal myocardial infarction and stroke)
1
MR Weir et al Selective COX-2 inhibition and cardiovascular effects a review of the rofecoxib development program American heart Journal 2003 146 591-604
2
WB White et al Cardiovascular thrombotic events in arthritis trials of the cyclooxygenase-2 inhibitor celecoxib American Journal of cardiology 2003 92 411-418
3
WB White et al Effects of the cyclooxygenase-2 specific inhibitor valdecoxib versus nonsteroidal anti-inflammatory agents and placebo on cardiovascular thrombotic events in patients with arthritis American Journal of Therapeutics 2004 11 244-250
4
S Curtis et al Cardiovascular safety summary associated with the etoricoxib development programme Arthritis amp Rheumatism 2003 48 Suppl S616
5
ME Farkouh et al Comparison of lumiracoxib with naproxen and ibuprofen in the therapeutic arthritis research and gastrointestinal event trial (TARGET) cardiovascular outcomes randomised controlled trial Lancet 2004 364 675-684
RECOMMENDATIONS
NSAIDs COXIBs
bull Use lowest effective dose shortest duration
bull Not for patients who have recently undergone coronary artery bypass graft (CABG) surgery and revascularisation procedures
bull Coxibs should not be prescribed for patients with established ischaemic heart disease stroke or congestive heart failure
bull Caution for Coxibs for patients who have hypertension hyperlipidaemia diabetes and smoking as well as peripheral arterial disease
bull Etoricoxib should not be prescribed for patients with hypertension whose blood pressure has not been adequately controlled
The EU Summit is supported by Pfizer
Tricyclic Agents
bull best documented analgesics here (NNT 22)bull amitriptyline best investigatedbull desipraminenortriptyline less AEs
bull start on low doses increases compliancebullOften adverse effects (NNH 28)bull effect needs timebull SSRIs not as effective (NNT 67)
bull noradrenergic effect necessarybull venlafaxine another option
Antidepressants Compared with Placebo
Condition Number of trials
Antidepressant improvedtotal
Placebo improvedtotal
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 13 180260 73205 19 (16 to
24)30 (24 to 40)
Postherpetic neuralgia 3 4377 868 48 (24 to
94)23 (17 to 33)
Atypical facial pain 2 6288 3085 20 (15 to
28)28 (20 to 47)
Central pain 1 1015 115 10 (15 to 69)
17 (11 to 30)
Bandolier
Anticonvulsants as Membrane Stabilisers
bull pregabalinbull gabapentin bull carbamazepinebull clonazepam pooled NNT 27bull valproatebull lamotriginebull baclofen
Anticonvulsants Compared with Placebo
Condition Number of trials
Anticonvulsant improvedtotal
Placebo improvedtot
al
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 3 5668 2668 19 (14 to 27) 25 (18
to 40)
Trigeminal neuralgia 3 178315 41224 31 (23 to 41) 26 (22
to 33)
Migraine prophylaxis 2 6374 1777 37 (24 to 59) 16 (13
to 20)
Other pain syndromes 1 514 115 54 (07 to 40)
not calculat ed
Bandolier
Relative Activity on Serotonin and Norepinephrine Reuptake Among
Antidepressants
CitalopramFluvoxamineSertralineParoxetineFluoxetine
VenlafaxineDuloxetine
MaprotilineDesipramineNortriptylineReboxetine
AmitriptylineMilnacipranImipramine
Serotonin Mixed Norepinephrine
Antidepressant Analgesic Antidepressant
Fishbain et al Pain Med 20001310-316
Opioidsbull In principle opioids are effective in nociceptive
and some neuropathic pain however not always and not necessarily completely for dynamic pain
bull Possibly preferable opioids here arendash tramadol
bull noradrenergic and serotoninergic effectndash morphine
bull Mu receptor anatagonistmonaminergic effect
ndash oxycodonebull kappa receptor effect
Opioids
bull lsquoLack of analgesic effect of opioids on neuropathic hellip painrsquo Pain 19883311
bull lsquohellip intravenous hellip morphine reduce the pain of Osteoarthritisrsquo Neurology
1991411024bull lsquoA call for more science not more
rhetoric regarding opioids and arthritic painrsquo Pain 2001471
bull lsquoEfficacy of oxycodone in neuropathic painhelliprsquo Neurology 1998501837
OPIOIDS FOR OA PAINbull Osteoarthritis guidelines provide limited guidance on opioid use bull The 1995 ACR guidelines for hip OA suggest opioids be avoided for
long term use but short term use may be helpful without reference to primary data15
bull The 1995 ACR knee OA guidelines do not discuss opioids directly16 bull The 1998 UK guidelines on degenerative arthritis suggest that if
relief is inadequate with 24 grams of ibuprofen and 40 grams of paracetamol a day other antiinflammatories or opioids may be considered18
bull The 2000 update of the ACR OA guidelines suggests that opioids might be used as a medication of last resort17
bull Opioids are effective in OA hip and knee pain and have predictable side effects
bull It would be unwise were physicians to discount an entire class of medications over unfounded fears and incomplete knowledge of their benefits44
USE OF ULTRACET IN OA KNEESbull The efficacy of tramadolacetaminophen combination tablets (Ultracetreg) as add-
on and maintenance therapy in knee osteoarthritis pain inadequately controlled by nonsteroidal anti-inflammatory drug (NSAID)
Park KS Choi JJ Kim WU Min JK Park SH Cho CS
bull TramadolAPAP add-on significantly improved knee OA pain which had been inadequately controlled by NSAIDs In those subjects who showed favorable response to tramadolAPAP and NSAID combination therapy both tramadolAPAP and NSAIDs were effective at maintaining the pain-reduced state and there was no significant difference in efficacy between tramadolAPAP and NSAIDs
Clinical Rheumatology 2011 3 Aug
Opioid Sparing Regimes
bull Multimodal analgesia (Kehlet et al 1999)
bull NSAIDs and COX-2 (Romsing Moiniche 2004)
bull Paracetamol (Romsing 2002)
bull Ketamine (Elia Tramer 2005)
bull Gabapentin and Pregabalin (Dahl et al 2004)
bull Gabapentin and Rofecoxib (Gilron et al 2005)
Opioid reduction 20 ndash 40 Reduction of PONV 30
Clinical effects
Single-modality treatment of a Multi- modality problem is
futile
ldquoTherersquos no pain thatrsquos so easy to bear than that of
someone elserdquo
ndashLeriche
Van Gogh ldquoOld Man in Sorrowrdquo
ETORICOXIB IN ACUTE PAIN
bull Etoricoxib 120 mg has been approved for treating acute pain which includes post-operative pain and other acute pain such as primary dysmenorrhea and acute gouty arthritis
bull Efficacy of etoricoxib in the post-operative setting as evaluated by NNT bull COCHRANE REVIEW Five randomized placebo-controlled studies
with a total number of 880 patients were included -- Four studies on patients with dental pain following extraction of at least one impacted third molar
--One study on patients with pain following uncomplicated orthopaedic surgery
bull NNT were calculated to measure at least 50 pain relief over 4-6 hrs (substantial pain relief) based on TOPAR scores
Results 120 mg etoricoxib with a NNT of 19 for acute post-operative pain
1 Chang DJ Desjardins PJ King TR Erb T Geba GP The analgesic efficacy of etoricoxib compared with oxycodoneacetaminophen in an acute postoperative pain model a randomized double-blind clinical trial Anesthesia and Analgesia 200499(3)807ndash15
2 Malmstrom K Sapre A Couglin H Agrawal NG Mazenko RS Fricke JR Jr Etoricoxib in acute pain associated with dental surgery a randomized double-blind placebo- and active comparator-controlled dose-ranging study Clinical Therapeutics 200426(5)667ndash79
3 Malmstrom K Kotey P Coughlin H Desjardins PJ A randomized double-blind parallel-group study comparing the analgesic effect of etoricoxib to placebo naproxen sodium and acetaminophen with codeine using the dental impaction pain model Clinical Journal of Pain 200420(3)147ndash 55
4 Malmstrom K Ang J Fricke JR Shingo S Reicin A The analgesic effect of etoricoxib relative to that of cetaminophen analgesics a randomized controlled single-dose study in acute dental impaction pain Current Medical Research and Opinion 200521(1)141ndash9 Rasmussen 2005 published data only
5 Rasmussen GL Malmstrom K Bourne MH Jove M Rhondeau SM Kotey P Etoricoxib provides analgesic efficacy to patients after knee or hip replacement surgery a randomized double-blind placebo-controlled study Anaesthesia and Analgesia 2005101(4) 1104ndash11
Etoricoxib in acute pain bull Indirect comparisons of NNTs for at least 50 pain
relief over 4 to 6 hours in reviews of other analgesics using identical methods indicate that etoricoxib 120 mg
-- has slightly better efficacy than rofecoxib 50 mg (22 (19 to 24) Barden 2005)
-- is significantly better than lumiracoxib 400mg (27 (22 to 35) Roy 2007) or-- celecoxib 400 mg (25 (22 to 29) Derry 2008)
-- better than the non-selective NSAIDs ibuprofen 400 mg (27 (25 to 30) Collins 1999) naproxen 500 mg (27 (23 to 32 Derry 2009a) and diclofenac 50mg (24 (18 to 33Derry 2009b)
Placebo
Paracetamol 10007
Paracetamolcodeine 1000606
Ibuprofen 4005
Celecoxib 4004
Naproxen 5005503
Rofecoxib 502
Etoricoxib 1201
0 4 8 12 16 20 24Median remedication time (hr)
Each bar is from a Cochrane review
Acute pain Time for patients to Re-medication
The weighted median time to re-medication with ARCOXIA 120mg is about 24hrs
vs placebo at 18hrs
1 Clarke R et al Cochrane Database Syst Rev 2009 Apr 15(2)CD004309 2 Bulley S et al Cochrane Database Syst Rev 2009 Oct 7(4)CD0046043 Derry C et al Cochrane Database Syst Rev 2009 Jan 21(1)CD004234 4 Derry S Cochrane Database Syst Rev 2008 Oct 8(4)CD0042335 Derry C et al Cochrane Database Syst Rev 2009 Jul 8(3)CD0015486 Toms L et al Cochrane Database Syst Rev 2009 Jan 21(1)CD0015477 Toms L et al Cochrane Database Syst Rev 2008 Oct 8(4)CD004602
Placebo (n=56)
Etoricoxib 60 mg (n=224)
Naproxen 1000 mgc
(n=221)
a0-
to 100-mm VAS (0 = none to 100 = extreme)
b0-
to 100-mm VAS (0 = very well to 100 = very poor) c500 mg twice dailyPlt0001 vs placebo for both etoricoxib and naproxen P = NS etoricoxib vs naproxen
Leung AT et al Curr Med Res Opin 200218(2)49ndash58
LS M
ean
Cha
nge
plusmnSE
Weeks Postrandomization
Osteoarthritis Etoricoxib 60 mg vs Naproxen
Results Etoricoxib relieved pain and improved mobility and disease statuEtoricoxib relieved pain and improved mobility and disease statuss
ndash35
ndash25
ndash5
5
ndash15
WOMAC Pain Subscalea
S R 4 82 12
WOMAC Physical Function Subscalea PGADSb
ndash35
ndash25
ndash5
5
ndash15
S R 4 82 12ndash35
ndash25
ndash5
5
ndash15
S R 4 82 12Weeks Postrandomization Weeks Postrandomization
Adverse effects of NSAIDsAdverse effects of NSAIDs
BNF March 2002
Dose-dependent toxicityIntolerability dyspepsiaGI bleedingUlcers ndash bleeds perforations
Upper-GI
Renal
Contributes to blood loss
Fluid retention oedema hypertensionRenal dysfunction failure ndash acute chronicHeart failure
Anti-platelet effects
Angioedema bronchospasmHypersensitivity
No Short-Term Adverse GI Effects -
The Big Mistake
bull Study designed to evaluate short-term GI effects in elderly
bull Study planned to enrol 160 patientsbull Study terminated by investigator at 17 subjects
ndash 8 patients had ulcersndash 4 of 4 in ketorolac group
lsquo hellip because of the unexpectedly high incidence of gastroduodenal ulcers observedhelliprsquo
Harris et al ClinTher 2001231422
Class Effect of All NSAIDs
httpwwwfdagovcderdruginfopageCOX2NSAIDdecisionMemopdf
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
33
Cardiovascular Safetybull Arthritis patients often have concomitant CV
disease1
bull Pain is an important predictor of CV risk23
bull Randomized controlled trials and observational data demonstrate that CV risk of etoricoxib appears similar to that of traditional NSAIDs4-6
bull Recent data suggest that differential CV effects of NSAIDs (selective and nonselective) may be independent of COX-2 inhibition78
References 1 Singh G et al Am J Manag Care 20028(suppl)S383-S391 2
Sokka T Pincus T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 3
Pincus T Sokka T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 4
httpwwwfdagovohrmsdocketsac05slides2005-4090S1_06_01_Pfizer-celecoxibppt (accessed 14 February 2006) 5
White WB et al Am J Cardiol 200289425ndash430 6
Graham DJ et al Lancet 2005365475ndash481 7 Yang HM et al Circulation 2004110301ndash308 8 Steffel J et al Circulation 20051111685ndash1689
Events per 100 patient years
Coxib Coxib Placebo Coxib NSAID Percent naproxen
Rofecoxib 17 19 11 08 73
Celecoxib 13 15 11 11 20
Valdecoxib 13 12 13 20 about 50
Etoricoxib 13 12 12 08 67
Lumiracoxib 09 08 52
34
APTC endpoint (cardiovascular haemorrhagic and unknown death and nonfatal myocardial infarction and stroke)
1
MR Weir et al Selective COX-2 inhibition and cardiovascular effects a review of the rofecoxib development program American heart Journal 2003 146 591-604
2
WB White et al Cardiovascular thrombotic events in arthritis trials of the cyclooxygenase-2 inhibitor celecoxib American Journal of cardiology 2003 92 411-418
3
WB White et al Effects of the cyclooxygenase-2 specific inhibitor valdecoxib versus nonsteroidal anti-inflammatory agents and placebo on cardiovascular thrombotic events in patients with arthritis American Journal of Therapeutics 2004 11 244-250
4
S Curtis et al Cardiovascular safety summary associated with the etoricoxib development programme Arthritis amp Rheumatism 2003 48 Suppl S616
5
ME Farkouh et al Comparison of lumiracoxib with naproxen and ibuprofen in the therapeutic arthritis research and gastrointestinal event trial (TARGET) cardiovascular outcomes randomised controlled trial Lancet 2004 364 675-684
RECOMMENDATIONS
NSAIDs COXIBs
bull Use lowest effective dose shortest duration
bull Not for patients who have recently undergone coronary artery bypass graft (CABG) surgery and revascularisation procedures
bull Coxibs should not be prescribed for patients with established ischaemic heart disease stroke or congestive heart failure
bull Caution for Coxibs for patients who have hypertension hyperlipidaemia diabetes and smoking as well as peripheral arterial disease
bull Etoricoxib should not be prescribed for patients with hypertension whose blood pressure has not been adequately controlled
The EU Summit is supported by Pfizer
Tricyclic Agents
bull best documented analgesics here (NNT 22)bull amitriptyline best investigatedbull desipraminenortriptyline less AEs
bull start on low doses increases compliancebullOften adverse effects (NNH 28)bull effect needs timebull SSRIs not as effective (NNT 67)
bull noradrenergic effect necessarybull venlafaxine another option
Antidepressants Compared with Placebo
Condition Number of trials
Antidepressant improvedtotal
Placebo improvedtotal
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 13 180260 73205 19 (16 to
24)30 (24 to 40)
Postherpetic neuralgia 3 4377 868 48 (24 to
94)23 (17 to 33)
Atypical facial pain 2 6288 3085 20 (15 to
28)28 (20 to 47)
Central pain 1 1015 115 10 (15 to 69)
17 (11 to 30)
Bandolier
Anticonvulsants as Membrane Stabilisers
bull pregabalinbull gabapentin bull carbamazepinebull clonazepam pooled NNT 27bull valproatebull lamotriginebull baclofen
Anticonvulsants Compared with Placebo
Condition Number of trials
Anticonvulsant improvedtotal
Placebo improvedtot
al
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 3 5668 2668 19 (14 to 27) 25 (18
to 40)
Trigeminal neuralgia 3 178315 41224 31 (23 to 41) 26 (22
to 33)
Migraine prophylaxis 2 6374 1777 37 (24 to 59) 16 (13
to 20)
Other pain syndromes 1 514 115 54 (07 to 40)
not calculat ed
Bandolier
Relative Activity on Serotonin and Norepinephrine Reuptake Among
Antidepressants
CitalopramFluvoxamineSertralineParoxetineFluoxetine
VenlafaxineDuloxetine
MaprotilineDesipramineNortriptylineReboxetine
AmitriptylineMilnacipranImipramine
Serotonin Mixed Norepinephrine
Antidepressant Analgesic Antidepressant
Fishbain et al Pain Med 20001310-316
Opioidsbull In principle opioids are effective in nociceptive
and some neuropathic pain however not always and not necessarily completely for dynamic pain
bull Possibly preferable opioids here arendash tramadol
bull noradrenergic and serotoninergic effectndash morphine
bull Mu receptor anatagonistmonaminergic effect
ndash oxycodonebull kappa receptor effect
Opioids
bull lsquoLack of analgesic effect of opioids on neuropathic hellip painrsquo Pain 19883311
bull lsquohellip intravenous hellip morphine reduce the pain of Osteoarthritisrsquo Neurology
1991411024bull lsquoA call for more science not more
rhetoric regarding opioids and arthritic painrsquo Pain 2001471
bull lsquoEfficacy of oxycodone in neuropathic painhelliprsquo Neurology 1998501837
OPIOIDS FOR OA PAINbull Osteoarthritis guidelines provide limited guidance on opioid use bull The 1995 ACR guidelines for hip OA suggest opioids be avoided for
long term use but short term use may be helpful without reference to primary data15
bull The 1995 ACR knee OA guidelines do not discuss opioids directly16 bull The 1998 UK guidelines on degenerative arthritis suggest that if
relief is inadequate with 24 grams of ibuprofen and 40 grams of paracetamol a day other antiinflammatories or opioids may be considered18
bull The 2000 update of the ACR OA guidelines suggests that opioids might be used as a medication of last resort17
bull Opioids are effective in OA hip and knee pain and have predictable side effects
bull It would be unwise were physicians to discount an entire class of medications over unfounded fears and incomplete knowledge of their benefits44
USE OF ULTRACET IN OA KNEESbull The efficacy of tramadolacetaminophen combination tablets (Ultracetreg) as add-
on and maintenance therapy in knee osteoarthritis pain inadequately controlled by nonsteroidal anti-inflammatory drug (NSAID)
Park KS Choi JJ Kim WU Min JK Park SH Cho CS
bull TramadolAPAP add-on significantly improved knee OA pain which had been inadequately controlled by NSAIDs In those subjects who showed favorable response to tramadolAPAP and NSAID combination therapy both tramadolAPAP and NSAIDs were effective at maintaining the pain-reduced state and there was no significant difference in efficacy between tramadolAPAP and NSAIDs
Clinical Rheumatology 2011 3 Aug
Opioid Sparing Regimes
bull Multimodal analgesia (Kehlet et al 1999)
bull NSAIDs and COX-2 (Romsing Moiniche 2004)
bull Paracetamol (Romsing 2002)
bull Ketamine (Elia Tramer 2005)
bull Gabapentin and Pregabalin (Dahl et al 2004)
bull Gabapentin and Rofecoxib (Gilron et al 2005)
Opioid reduction 20 ndash 40 Reduction of PONV 30
Clinical effects
Single-modality treatment of a Multi- modality problem is
futile
ldquoTherersquos no pain thatrsquos so easy to bear than that of
someone elserdquo
ndashLeriche
Van Gogh ldquoOld Man in Sorrowrdquo
Results 120 mg etoricoxib with a NNT of 19 for acute post-operative pain
1 Chang DJ Desjardins PJ King TR Erb T Geba GP The analgesic efficacy of etoricoxib compared with oxycodoneacetaminophen in an acute postoperative pain model a randomized double-blind clinical trial Anesthesia and Analgesia 200499(3)807ndash15
2 Malmstrom K Sapre A Couglin H Agrawal NG Mazenko RS Fricke JR Jr Etoricoxib in acute pain associated with dental surgery a randomized double-blind placebo- and active comparator-controlled dose-ranging study Clinical Therapeutics 200426(5)667ndash79
3 Malmstrom K Kotey P Coughlin H Desjardins PJ A randomized double-blind parallel-group study comparing the analgesic effect of etoricoxib to placebo naproxen sodium and acetaminophen with codeine using the dental impaction pain model Clinical Journal of Pain 200420(3)147ndash 55
4 Malmstrom K Ang J Fricke JR Shingo S Reicin A The analgesic effect of etoricoxib relative to that of cetaminophen analgesics a randomized controlled single-dose study in acute dental impaction pain Current Medical Research and Opinion 200521(1)141ndash9 Rasmussen 2005 published data only
5 Rasmussen GL Malmstrom K Bourne MH Jove M Rhondeau SM Kotey P Etoricoxib provides analgesic efficacy to patients after knee or hip replacement surgery a randomized double-blind placebo-controlled study Anaesthesia and Analgesia 2005101(4) 1104ndash11
Etoricoxib in acute pain bull Indirect comparisons of NNTs for at least 50 pain
relief over 4 to 6 hours in reviews of other analgesics using identical methods indicate that etoricoxib 120 mg
-- has slightly better efficacy than rofecoxib 50 mg (22 (19 to 24) Barden 2005)
-- is significantly better than lumiracoxib 400mg (27 (22 to 35) Roy 2007) or-- celecoxib 400 mg (25 (22 to 29) Derry 2008)
-- better than the non-selective NSAIDs ibuprofen 400 mg (27 (25 to 30) Collins 1999) naproxen 500 mg (27 (23 to 32 Derry 2009a) and diclofenac 50mg (24 (18 to 33Derry 2009b)
Placebo
Paracetamol 10007
Paracetamolcodeine 1000606
Ibuprofen 4005
Celecoxib 4004
Naproxen 5005503
Rofecoxib 502
Etoricoxib 1201
0 4 8 12 16 20 24Median remedication time (hr)
Each bar is from a Cochrane review
Acute pain Time for patients to Re-medication
The weighted median time to re-medication with ARCOXIA 120mg is about 24hrs
vs placebo at 18hrs
1 Clarke R et al Cochrane Database Syst Rev 2009 Apr 15(2)CD004309 2 Bulley S et al Cochrane Database Syst Rev 2009 Oct 7(4)CD0046043 Derry C et al Cochrane Database Syst Rev 2009 Jan 21(1)CD004234 4 Derry S Cochrane Database Syst Rev 2008 Oct 8(4)CD0042335 Derry C et al Cochrane Database Syst Rev 2009 Jul 8(3)CD0015486 Toms L et al Cochrane Database Syst Rev 2009 Jan 21(1)CD0015477 Toms L et al Cochrane Database Syst Rev 2008 Oct 8(4)CD004602
Placebo (n=56)
Etoricoxib 60 mg (n=224)
Naproxen 1000 mgc
(n=221)
a0-
to 100-mm VAS (0 = none to 100 = extreme)
b0-
to 100-mm VAS (0 = very well to 100 = very poor) c500 mg twice dailyPlt0001 vs placebo for both etoricoxib and naproxen P = NS etoricoxib vs naproxen
Leung AT et al Curr Med Res Opin 200218(2)49ndash58
LS M
ean
Cha
nge
plusmnSE
Weeks Postrandomization
Osteoarthritis Etoricoxib 60 mg vs Naproxen
Results Etoricoxib relieved pain and improved mobility and disease statuEtoricoxib relieved pain and improved mobility and disease statuss
ndash35
ndash25
ndash5
5
ndash15
WOMAC Pain Subscalea
S R 4 82 12
WOMAC Physical Function Subscalea PGADSb
ndash35
ndash25
ndash5
5
ndash15
S R 4 82 12ndash35
ndash25
ndash5
5
ndash15
S R 4 82 12Weeks Postrandomization Weeks Postrandomization
Adverse effects of NSAIDsAdverse effects of NSAIDs
BNF March 2002
Dose-dependent toxicityIntolerability dyspepsiaGI bleedingUlcers ndash bleeds perforations
Upper-GI
Renal
Contributes to blood loss
Fluid retention oedema hypertensionRenal dysfunction failure ndash acute chronicHeart failure
Anti-platelet effects
Angioedema bronchospasmHypersensitivity
No Short-Term Adverse GI Effects -
The Big Mistake
bull Study designed to evaluate short-term GI effects in elderly
bull Study planned to enrol 160 patientsbull Study terminated by investigator at 17 subjects
ndash 8 patients had ulcersndash 4 of 4 in ketorolac group
lsquo hellip because of the unexpectedly high incidence of gastroduodenal ulcers observedhelliprsquo
Harris et al ClinTher 2001231422
Class Effect of All NSAIDs
httpwwwfdagovcderdruginfopageCOX2NSAIDdecisionMemopdf
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
33
Cardiovascular Safetybull Arthritis patients often have concomitant CV
disease1
bull Pain is an important predictor of CV risk23
bull Randomized controlled trials and observational data demonstrate that CV risk of etoricoxib appears similar to that of traditional NSAIDs4-6
bull Recent data suggest that differential CV effects of NSAIDs (selective and nonselective) may be independent of COX-2 inhibition78
References 1 Singh G et al Am J Manag Care 20028(suppl)S383-S391 2
Sokka T Pincus T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 3
Pincus T Sokka T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 4
httpwwwfdagovohrmsdocketsac05slides2005-4090S1_06_01_Pfizer-celecoxibppt (accessed 14 February 2006) 5
White WB et al Am J Cardiol 200289425ndash430 6
Graham DJ et al Lancet 2005365475ndash481 7 Yang HM et al Circulation 2004110301ndash308 8 Steffel J et al Circulation 20051111685ndash1689
Events per 100 patient years
Coxib Coxib Placebo Coxib NSAID Percent naproxen
Rofecoxib 17 19 11 08 73
Celecoxib 13 15 11 11 20
Valdecoxib 13 12 13 20 about 50
Etoricoxib 13 12 12 08 67
Lumiracoxib 09 08 52
34
APTC endpoint (cardiovascular haemorrhagic and unknown death and nonfatal myocardial infarction and stroke)
1
MR Weir et al Selective COX-2 inhibition and cardiovascular effects a review of the rofecoxib development program American heart Journal 2003 146 591-604
2
WB White et al Cardiovascular thrombotic events in arthritis trials of the cyclooxygenase-2 inhibitor celecoxib American Journal of cardiology 2003 92 411-418
3
WB White et al Effects of the cyclooxygenase-2 specific inhibitor valdecoxib versus nonsteroidal anti-inflammatory agents and placebo on cardiovascular thrombotic events in patients with arthritis American Journal of Therapeutics 2004 11 244-250
4
S Curtis et al Cardiovascular safety summary associated with the etoricoxib development programme Arthritis amp Rheumatism 2003 48 Suppl S616
5
ME Farkouh et al Comparison of lumiracoxib with naproxen and ibuprofen in the therapeutic arthritis research and gastrointestinal event trial (TARGET) cardiovascular outcomes randomised controlled trial Lancet 2004 364 675-684
RECOMMENDATIONS
NSAIDs COXIBs
bull Use lowest effective dose shortest duration
bull Not for patients who have recently undergone coronary artery bypass graft (CABG) surgery and revascularisation procedures
bull Coxibs should not be prescribed for patients with established ischaemic heart disease stroke or congestive heart failure
bull Caution for Coxibs for patients who have hypertension hyperlipidaemia diabetes and smoking as well as peripheral arterial disease
bull Etoricoxib should not be prescribed for patients with hypertension whose blood pressure has not been adequately controlled
The EU Summit is supported by Pfizer
Tricyclic Agents
bull best documented analgesics here (NNT 22)bull amitriptyline best investigatedbull desipraminenortriptyline less AEs
bull start on low doses increases compliancebullOften adverse effects (NNH 28)bull effect needs timebull SSRIs not as effective (NNT 67)
bull noradrenergic effect necessarybull venlafaxine another option
Antidepressants Compared with Placebo
Condition Number of trials
Antidepressant improvedtotal
Placebo improvedtotal
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 13 180260 73205 19 (16 to
24)30 (24 to 40)
Postherpetic neuralgia 3 4377 868 48 (24 to
94)23 (17 to 33)
Atypical facial pain 2 6288 3085 20 (15 to
28)28 (20 to 47)
Central pain 1 1015 115 10 (15 to 69)
17 (11 to 30)
Bandolier
Anticonvulsants as Membrane Stabilisers
bull pregabalinbull gabapentin bull carbamazepinebull clonazepam pooled NNT 27bull valproatebull lamotriginebull baclofen
Anticonvulsants Compared with Placebo
Condition Number of trials
Anticonvulsant improvedtotal
Placebo improvedtot
al
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 3 5668 2668 19 (14 to 27) 25 (18
to 40)
Trigeminal neuralgia 3 178315 41224 31 (23 to 41) 26 (22
to 33)
Migraine prophylaxis 2 6374 1777 37 (24 to 59) 16 (13
to 20)
Other pain syndromes 1 514 115 54 (07 to 40)
not calculat ed
Bandolier
Relative Activity on Serotonin and Norepinephrine Reuptake Among
Antidepressants
CitalopramFluvoxamineSertralineParoxetineFluoxetine
VenlafaxineDuloxetine
MaprotilineDesipramineNortriptylineReboxetine
AmitriptylineMilnacipranImipramine
Serotonin Mixed Norepinephrine
Antidepressant Analgesic Antidepressant
Fishbain et al Pain Med 20001310-316
Opioidsbull In principle opioids are effective in nociceptive
and some neuropathic pain however not always and not necessarily completely for dynamic pain
bull Possibly preferable opioids here arendash tramadol
bull noradrenergic and serotoninergic effectndash morphine
bull Mu receptor anatagonistmonaminergic effect
ndash oxycodonebull kappa receptor effect
Opioids
bull lsquoLack of analgesic effect of opioids on neuropathic hellip painrsquo Pain 19883311
bull lsquohellip intravenous hellip morphine reduce the pain of Osteoarthritisrsquo Neurology
1991411024bull lsquoA call for more science not more
rhetoric regarding opioids and arthritic painrsquo Pain 2001471
bull lsquoEfficacy of oxycodone in neuropathic painhelliprsquo Neurology 1998501837
OPIOIDS FOR OA PAINbull Osteoarthritis guidelines provide limited guidance on opioid use bull The 1995 ACR guidelines for hip OA suggest opioids be avoided for
long term use but short term use may be helpful without reference to primary data15
bull The 1995 ACR knee OA guidelines do not discuss opioids directly16 bull The 1998 UK guidelines on degenerative arthritis suggest that if
relief is inadequate with 24 grams of ibuprofen and 40 grams of paracetamol a day other antiinflammatories or opioids may be considered18
bull The 2000 update of the ACR OA guidelines suggests that opioids might be used as a medication of last resort17
bull Opioids are effective in OA hip and knee pain and have predictable side effects
bull It would be unwise were physicians to discount an entire class of medications over unfounded fears and incomplete knowledge of their benefits44
USE OF ULTRACET IN OA KNEESbull The efficacy of tramadolacetaminophen combination tablets (Ultracetreg) as add-
on and maintenance therapy in knee osteoarthritis pain inadequately controlled by nonsteroidal anti-inflammatory drug (NSAID)
Park KS Choi JJ Kim WU Min JK Park SH Cho CS
bull TramadolAPAP add-on significantly improved knee OA pain which had been inadequately controlled by NSAIDs In those subjects who showed favorable response to tramadolAPAP and NSAID combination therapy both tramadolAPAP and NSAIDs were effective at maintaining the pain-reduced state and there was no significant difference in efficacy between tramadolAPAP and NSAIDs
Clinical Rheumatology 2011 3 Aug
Opioid Sparing Regimes
bull Multimodal analgesia (Kehlet et al 1999)
bull NSAIDs and COX-2 (Romsing Moiniche 2004)
bull Paracetamol (Romsing 2002)
bull Ketamine (Elia Tramer 2005)
bull Gabapentin and Pregabalin (Dahl et al 2004)
bull Gabapentin and Rofecoxib (Gilron et al 2005)
Opioid reduction 20 ndash 40 Reduction of PONV 30
Clinical effects
Single-modality treatment of a Multi- modality problem is
futile
ldquoTherersquos no pain thatrsquos so easy to bear than that of
someone elserdquo
ndashLeriche
Van Gogh ldquoOld Man in Sorrowrdquo
Etoricoxib in acute pain bull Indirect comparisons of NNTs for at least 50 pain
relief over 4 to 6 hours in reviews of other analgesics using identical methods indicate that etoricoxib 120 mg
-- has slightly better efficacy than rofecoxib 50 mg (22 (19 to 24) Barden 2005)
-- is significantly better than lumiracoxib 400mg (27 (22 to 35) Roy 2007) or-- celecoxib 400 mg (25 (22 to 29) Derry 2008)
-- better than the non-selective NSAIDs ibuprofen 400 mg (27 (25 to 30) Collins 1999) naproxen 500 mg (27 (23 to 32 Derry 2009a) and diclofenac 50mg (24 (18 to 33Derry 2009b)
Placebo
Paracetamol 10007
Paracetamolcodeine 1000606
Ibuprofen 4005
Celecoxib 4004
Naproxen 5005503
Rofecoxib 502
Etoricoxib 1201
0 4 8 12 16 20 24Median remedication time (hr)
Each bar is from a Cochrane review
Acute pain Time for patients to Re-medication
The weighted median time to re-medication with ARCOXIA 120mg is about 24hrs
vs placebo at 18hrs
1 Clarke R et al Cochrane Database Syst Rev 2009 Apr 15(2)CD004309 2 Bulley S et al Cochrane Database Syst Rev 2009 Oct 7(4)CD0046043 Derry C et al Cochrane Database Syst Rev 2009 Jan 21(1)CD004234 4 Derry S Cochrane Database Syst Rev 2008 Oct 8(4)CD0042335 Derry C et al Cochrane Database Syst Rev 2009 Jul 8(3)CD0015486 Toms L et al Cochrane Database Syst Rev 2009 Jan 21(1)CD0015477 Toms L et al Cochrane Database Syst Rev 2008 Oct 8(4)CD004602
Placebo (n=56)
Etoricoxib 60 mg (n=224)
Naproxen 1000 mgc
(n=221)
a0-
to 100-mm VAS (0 = none to 100 = extreme)
b0-
to 100-mm VAS (0 = very well to 100 = very poor) c500 mg twice dailyPlt0001 vs placebo for both etoricoxib and naproxen P = NS etoricoxib vs naproxen
Leung AT et al Curr Med Res Opin 200218(2)49ndash58
LS M
ean
Cha
nge
plusmnSE
Weeks Postrandomization
Osteoarthritis Etoricoxib 60 mg vs Naproxen
Results Etoricoxib relieved pain and improved mobility and disease statuEtoricoxib relieved pain and improved mobility and disease statuss
ndash35
ndash25
ndash5
5
ndash15
WOMAC Pain Subscalea
S R 4 82 12
WOMAC Physical Function Subscalea PGADSb
ndash35
ndash25
ndash5
5
ndash15
S R 4 82 12ndash35
ndash25
ndash5
5
ndash15
S R 4 82 12Weeks Postrandomization Weeks Postrandomization
Adverse effects of NSAIDsAdverse effects of NSAIDs
BNF March 2002
Dose-dependent toxicityIntolerability dyspepsiaGI bleedingUlcers ndash bleeds perforations
Upper-GI
Renal
Contributes to blood loss
Fluid retention oedema hypertensionRenal dysfunction failure ndash acute chronicHeart failure
Anti-platelet effects
Angioedema bronchospasmHypersensitivity
No Short-Term Adverse GI Effects -
The Big Mistake
bull Study designed to evaluate short-term GI effects in elderly
bull Study planned to enrol 160 patientsbull Study terminated by investigator at 17 subjects
ndash 8 patients had ulcersndash 4 of 4 in ketorolac group
lsquo hellip because of the unexpectedly high incidence of gastroduodenal ulcers observedhelliprsquo
Harris et al ClinTher 2001231422
Class Effect of All NSAIDs
httpwwwfdagovcderdruginfopageCOX2NSAIDdecisionMemopdf
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
33
Cardiovascular Safetybull Arthritis patients often have concomitant CV
disease1
bull Pain is an important predictor of CV risk23
bull Randomized controlled trials and observational data demonstrate that CV risk of etoricoxib appears similar to that of traditional NSAIDs4-6
bull Recent data suggest that differential CV effects of NSAIDs (selective and nonselective) may be independent of COX-2 inhibition78
References 1 Singh G et al Am J Manag Care 20028(suppl)S383-S391 2
Sokka T Pincus T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 3
Pincus T Sokka T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 4
httpwwwfdagovohrmsdocketsac05slides2005-4090S1_06_01_Pfizer-celecoxibppt (accessed 14 February 2006) 5
White WB et al Am J Cardiol 200289425ndash430 6
Graham DJ et al Lancet 2005365475ndash481 7 Yang HM et al Circulation 2004110301ndash308 8 Steffel J et al Circulation 20051111685ndash1689
Events per 100 patient years
Coxib Coxib Placebo Coxib NSAID Percent naproxen
Rofecoxib 17 19 11 08 73
Celecoxib 13 15 11 11 20
Valdecoxib 13 12 13 20 about 50
Etoricoxib 13 12 12 08 67
Lumiracoxib 09 08 52
34
APTC endpoint (cardiovascular haemorrhagic and unknown death and nonfatal myocardial infarction and stroke)
1
MR Weir et al Selective COX-2 inhibition and cardiovascular effects a review of the rofecoxib development program American heart Journal 2003 146 591-604
2
WB White et al Cardiovascular thrombotic events in arthritis trials of the cyclooxygenase-2 inhibitor celecoxib American Journal of cardiology 2003 92 411-418
3
WB White et al Effects of the cyclooxygenase-2 specific inhibitor valdecoxib versus nonsteroidal anti-inflammatory agents and placebo on cardiovascular thrombotic events in patients with arthritis American Journal of Therapeutics 2004 11 244-250
4
S Curtis et al Cardiovascular safety summary associated with the etoricoxib development programme Arthritis amp Rheumatism 2003 48 Suppl S616
5
ME Farkouh et al Comparison of lumiracoxib with naproxen and ibuprofen in the therapeutic arthritis research and gastrointestinal event trial (TARGET) cardiovascular outcomes randomised controlled trial Lancet 2004 364 675-684
RECOMMENDATIONS
NSAIDs COXIBs
bull Use lowest effective dose shortest duration
bull Not for patients who have recently undergone coronary artery bypass graft (CABG) surgery and revascularisation procedures
bull Coxibs should not be prescribed for patients with established ischaemic heart disease stroke or congestive heart failure
bull Caution for Coxibs for patients who have hypertension hyperlipidaemia diabetes and smoking as well as peripheral arterial disease
bull Etoricoxib should not be prescribed for patients with hypertension whose blood pressure has not been adequately controlled
The EU Summit is supported by Pfizer
Tricyclic Agents
bull best documented analgesics here (NNT 22)bull amitriptyline best investigatedbull desipraminenortriptyline less AEs
bull start on low doses increases compliancebullOften adverse effects (NNH 28)bull effect needs timebull SSRIs not as effective (NNT 67)
bull noradrenergic effect necessarybull venlafaxine another option
Antidepressants Compared with Placebo
Condition Number of trials
Antidepressant improvedtotal
Placebo improvedtotal
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 13 180260 73205 19 (16 to
24)30 (24 to 40)
Postherpetic neuralgia 3 4377 868 48 (24 to
94)23 (17 to 33)
Atypical facial pain 2 6288 3085 20 (15 to
28)28 (20 to 47)
Central pain 1 1015 115 10 (15 to 69)
17 (11 to 30)
Bandolier
Anticonvulsants as Membrane Stabilisers
bull pregabalinbull gabapentin bull carbamazepinebull clonazepam pooled NNT 27bull valproatebull lamotriginebull baclofen
Anticonvulsants Compared with Placebo
Condition Number of trials
Anticonvulsant improvedtotal
Placebo improvedtot
al
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 3 5668 2668 19 (14 to 27) 25 (18
to 40)
Trigeminal neuralgia 3 178315 41224 31 (23 to 41) 26 (22
to 33)
Migraine prophylaxis 2 6374 1777 37 (24 to 59) 16 (13
to 20)
Other pain syndromes 1 514 115 54 (07 to 40)
not calculat ed
Bandolier
Relative Activity on Serotonin and Norepinephrine Reuptake Among
Antidepressants
CitalopramFluvoxamineSertralineParoxetineFluoxetine
VenlafaxineDuloxetine
MaprotilineDesipramineNortriptylineReboxetine
AmitriptylineMilnacipranImipramine
Serotonin Mixed Norepinephrine
Antidepressant Analgesic Antidepressant
Fishbain et al Pain Med 20001310-316
Opioidsbull In principle opioids are effective in nociceptive
and some neuropathic pain however not always and not necessarily completely for dynamic pain
bull Possibly preferable opioids here arendash tramadol
bull noradrenergic and serotoninergic effectndash morphine
bull Mu receptor anatagonistmonaminergic effect
ndash oxycodonebull kappa receptor effect
Opioids
bull lsquoLack of analgesic effect of opioids on neuropathic hellip painrsquo Pain 19883311
bull lsquohellip intravenous hellip morphine reduce the pain of Osteoarthritisrsquo Neurology
1991411024bull lsquoA call for more science not more
rhetoric regarding opioids and arthritic painrsquo Pain 2001471
bull lsquoEfficacy of oxycodone in neuropathic painhelliprsquo Neurology 1998501837
OPIOIDS FOR OA PAINbull Osteoarthritis guidelines provide limited guidance on opioid use bull The 1995 ACR guidelines for hip OA suggest opioids be avoided for
long term use but short term use may be helpful without reference to primary data15
bull The 1995 ACR knee OA guidelines do not discuss opioids directly16 bull The 1998 UK guidelines on degenerative arthritis suggest that if
relief is inadequate with 24 grams of ibuprofen and 40 grams of paracetamol a day other antiinflammatories or opioids may be considered18
bull The 2000 update of the ACR OA guidelines suggests that opioids might be used as a medication of last resort17
bull Opioids are effective in OA hip and knee pain and have predictable side effects
bull It would be unwise were physicians to discount an entire class of medications over unfounded fears and incomplete knowledge of their benefits44
USE OF ULTRACET IN OA KNEESbull The efficacy of tramadolacetaminophen combination tablets (Ultracetreg) as add-
on and maintenance therapy in knee osteoarthritis pain inadequately controlled by nonsteroidal anti-inflammatory drug (NSAID)
Park KS Choi JJ Kim WU Min JK Park SH Cho CS
bull TramadolAPAP add-on significantly improved knee OA pain which had been inadequately controlled by NSAIDs In those subjects who showed favorable response to tramadolAPAP and NSAID combination therapy both tramadolAPAP and NSAIDs were effective at maintaining the pain-reduced state and there was no significant difference in efficacy between tramadolAPAP and NSAIDs
Clinical Rheumatology 2011 3 Aug
Opioid Sparing Regimes
bull Multimodal analgesia (Kehlet et al 1999)
bull NSAIDs and COX-2 (Romsing Moiniche 2004)
bull Paracetamol (Romsing 2002)
bull Ketamine (Elia Tramer 2005)
bull Gabapentin and Pregabalin (Dahl et al 2004)
bull Gabapentin and Rofecoxib (Gilron et al 2005)
Opioid reduction 20 ndash 40 Reduction of PONV 30
Clinical effects
Single-modality treatment of a Multi- modality problem is
futile
ldquoTherersquos no pain thatrsquos so easy to bear than that of
someone elserdquo
ndashLeriche
Van Gogh ldquoOld Man in Sorrowrdquo
Placebo
Paracetamol 10007
Paracetamolcodeine 1000606
Ibuprofen 4005
Celecoxib 4004
Naproxen 5005503
Rofecoxib 502
Etoricoxib 1201
0 4 8 12 16 20 24Median remedication time (hr)
Each bar is from a Cochrane review
Acute pain Time for patients to Re-medication
The weighted median time to re-medication with ARCOXIA 120mg is about 24hrs
vs placebo at 18hrs
1 Clarke R et al Cochrane Database Syst Rev 2009 Apr 15(2)CD004309 2 Bulley S et al Cochrane Database Syst Rev 2009 Oct 7(4)CD0046043 Derry C et al Cochrane Database Syst Rev 2009 Jan 21(1)CD004234 4 Derry S Cochrane Database Syst Rev 2008 Oct 8(4)CD0042335 Derry C et al Cochrane Database Syst Rev 2009 Jul 8(3)CD0015486 Toms L et al Cochrane Database Syst Rev 2009 Jan 21(1)CD0015477 Toms L et al Cochrane Database Syst Rev 2008 Oct 8(4)CD004602
Placebo (n=56)
Etoricoxib 60 mg (n=224)
Naproxen 1000 mgc
(n=221)
a0-
to 100-mm VAS (0 = none to 100 = extreme)
b0-
to 100-mm VAS (0 = very well to 100 = very poor) c500 mg twice dailyPlt0001 vs placebo for both etoricoxib and naproxen P = NS etoricoxib vs naproxen
Leung AT et al Curr Med Res Opin 200218(2)49ndash58
LS M
ean
Cha
nge
plusmnSE
Weeks Postrandomization
Osteoarthritis Etoricoxib 60 mg vs Naproxen
Results Etoricoxib relieved pain and improved mobility and disease statuEtoricoxib relieved pain and improved mobility and disease statuss
ndash35
ndash25
ndash5
5
ndash15
WOMAC Pain Subscalea
S R 4 82 12
WOMAC Physical Function Subscalea PGADSb
ndash35
ndash25
ndash5
5
ndash15
S R 4 82 12ndash35
ndash25
ndash5
5
ndash15
S R 4 82 12Weeks Postrandomization Weeks Postrandomization
Adverse effects of NSAIDsAdverse effects of NSAIDs
BNF March 2002
Dose-dependent toxicityIntolerability dyspepsiaGI bleedingUlcers ndash bleeds perforations
Upper-GI
Renal
Contributes to blood loss
Fluid retention oedema hypertensionRenal dysfunction failure ndash acute chronicHeart failure
Anti-platelet effects
Angioedema bronchospasmHypersensitivity
No Short-Term Adverse GI Effects -
The Big Mistake
bull Study designed to evaluate short-term GI effects in elderly
bull Study planned to enrol 160 patientsbull Study terminated by investigator at 17 subjects
ndash 8 patients had ulcersndash 4 of 4 in ketorolac group
lsquo hellip because of the unexpectedly high incidence of gastroduodenal ulcers observedhelliprsquo
Harris et al ClinTher 2001231422
Class Effect of All NSAIDs
httpwwwfdagovcderdruginfopageCOX2NSAIDdecisionMemopdf
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
33
Cardiovascular Safetybull Arthritis patients often have concomitant CV
disease1
bull Pain is an important predictor of CV risk23
bull Randomized controlled trials and observational data demonstrate that CV risk of etoricoxib appears similar to that of traditional NSAIDs4-6
bull Recent data suggest that differential CV effects of NSAIDs (selective and nonselective) may be independent of COX-2 inhibition78
References 1 Singh G et al Am J Manag Care 20028(suppl)S383-S391 2
Sokka T Pincus T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 3
Pincus T Sokka T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 4
httpwwwfdagovohrmsdocketsac05slides2005-4090S1_06_01_Pfizer-celecoxibppt (accessed 14 February 2006) 5
White WB et al Am J Cardiol 200289425ndash430 6
Graham DJ et al Lancet 2005365475ndash481 7 Yang HM et al Circulation 2004110301ndash308 8 Steffel J et al Circulation 20051111685ndash1689
Events per 100 patient years
Coxib Coxib Placebo Coxib NSAID Percent naproxen
Rofecoxib 17 19 11 08 73
Celecoxib 13 15 11 11 20
Valdecoxib 13 12 13 20 about 50
Etoricoxib 13 12 12 08 67
Lumiracoxib 09 08 52
34
APTC endpoint (cardiovascular haemorrhagic and unknown death and nonfatal myocardial infarction and stroke)
1
MR Weir et al Selective COX-2 inhibition and cardiovascular effects a review of the rofecoxib development program American heart Journal 2003 146 591-604
2
WB White et al Cardiovascular thrombotic events in arthritis trials of the cyclooxygenase-2 inhibitor celecoxib American Journal of cardiology 2003 92 411-418
3
WB White et al Effects of the cyclooxygenase-2 specific inhibitor valdecoxib versus nonsteroidal anti-inflammatory agents and placebo on cardiovascular thrombotic events in patients with arthritis American Journal of Therapeutics 2004 11 244-250
4
S Curtis et al Cardiovascular safety summary associated with the etoricoxib development programme Arthritis amp Rheumatism 2003 48 Suppl S616
5
ME Farkouh et al Comparison of lumiracoxib with naproxen and ibuprofen in the therapeutic arthritis research and gastrointestinal event trial (TARGET) cardiovascular outcomes randomised controlled trial Lancet 2004 364 675-684
RECOMMENDATIONS
NSAIDs COXIBs
bull Use lowest effective dose shortest duration
bull Not for patients who have recently undergone coronary artery bypass graft (CABG) surgery and revascularisation procedures
bull Coxibs should not be prescribed for patients with established ischaemic heart disease stroke or congestive heart failure
bull Caution for Coxibs for patients who have hypertension hyperlipidaemia diabetes and smoking as well as peripheral arterial disease
bull Etoricoxib should not be prescribed for patients with hypertension whose blood pressure has not been adequately controlled
The EU Summit is supported by Pfizer
Tricyclic Agents
bull best documented analgesics here (NNT 22)bull amitriptyline best investigatedbull desipraminenortriptyline less AEs
bull start on low doses increases compliancebullOften adverse effects (NNH 28)bull effect needs timebull SSRIs not as effective (NNT 67)
bull noradrenergic effect necessarybull venlafaxine another option
Antidepressants Compared with Placebo
Condition Number of trials
Antidepressant improvedtotal
Placebo improvedtotal
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 13 180260 73205 19 (16 to
24)30 (24 to 40)
Postherpetic neuralgia 3 4377 868 48 (24 to
94)23 (17 to 33)
Atypical facial pain 2 6288 3085 20 (15 to
28)28 (20 to 47)
Central pain 1 1015 115 10 (15 to 69)
17 (11 to 30)
Bandolier
Anticonvulsants as Membrane Stabilisers
bull pregabalinbull gabapentin bull carbamazepinebull clonazepam pooled NNT 27bull valproatebull lamotriginebull baclofen
Anticonvulsants Compared with Placebo
Condition Number of trials
Anticonvulsant improvedtotal
Placebo improvedtot
al
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 3 5668 2668 19 (14 to 27) 25 (18
to 40)
Trigeminal neuralgia 3 178315 41224 31 (23 to 41) 26 (22
to 33)
Migraine prophylaxis 2 6374 1777 37 (24 to 59) 16 (13
to 20)
Other pain syndromes 1 514 115 54 (07 to 40)
not calculat ed
Bandolier
Relative Activity on Serotonin and Norepinephrine Reuptake Among
Antidepressants
CitalopramFluvoxamineSertralineParoxetineFluoxetine
VenlafaxineDuloxetine
MaprotilineDesipramineNortriptylineReboxetine
AmitriptylineMilnacipranImipramine
Serotonin Mixed Norepinephrine
Antidepressant Analgesic Antidepressant
Fishbain et al Pain Med 20001310-316
Opioidsbull In principle opioids are effective in nociceptive
and some neuropathic pain however not always and not necessarily completely for dynamic pain
bull Possibly preferable opioids here arendash tramadol
bull noradrenergic and serotoninergic effectndash morphine
bull Mu receptor anatagonistmonaminergic effect
ndash oxycodonebull kappa receptor effect
Opioids
bull lsquoLack of analgesic effect of opioids on neuropathic hellip painrsquo Pain 19883311
bull lsquohellip intravenous hellip morphine reduce the pain of Osteoarthritisrsquo Neurology
1991411024bull lsquoA call for more science not more
rhetoric regarding opioids and arthritic painrsquo Pain 2001471
bull lsquoEfficacy of oxycodone in neuropathic painhelliprsquo Neurology 1998501837
OPIOIDS FOR OA PAINbull Osteoarthritis guidelines provide limited guidance on opioid use bull The 1995 ACR guidelines for hip OA suggest opioids be avoided for
long term use but short term use may be helpful without reference to primary data15
bull The 1995 ACR knee OA guidelines do not discuss opioids directly16 bull The 1998 UK guidelines on degenerative arthritis suggest that if
relief is inadequate with 24 grams of ibuprofen and 40 grams of paracetamol a day other antiinflammatories or opioids may be considered18
bull The 2000 update of the ACR OA guidelines suggests that opioids might be used as a medication of last resort17
bull Opioids are effective in OA hip and knee pain and have predictable side effects
bull It would be unwise were physicians to discount an entire class of medications over unfounded fears and incomplete knowledge of their benefits44
USE OF ULTRACET IN OA KNEESbull The efficacy of tramadolacetaminophen combination tablets (Ultracetreg) as add-
on and maintenance therapy in knee osteoarthritis pain inadequately controlled by nonsteroidal anti-inflammatory drug (NSAID)
Park KS Choi JJ Kim WU Min JK Park SH Cho CS
bull TramadolAPAP add-on significantly improved knee OA pain which had been inadequately controlled by NSAIDs In those subjects who showed favorable response to tramadolAPAP and NSAID combination therapy both tramadolAPAP and NSAIDs were effective at maintaining the pain-reduced state and there was no significant difference in efficacy between tramadolAPAP and NSAIDs
Clinical Rheumatology 2011 3 Aug
Opioid Sparing Regimes
bull Multimodal analgesia (Kehlet et al 1999)
bull NSAIDs and COX-2 (Romsing Moiniche 2004)
bull Paracetamol (Romsing 2002)
bull Ketamine (Elia Tramer 2005)
bull Gabapentin and Pregabalin (Dahl et al 2004)
bull Gabapentin and Rofecoxib (Gilron et al 2005)
Opioid reduction 20 ndash 40 Reduction of PONV 30
Clinical effects
Single-modality treatment of a Multi- modality problem is
futile
ldquoTherersquos no pain thatrsquos so easy to bear than that of
someone elserdquo
ndashLeriche
Van Gogh ldquoOld Man in Sorrowrdquo
Placebo (n=56)
Etoricoxib 60 mg (n=224)
Naproxen 1000 mgc
(n=221)
a0-
to 100-mm VAS (0 = none to 100 = extreme)
b0-
to 100-mm VAS (0 = very well to 100 = very poor) c500 mg twice dailyPlt0001 vs placebo for both etoricoxib and naproxen P = NS etoricoxib vs naproxen
Leung AT et al Curr Med Res Opin 200218(2)49ndash58
LS M
ean
Cha
nge
plusmnSE
Weeks Postrandomization
Osteoarthritis Etoricoxib 60 mg vs Naproxen
Results Etoricoxib relieved pain and improved mobility and disease statuEtoricoxib relieved pain and improved mobility and disease statuss
ndash35
ndash25
ndash5
5
ndash15
WOMAC Pain Subscalea
S R 4 82 12
WOMAC Physical Function Subscalea PGADSb
ndash35
ndash25
ndash5
5
ndash15
S R 4 82 12ndash35
ndash25
ndash5
5
ndash15
S R 4 82 12Weeks Postrandomization Weeks Postrandomization
Adverse effects of NSAIDsAdverse effects of NSAIDs
BNF March 2002
Dose-dependent toxicityIntolerability dyspepsiaGI bleedingUlcers ndash bleeds perforations
Upper-GI
Renal
Contributes to blood loss
Fluid retention oedema hypertensionRenal dysfunction failure ndash acute chronicHeart failure
Anti-platelet effects
Angioedema bronchospasmHypersensitivity
No Short-Term Adverse GI Effects -
The Big Mistake
bull Study designed to evaluate short-term GI effects in elderly
bull Study planned to enrol 160 patientsbull Study terminated by investigator at 17 subjects
ndash 8 patients had ulcersndash 4 of 4 in ketorolac group
lsquo hellip because of the unexpectedly high incidence of gastroduodenal ulcers observedhelliprsquo
Harris et al ClinTher 2001231422
Class Effect of All NSAIDs
httpwwwfdagovcderdruginfopageCOX2NSAIDdecisionMemopdf
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
33
Cardiovascular Safetybull Arthritis patients often have concomitant CV
disease1
bull Pain is an important predictor of CV risk23
bull Randomized controlled trials and observational data demonstrate that CV risk of etoricoxib appears similar to that of traditional NSAIDs4-6
bull Recent data suggest that differential CV effects of NSAIDs (selective and nonselective) may be independent of COX-2 inhibition78
References 1 Singh G et al Am J Manag Care 20028(suppl)S383-S391 2
Sokka T Pincus T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 3
Pincus T Sokka T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 4
httpwwwfdagovohrmsdocketsac05slides2005-4090S1_06_01_Pfizer-celecoxibppt (accessed 14 February 2006) 5
White WB et al Am J Cardiol 200289425ndash430 6
Graham DJ et al Lancet 2005365475ndash481 7 Yang HM et al Circulation 2004110301ndash308 8 Steffel J et al Circulation 20051111685ndash1689
Events per 100 patient years
Coxib Coxib Placebo Coxib NSAID Percent naproxen
Rofecoxib 17 19 11 08 73
Celecoxib 13 15 11 11 20
Valdecoxib 13 12 13 20 about 50
Etoricoxib 13 12 12 08 67
Lumiracoxib 09 08 52
34
APTC endpoint (cardiovascular haemorrhagic and unknown death and nonfatal myocardial infarction and stroke)
1
MR Weir et al Selective COX-2 inhibition and cardiovascular effects a review of the rofecoxib development program American heart Journal 2003 146 591-604
2
WB White et al Cardiovascular thrombotic events in arthritis trials of the cyclooxygenase-2 inhibitor celecoxib American Journal of cardiology 2003 92 411-418
3
WB White et al Effects of the cyclooxygenase-2 specific inhibitor valdecoxib versus nonsteroidal anti-inflammatory agents and placebo on cardiovascular thrombotic events in patients with arthritis American Journal of Therapeutics 2004 11 244-250
4
S Curtis et al Cardiovascular safety summary associated with the etoricoxib development programme Arthritis amp Rheumatism 2003 48 Suppl S616
5
ME Farkouh et al Comparison of lumiracoxib with naproxen and ibuprofen in the therapeutic arthritis research and gastrointestinal event trial (TARGET) cardiovascular outcomes randomised controlled trial Lancet 2004 364 675-684
RECOMMENDATIONS
NSAIDs COXIBs
bull Use lowest effective dose shortest duration
bull Not for patients who have recently undergone coronary artery bypass graft (CABG) surgery and revascularisation procedures
bull Coxibs should not be prescribed for patients with established ischaemic heart disease stroke or congestive heart failure
bull Caution for Coxibs for patients who have hypertension hyperlipidaemia diabetes and smoking as well as peripheral arterial disease
bull Etoricoxib should not be prescribed for patients with hypertension whose blood pressure has not been adequately controlled
The EU Summit is supported by Pfizer
Tricyclic Agents
bull best documented analgesics here (NNT 22)bull amitriptyline best investigatedbull desipraminenortriptyline less AEs
bull start on low doses increases compliancebullOften adverse effects (NNH 28)bull effect needs timebull SSRIs not as effective (NNT 67)
bull noradrenergic effect necessarybull venlafaxine another option
Antidepressants Compared with Placebo
Condition Number of trials
Antidepressant improvedtotal
Placebo improvedtotal
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 13 180260 73205 19 (16 to
24)30 (24 to 40)
Postherpetic neuralgia 3 4377 868 48 (24 to
94)23 (17 to 33)
Atypical facial pain 2 6288 3085 20 (15 to
28)28 (20 to 47)
Central pain 1 1015 115 10 (15 to 69)
17 (11 to 30)
Bandolier
Anticonvulsants as Membrane Stabilisers
bull pregabalinbull gabapentin bull carbamazepinebull clonazepam pooled NNT 27bull valproatebull lamotriginebull baclofen
Anticonvulsants Compared with Placebo
Condition Number of trials
Anticonvulsant improvedtotal
Placebo improvedtot
al
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 3 5668 2668 19 (14 to 27) 25 (18
to 40)
Trigeminal neuralgia 3 178315 41224 31 (23 to 41) 26 (22
to 33)
Migraine prophylaxis 2 6374 1777 37 (24 to 59) 16 (13
to 20)
Other pain syndromes 1 514 115 54 (07 to 40)
not calculat ed
Bandolier
Relative Activity on Serotonin and Norepinephrine Reuptake Among
Antidepressants
CitalopramFluvoxamineSertralineParoxetineFluoxetine
VenlafaxineDuloxetine
MaprotilineDesipramineNortriptylineReboxetine
AmitriptylineMilnacipranImipramine
Serotonin Mixed Norepinephrine
Antidepressant Analgesic Antidepressant
Fishbain et al Pain Med 20001310-316
Opioidsbull In principle opioids are effective in nociceptive
and some neuropathic pain however not always and not necessarily completely for dynamic pain
bull Possibly preferable opioids here arendash tramadol
bull noradrenergic and serotoninergic effectndash morphine
bull Mu receptor anatagonistmonaminergic effect
ndash oxycodonebull kappa receptor effect
Opioids
bull lsquoLack of analgesic effect of opioids on neuropathic hellip painrsquo Pain 19883311
bull lsquohellip intravenous hellip morphine reduce the pain of Osteoarthritisrsquo Neurology
1991411024bull lsquoA call for more science not more
rhetoric regarding opioids and arthritic painrsquo Pain 2001471
bull lsquoEfficacy of oxycodone in neuropathic painhelliprsquo Neurology 1998501837
OPIOIDS FOR OA PAINbull Osteoarthritis guidelines provide limited guidance on opioid use bull The 1995 ACR guidelines for hip OA suggest opioids be avoided for
long term use but short term use may be helpful without reference to primary data15
bull The 1995 ACR knee OA guidelines do not discuss opioids directly16 bull The 1998 UK guidelines on degenerative arthritis suggest that if
relief is inadequate with 24 grams of ibuprofen and 40 grams of paracetamol a day other antiinflammatories or opioids may be considered18
bull The 2000 update of the ACR OA guidelines suggests that opioids might be used as a medication of last resort17
bull Opioids are effective in OA hip and knee pain and have predictable side effects
bull It would be unwise were physicians to discount an entire class of medications over unfounded fears and incomplete knowledge of their benefits44
USE OF ULTRACET IN OA KNEESbull The efficacy of tramadolacetaminophen combination tablets (Ultracetreg) as add-
on and maintenance therapy in knee osteoarthritis pain inadequately controlled by nonsteroidal anti-inflammatory drug (NSAID)
Park KS Choi JJ Kim WU Min JK Park SH Cho CS
bull TramadolAPAP add-on significantly improved knee OA pain which had been inadequately controlled by NSAIDs In those subjects who showed favorable response to tramadolAPAP and NSAID combination therapy both tramadolAPAP and NSAIDs were effective at maintaining the pain-reduced state and there was no significant difference in efficacy between tramadolAPAP and NSAIDs
Clinical Rheumatology 2011 3 Aug
Opioid Sparing Regimes
bull Multimodal analgesia (Kehlet et al 1999)
bull NSAIDs and COX-2 (Romsing Moiniche 2004)
bull Paracetamol (Romsing 2002)
bull Ketamine (Elia Tramer 2005)
bull Gabapentin and Pregabalin (Dahl et al 2004)
bull Gabapentin and Rofecoxib (Gilron et al 2005)
Opioid reduction 20 ndash 40 Reduction of PONV 30
Clinical effects
Single-modality treatment of a Multi- modality problem is
futile
ldquoTherersquos no pain thatrsquos so easy to bear than that of
someone elserdquo
ndashLeriche
Van Gogh ldquoOld Man in Sorrowrdquo
Adverse effects of NSAIDsAdverse effects of NSAIDs
BNF March 2002
Dose-dependent toxicityIntolerability dyspepsiaGI bleedingUlcers ndash bleeds perforations
Upper-GI
Renal
Contributes to blood loss
Fluid retention oedema hypertensionRenal dysfunction failure ndash acute chronicHeart failure
Anti-platelet effects
Angioedema bronchospasmHypersensitivity
No Short-Term Adverse GI Effects -
The Big Mistake
bull Study designed to evaluate short-term GI effects in elderly
bull Study planned to enrol 160 patientsbull Study terminated by investigator at 17 subjects
ndash 8 patients had ulcersndash 4 of 4 in ketorolac group
lsquo hellip because of the unexpectedly high incidence of gastroduodenal ulcers observedhelliprsquo
Harris et al ClinTher 2001231422
Class Effect of All NSAIDs
httpwwwfdagovcderdruginfopageCOX2NSAIDdecisionMemopdf
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
33
Cardiovascular Safetybull Arthritis patients often have concomitant CV
disease1
bull Pain is an important predictor of CV risk23
bull Randomized controlled trials and observational data demonstrate that CV risk of etoricoxib appears similar to that of traditional NSAIDs4-6
bull Recent data suggest that differential CV effects of NSAIDs (selective and nonselective) may be independent of COX-2 inhibition78
References 1 Singh G et al Am J Manag Care 20028(suppl)S383-S391 2
Sokka T Pincus T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 3
Pincus T Sokka T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 4
httpwwwfdagovohrmsdocketsac05slides2005-4090S1_06_01_Pfizer-celecoxibppt (accessed 14 February 2006) 5
White WB et al Am J Cardiol 200289425ndash430 6
Graham DJ et al Lancet 2005365475ndash481 7 Yang HM et al Circulation 2004110301ndash308 8 Steffel J et al Circulation 20051111685ndash1689
Events per 100 patient years
Coxib Coxib Placebo Coxib NSAID Percent naproxen
Rofecoxib 17 19 11 08 73
Celecoxib 13 15 11 11 20
Valdecoxib 13 12 13 20 about 50
Etoricoxib 13 12 12 08 67
Lumiracoxib 09 08 52
34
APTC endpoint (cardiovascular haemorrhagic and unknown death and nonfatal myocardial infarction and stroke)
1
MR Weir et al Selective COX-2 inhibition and cardiovascular effects a review of the rofecoxib development program American heart Journal 2003 146 591-604
2
WB White et al Cardiovascular thrombotic events in arthritis trials of the cyclooxygenase-2 inhibitor celecoxib American Journal of cardiology 2003 92 411-418
3
WB White et al Effects of the cyclooxygenase-2 specific inhibitor valdecoxib versus nonsteroidal anti-inflammatory agents and placebo on cardiovascular thrombotic events in patients with arthritis American Journal of Therapeutics 2004 11 244-250
4
S Curtis et al Cardiovascular safety summary associated with the etoricoxib development programme Arthritis amp Rheumatism 2003 48 Suppl S616
5
ME Farkouh et al Comparison of lumiracoxib with naproxen and ibuprofen in the therapeutic arthritis research and gastrointestinal event trial (TARGET) cardiovascular outcomes randomised controlled trial Lancet 2004 364 675-684
RECOMMENDATIONS
NSAIDs COXIBs
bull Use lowest effective dose shortest duration
bull Not for patients who have recently undergone coronary artery bypass graft (CABG) surgery and revascularisation procedures
bull Coxibs should not be prescribed for patients with established ischaemic heart disease stroke or congestive heart failure
bull Caution for Coxibs for patients who have hypertension hyperlipidaemia diabetes and smoking as well as peripheral arterial disease
bull Etoricoxib should not be prescribed for patients with hypertension whose blood pressure has not been adequately controlled
The EU Summit is supported by Pfizer
Tricyclic Agents
bull best documented analgesics here (NNT 22)bull amitriptyline best investigatedbull desipraminenortriptyline less AEs
bull start on low doses increases compliancebullOften adverse effects (NNH 28)bull effect needs timebull SSRIs not as effective (NNT 67)
bull noradrenergic effect necessarybull venlafaxine another option
Antidepressants Compared with Placebo
Condition Number of trials
Antidepressant improvedtotal
Placebo improvedtotal
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 13 180260 73205 19 (16 to
24)30 (24 to 40)
Postherpetic neuralgia 3 4377 868 48 (24 to
94)23 (17 to 33)
Atypical facial pain 2 6288 3085 20 (15 to
28)28 (20 to 47)
Central pain 1 1015 115 10 (15 to 69)
17 (11 to 30)
Bandolier
Anticonvulsants as Membrane Stabilisers
bull pregabalinbull gabapentin bull carbamazepinebull clonazepam pooled NNT 27bull valproatebull lamotriginebull baclofen
Anticonvulsants Compared with Placebo
Condition Number of trials
Anticonvulsant improvedtotal
Placebo improvedtot
al
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 3 5668 2668 19 (14 to 27) 25 (18
to 40)
Trigeminal neuralgia 3 178315 41224 31 (23 to 41) 26 (22
to 33)
Migraine prophylaxis 2 6374 1777 37 (24 to 59) 16 (13
to 20)
Other pain syndromes 1 514 115 54 (07 to 40)
not calculat ed
Bandolier
Relative Activity on Serotonin and Norepinephrine Reuptake Among
Antidepressants
CitalopramFluvoxamineSertralineParoxetineFluoxetine
VenlafaxineDuloxetine
MaprotilineDesipramineNortriptylineReboxetine
AmitriptylineMilnacipranImipramine
Serotonin Mixed Norepinephrine
Antidepressant Analgesic Antidepressant
Fishbain et al Pain Med 20001310-316
Opioidsbull In principle opioids are effective in nociceptive
and some neuropathic pain however not always and not necessarily completely for dynamic pain
bull Possibly preferable opioids here arendash tramadol
bull noradrenergic and serotoninergic effectndash morphine
bull Mu receptor anatagonistmonaminergic effect
ndash oxycodonebull kappa receptor effect
Opioids
bull lsquoLack of analgesic effect of opioids on neuropathic hellip painrsquo Pain 19883311
bull lsquohellip intravenous hellip morphine reduce the pain of Osteoarthritisrsquo Neurology
1991411024bull lsquoA call for more science not more
rhetoric regarding opioids and arthritic painrsquo Pain 2001471
bull lsquoEfficacy of oxycodone in neuropathic painhelliprsquo Neurology 1998501837
OPIOIDS FOR OA PAINbull Osteoarthritis guidelines provide limited guidance on opioid use bull The 1995 ACR guidelines for hip OA suggest opioids be avoided for
long term use but short term use may be helpful without reference to primary data15
bull The 1995 ACR knee OA guidelines do not discuss opioids directly16 bull The 1998 UK guidelines on degenerative arthritis suggest that if
relief is inadequate with 24 grams of ibuprofen and 40 grams of paracetamol a day other antiinflammatories or opioids may be considered18
bull The 2000 update of the ACR OA guidelines suggests that opioids might be used as a medication of last resort17
bull Opioids are effective in OA hip and knee pain and have predictable side effects
bull It would be unwise were physicians to discount an entire class of medications over unfounded fears and incomplete knowledge of their benefits44
USE OF ULTRACET IN OA KNEESbull The efficacy of tramadolacetaminophen combination tablets (Ultracetreg) as add-
on and maintenance therapy in knee osteoarthritis pain inadequately controlled by nonsteroidal anti-inflammatory drug (NSAID)
Park KS Choi JJ Kim WU Min JK Park SH Cho CS
bull TramadolAPAP add-on significantly improved knee OA pain which had been inadequately controlled by NSAIDs In those subjects who showed favorable response to tramadolAPAP and NSAID combination therapy both tramadolAPAP and NSAIDs were effective at maintaining the pain-reduced state and there was no significant difference in efficacy between tramadolAPAP and NSAIDs
Clinical Rheumatology 2011 3 Aug
Opioid Sparing Regimes
bull Multimodal analgesia (Kehlet et al 1999)
bull NSAIDs and COX-2 (Romsing Moiniche 2004)
bull Paracetamol (Romsing 2002)
bull Ketamine (Elia Tramer 2005)
bull Gabapentin and Pregabalin (Dahl et al 2004)
bull Gabapentin and Rofecoxib (Gilron et al 2005)
Opioid reduction 20 ndash 40 Reduction of PONV 30
Clinical effects
Single-modality treatment of a Multi- modality problem is
futile
ldquoTherersquos no pain thatrsquos so easy to bear than that of
someone elserdquo
ndashLeriche
Van Gogh ldquoOld Man in Sorrowrdquo
No Short-Term Adverse GI Effects -
The Big Mistake
bull Study designed to evaluate short-term GI effects in elderly
bull Study planned to enrol 160 patientsbull Study terminated by investigator at 17 subjects
ndash 8 patients had ulcersndash 4 of 4 in ketorolac group
lsquo hellip because of the unexpectedly high incidence of gastroduodenal ulcers observedhelliprsquo
Harris et al ClinTher 2001231422
Class Effect of All NSAIDs
httpwwwfdagovcderdruginfopageCOX2NSAIDdecisionMemopdf
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
33
Cardiovascular Safetybull Arthritis patients often have concomitant CV
disease1
bull Pain is an important predictor of CV risk23
bull Randomized controlled trials and observational data demonstrate that CV risk of etoricoxib appears similar to that of traditional NSAIDs4-6
bull Recent data suggest that differential CV effects of NSAIDs (selective and nonselective) may be independent of COX-2 inhibition78
References 1 Singh G et al Am J Manag Care 20028(suppl)S383-S391 2
Sokka T Pincus T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 3
Pincus T Sokka T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 4
httpwwwfdagovohrmsdocketsac05slides2005-4090S1_06_01_Pfizer-celecoxibppt (accessed 14 February 2006) 5
White WB et al Am J Cardiol 200289425ndash430 6
Graham DJ et al Lancet 2005365475ndash481 7 Yang HM et al Circulation 2004110301ndash308 8 Steffel J et al Circulation 20051111685ndash1689
Events per 100 patient years
Coxib Coxib Placebo Coxib NSAID Percent naproxen
Rofecoxib 17 19 11 08 73
Celecoxib 13 15 11 11 20
Valdecoxib 13 12 13 20 about 50
Etoricoxib 13 12 12 08 67
Lumiracoxib 09 08 52
34
APTC endpoint (cardiovascular haemorrhagic and unknown death and nonfatal myocardial infarction and stroke)
1
MR Weir et al Selective COX-2 inhibition and cardiovascular effects a review of the rofecoxib development program American heart Journal 2003 146 591-604
2
WB White et al Cardiovascular thrombotic events in arthritis trials of the cyclooxygenase-2 inhibitor celecoxib American Journal of cardiology 2003 92 411-418
3
WB White et al Effects of the cyclooxygenase-2 specific inhibitor valdecoxib versus nonsteroidal anti-inflammatory agents and placebo on cardiovascular thrombotic events in patients with arthritis American Journal of Therapeutics 2004 11 244-250
4
S Curtis et al Cardiovascular safety summary associated with the etoricoxib development programme Arthritis amp Rheumatism 2003 48 Suppl S616
5
ME Farkouh et al Comparison of lumiracoxib with naproxen and ibuprofen in the therapeutic arthritis research and gastrointestinal event trial (TARGET) cardiovascular outcomes randomised controlled trial Lancet 2004 364 675-684
RECOMMENDATIONS
NSAIDs COXIBs
bull Use lowest effective dose shortest duration
bull Not for patients who have recently undergone coronary artery bypass graft (CABG) surgery and revascularisation procedures
bull Coxibs should not be prescribed for patients with established ischaemic heart disease stroke or congestive heart failure
bull Caution for Coxibs for patients who have hypertension hyperlipidaemia diabetes and smoking as well as peripheral arterial disease
bull Etoricoxib should not be prescribed for patients with hypertension whose blood pressure has not been adequately controlled
The EU Summit is supported by Pfizer
Tricyclic Agents
bull best documented analgesics here (NNT 22)bull amitriptyline best investigatedbull desipraminenortriptyline less AEs
bull start on low doses increases compliancebullOften adverse effects (NNH 28)bull effect needs timebull SSRIs not as effective (NNT 67)
bull noradrenergic effect necessarybull venlafaxine another option
Antidepressants Compared with Placebo
Condition Number of trials
Antidepressant improvedtotal
Placebo improvedtotal
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 13 180260 73205 19 (16 to
24)30 (24 to 40)
Postherpetic neuralgia 3 4377 868 48 (24 to
94)23 (17 to 33)
Atypical facial pain 2 6288 3085 20 (15 to
28)28 (20 to 47)
Central pain 1 1015 115 10 (15 to 69)
17 (11 to 30)
Bandolier
Anticonvulsants as Membrane Stabilisers
bull pregabalinbull gabapentin bull carbamazepinebull clonazepam pooled NNT 27bull valproatebull lamotriginebull baclofen
Anticonvulsants Compared with Placebo
Condition Number of trials
Anticonvulsant improvedtotal
Placebo improvedtot
al
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 3 5668 2668 19 (14 to 27) 25 (18
to 40)
Trigeminal neuralgia 3 178315 41224 31 (23 to 41) 26 (22
to 33)
Migraine prophylaxis 2 6374 1777 37 (24 to 59) 16 (13
to 20)
Other pain syndromes 1 514 115 54 (07 to 40)
not calculat ed
Bandolier
Relative Activity on Serotonin and Norepinephrine Reuptake Among
Antidepressants
CitalopramFluvoxamineSertralineParoxetineFluoxetine
VenlafaxineDuloxetine
MaprotilineDesipramineNortriptylineReboxetine
AmitriptylineMilnacipranImipramine
Serotonin Mixed Norepinephrine
Antidepressant Analgesic Antidepressant
Fishbain et al Pain Med 20001310-316
Opioidsbull In principle opioids are effective in nociceptive
and some neuropathic pain however not always and not necessarily completely for dynamic pain
bull Possibly preferable opioids here arendash tramadol
bull noradrenergic and serotoninergic effectndash morphine
bull Mu receptor anatagonistmonaminergic effect
ndash oxycodonebull kappa receptor effect
Opioids
bull lsquoLack of analgesic effect of opioids on neuropathic hellip painrsquo Pain 19883311
bull lsquohellip intravenous hellip morphine reduce the pain of Osteoarthritisrsquo Neurology
1991411024bull lsquoA call for more science not more
rhetoric regarding opioids and arthritic painrsquo Pain 2001471
bull lsquoEfficacy of oxycodone in neuropathic painhelliprsquo Neurology 1998501837
OPIOIDS FOR OA PAINbull Osteoarthritis guidelines provide limited guidance on opioid use bull The 1995 ACR guidelines for hip OA suggest opioids be avoided for
long term use but short term use may be helpful without reference to primary data15
bull The 1995 ACR knee OA guidelines do not discuss opioids directly16 bull The 1998 UK guidelines on degenerative arthritis suggest that if
relief is inadequate with 24 grams of ibuprofen and 40 grams of paracetamol a day other antiinflammatories or opioids may be considered18
bull The 2000 update of the ACR OA guidelines suggests that opioids might be used as a medication of last resort17
bull Opioids are effective in OA hip and knee pain and have predictable side effects
bull It would be unwise were physicians to discount an entire class of medications over unfounded fears and incomplete knowledge of their benefits44
USE OF ULTRACET IN OA KNEESbull The efficacy of tramadolacetaminophen combination tablets (Ultracetreg) as add-
on and maintenance therapy in knee osteoarthritis pain inadequately controlled by nonsteroidal anti-inflammatory drug (NSAID)
Park KS Choi JJ Kim WU Min JK Park SH Cho CS
bull TramadolAPAP add-on significantly improved knee OA pain which had been inadequately controlled by NSAIDs In those subjects who showed favorable response to tramadolAPAP and NSAID combination therapy both tramadolAPAP and NSAIDs were effective at maintaining the pain-reduced state and there was no significant difference in efficacy between tramadolAPAP and NSAIDs
Clinical Rheumatology 2011 3 Aug
Opioid Sparing Regimes
bull Multimodal analgesia (Kehlet et al 1999)
bull NSAIDs and COX-2 (Romsing Moiniche 2004)
bull Paracetamol (Romsing 2002)
bull Ketamine (Elia Tramer 2005)
bull Gabapentin and Pregabalin (Dahl et al 2004)
bull Gabapentin and Rofecoxib (Gilron et al 2005)
Opioid reduction 20 ndash 40 Reduction of PONV 30
Clinical effects
Single-modality treatment of a Multi- modality problem is
futile
ldquoTherersquos no pain thatrsquos so easy to bear than that of
someone elserdquo
ndashLeriche
Van Gogh ldquoOld Man in Sorrowrdquo
Class Effect of All NSAIDs
httpwwwfdagovcderdruginfopageCOX2NSAIDdecisionMemopdf
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
FDA Memorandum on NSAIDs amp CV Risk 6 April 2005
33
Cardiovascular Safetybull Arthritis patients often have concomitant CV
disease1
bull Pain is an important predictor of CV risk23
bull Randomized controlled trials and observational data demonstrate that CV risk of etoricoxib appears similar to that of traditional NSAIDs4-6
bull Recent data suggest that differential CV effects of NSAIDs (selective and nonselective) may be independent of COX-2 inhibition78
References 1 Singh G et al Am J Manag Care 20028(suppl)S383-S391 2
Sokka T Pincus T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 3
Pincus T Sokka T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 4
httpwwwfdagovohrmsdocketsac05slides2005-4090S1_06_01_Pfizer-celecoxibppt (accessed 14 February 2006) 5
White WB et al Am J Cardiol 200289425ndash430 6
Graham DJ et al Lancet 2005365475ndash481 7 Yang HM et al Circulation 2004110301ndash308 8 Steffel J et al Circulation 20051111685ndash1689
Events per 100 patient years
Coxib Coxib Placebo Coxib NSAID Percent naproxen
Rofecoxib 17 19 11 08 73
Celecoxib 13 15 11 11 20
Valdecoxib 13 12 13 20 about 50
Etoricoxib 13 12 12 08 67
Lumiracoxib 09 08 52
34
APTC endpoint (cardiovascular haemorrhagic and unknown death and nonfatal myocardial infarction and stroke)
1
MR Weir et al Selective COX-2 inhibition and cardiovascular effects a review of the rofecoxib development program American heart Journal 2003 146 591-604
2
WB White et al Cardiovascular thrombotic events in arthritis trials of the cyclooxygenase-2 inhibitor celecoxib American Journal of cardiology 2003 92 411-418
3
WB White et al Effects of the cyclooxygenase-2 specific inhibitor valdecoxib versus nonsteroidal anti-inflammatory agents and placebo on cardiovascular thrombotic events in patients with arthritis American Journal of Therapeutics 2004 11 244-250
4
S Curtis et al Cardiovascular safety summary associated with the etoricoxib development programme Arthritis amp Rheumatism 2003 48 Suppl S616
5
ME Farkouh et al Comparison of lumiracoxib with naproxen and ibuprofen in the therapeutic arthritis research and gastrointestinal event trial (TARGET) cardiovascular outcomes randomised controlled trial Lancet 2004 364 675-684
RECOMMENDATIONS
NSAIDs COXIBs
bull Use lowest effective dose shortest duration
bull Not for patients who have recently undergone coronary artery bypass graft (CABG) surgery and revascularisation procedures
bull Coxibs should not be prescribed for patients with established ischaemic heart disease stroke or congestive heart failure
bull Caution for Coxibs for patients who have hypertension hyperlipidaemia diabetes and smoking as well as peripheral arterial disease
bull Etoricoxib should not be prescribed for patients with hypertension whose blood pressure has not been adequately controlled
The EU Summit is supported by Pfizer
Tricyclic Agents
bull best documented analgesics here (NNT 22)bull amitriptyline best investigatedbull desipraminenortriptyline less AEs
bull start on low doses increases compliancebullOften adverse effects (NNH 28)bull effect needs timebull SSRIs not as effective (NNT 67)
bull noradrenergic effect necessarybull venlafaxine another option
Antidepressants Compared with Placebo
Condition Number of trials
Antidepressant improvedtotal
Placebo improvedtotal
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 13 180260 73205 19 (16 to
24)30 (24 to 40)
Postherpetic neuralgia 3 4377 868 48 (24 to
94)23 (17 to 33)
Atypical facial pain 2 6288 3085 20 (15 to
28)28 (20 to 47)
Central pain 1 1015 115 10 (15 to 69)
17 (11 to 30)
Bandolier
Anticonvulsants as Membrane Stabilisers
bull pregabalinbull gabapentin bull carbamazepinebull clonazepam pooled NNT 27bull valproatebull lamotriginebull baclofen
Anticonvulsants Compared with Placebo
Condition Number of trials
Anticonvulsant improvedtotal
Placebo improvedtot
al
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 3 5668 2668 19 (14 to 27) 25 (18
to 40)
Trigeminal neuralgia 3 178315 41224 31 (23 to 41) 26 (22
to 33)
Migraine prophylaxis 2 6374 1777 37 (24 to 59) 16 (13
to 20)
Other pain syndromes 1 514 115 54 (07 to 40)
not calculat ed
Bandolier
Relative Activity on Serotonin and Norepinephrine Reuptake Among
Antidepressants
CitalopramFluvoxamineSertralineParoxetineFluoxetine
VenlafaxineDuloxetine
MaprotilineDesipramineNortriptylineReboxetine
AmitriptylineMilnacipranImipramine
Serotonin Mixed Norepinephrine
Antidepressant Analgesic Antidepressant
Fishbain et al Pain Med 20001310-316
Opioidsbull In principle opioids are effective in nociceptive
and some neuropathic pain however not always and not necessarily completely for dynamic pain
bull Possibly preferable opioids here arendash tramadol
bull noradrenergic and serotoninergic effectndash morphine
bull Mu receptor anatagonistmonaminergic effect
ndash oxycodonebull kappa receptor effect
Opioids
bull lsquoLack of analgesic effect of opioids on neuropathic hellip painrsquo Pain 19883311
bull lsquohellip intravenous hellip morphine reduce the pain of Osteoarthritisrsquo Neurology
1991411024bull lsquoA call for more science not more
rhetoric regarding opioids and arthritic painrsquo Pain 2001471
bull lsquoEfficacy of oxycodone in neuropathic painhelliprsquo Neurology 1998501837
OPIOIDS FOR OA PAINbull Osteoarthritis guidelines provide limited guidance on opioid use bull The 1995 ACR guidelines for hip OA suggest opioids be avoided for
long term use but short term use may be helpful without reference to primary data15
bull The 1995 ACR knee OA guidelines do not discuss opioids directly16 bull The 1998 UK guidelines on degenerative arthritis suggest that if
relief is inadequate with 24 grams of ibuprofen and 40 grams of paracetamol a day other antiinflammatories or opioids may be considered18
bull The 2000 update of the ACR OA guidelines suggests that opioids might be used as a medication of last resort17
bull Opioids are effective in OA hip and knee pain and have predictable side effects
bull It would be unwise were physicians to discount an entire class of medications over unfounded fears and incomplete knowledge of their benefits44
USE OF ULTRACET IN OA KNEESbull The efficacy of tramadolacetaminophen combination tablets (Ultracetreg) as add-
on and maintenance therapy in knee osteoarthritis pain inadequately controlled by nonsteroidal anti-inflammatory drug (NSAID)
Park KS Choi JJ Kim WU Min JK Park SH Cho CS
bull TramadolAPAP add-on significantly improved knee OA pain which had been inadequately controlled by NSAIDs In those subjects who showed favorable response to tramadolAPAP and NSAID combination therapy both tramadolAPAP and NSAIDs were effective at maintaining the pain-reduced state and there was no significant difference in efficacy between tramadolAPAP and NSAIDs
Clinical Rheumatology 2011 3 Aug
Opioid Sparing Regimes
bull Multimodal analgesia (Kehlet et al 1999)
bull NSAIDs and COX-2 (Romsing Moiniche 2004)
bull Paracetamol (Romsing 2002)
bull Ketamine (Elia Tramer 2005)
bull Gabapentin and Pregabalin (Dahl et al 2004)
bull Gabapentin and Rofecoxib (Gilron et al 2005)
Opioid reduction 20 ndash 40 Reduction of PONV 30
Clinical effects
Single-modality treatment of a Multi- modality problem is
futile
ldquoTherersquos no pain thatrsquos so easy to bear than that of
someone elserdquo
ndashLeriche
Van Gogh ldquoOld Man in Sorrowrdquo
33
Cardiovascular Safetybull Arthritis patients often have concomitant CV
disease1
bull Pain is an important predictor of CV risk23
bull Randomized controlled trials and observational data demonstrate that CV risk of etoricoxib appears similar to that of traditional NSAIDs4-6
bull Recent data suggest that differential CV effects of NSAIDs (selective and nonselective) may be independent of COX-2 inhibition78
References 1 Singh G et al Am J Manag Care 20028(suppl)S383-S391 2
Sokka T Pincus T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 3
Pincus T Sokka T Abstract presented during the American College of Rheumatology 2005 Scientific Sessions San Diego California 4
httpwwwfdagovohrmsdocketsac05slides2005-4090S1_06_01_Pfizer-celecoxibppt (accessed 14 February 2006) 5
White WB et al Am J Cardiol 200289425ndash430 6
Graham DJ et al Lancet 2005365475ndash481 7 Yang HM et al Circulation 2004110301ndash308 8 Steffel J et al Circulation 20051111685ndash1689
Events per 100 patient years
Coxib Coxib Placebo Coxib NSAID Percent naproxen
Rofecoxib 17 19 11 08 73
Celecoxib 13 15 11 11 20
Valdecoxib 13 12 13 20 about 50
Etoricoxib 13 12 12 08 67
Lumiracoxib 09 08 52
34
APTC endpoint (cardiovascular haemorrhagic and unknown death and nonfatal myocardial infarction and stroke)
1
MR Weir et al Selective COX-2 inhibition and cardiovascular effects a review of the rofecoxib development program American heart Journal 2003 146 591-604
2
WB White et al Cardiovascular thrombotic events in arthritis trials of the cyclooxygenase-2 inhibitor celecoxib American Journal of cardiology 2003 92 411-418
3
WB White et al Effects of the cyclooxygenase-2 specific inhibitor valdecoxib versus nonsteroidal anti-inflammatory agents and placebo on cardiovascular thrombotic events in patients with arthritis American Journal of Therapeutics 2004 11 244-250
4
S Curtis et al Cardiovascular safety summary associated with the etoricoxib development programme Arthritis amp Rheumatism 2003 48 Suppl S616
5
ME Farkouh et al Comparison of lumiracoxib with naproxen and ibuprofen in the therapeutic arthritis research and gastrointestinal event trial (TARGET) cardiovascular outcomes randomised controlled trial Lancet 2004 364 675-684
RECOMMENDATIONS
NSAIDs COXIBs
bull Use lowest effective dose shortest duration
bull Not for patients who have recently undergone coronary artery bypass graft (CABG) surgery and revascularisation procedures
bull Coxibs should not be prescribed for patients with established ischaemic heart disease stroke or congestive heart failure
bull Caution for Coxibs for patients who have hypertension hyperlipidaemia diabetes and smoking as well as peripheral arterial disease
bull Etoricoxib should not be prescribed for patients with hypertension whose blood pressure has not been adequately controlled
The EU Summit is supported by Pfizer
Tricyclic Agents
bull best documented analgesics here (NNT 22)bull amitriptyline best investigatedbull desipraminenortriptyline less AEs
bull start on low doses increases compliancebullOften adverse effects (NNH 28)bull effect needs timebull SSRIs not as effective (NNT 67)
bull noradrenergic effect necessarybull venlafaxine another option
Antidepressants Compared with Placebo
Condition Number of trials
Antidepressant improvedtotal
Placebo improvedtotal
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 13 180260 73205 19 (16 to
24)30 (24 to 40)
Postherpetic neuralgia 3 4377 868 48 (24 to
94)23 (17 to 33)
Atypical facial pain 2 6288 3085 20 (15 to
28)28 (20 to 47)
Central pain 1 1015 115 10 (15 to 69)
17 (11 to 30)
Bandolier
Anticonvulsants as Membrane Stabilisers
bull pregabalinbull gabapentin bull carbamazepinebull clonazepam pooled NNT 27bull valproatebull lamotriginebull baclofen
Anticonvulsants Compared with Placebo
Condition Number of trials
Anticonvulsant improvedtotal
Placebo improvedtot
al
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 3 5668 2668 19 (14 to 27) 25 (18
to 40)
Trigeminal neuralgia 3 178315 41224 31 (23 to 41) 26 (22
to 33)
Migraine prophylaxis 2 6374 1777 37 (24 to 59) 16 (13
to 20)
Other pain syndromes 1 514 115 54 (07 to 40)
not calculat ed
Bandolier
Relative Activity on Serotonin and Norepinephrine Reuptake Among
Antidepressants
CitalopramFluvoxamineSertralineParoxetineFluoxetine
VenlafaxineDuloxetine
MaprotilineDesipramineNortriptylineReboxetine
AmitriptylineMilnacipranImipramine
Serotonin Mixed Norepinephrine
Antidepressant Analgesic Antidepressant
Fishbain et al Pain Med 20001310-316
Opioidsbull In principle opioids are effective in nociceptive
and some neuropathic pain however not always and not necessarily completely for dynamic pain
bull Possibly preferable opioids here arendash tramadol
bull noradrenergic and serotoninergic effectndash morphine
bull Mu receptor anatagonistmonaminergic effect
ndash oxycodonebull kappa receptor effect
Opioids
bull lsquoLack of analgesic effect of opioids on neuropathic hellip painrsquo Pain 19883311
bull lsquohellip intravenous hellip morphine reduce the pain of Osteoarthritisrsquo Neurology
1991411024bull lsquoA call for more science not more
rhetoric regarding opioids and arthritic painrsquo Pain 2001471
bull lsquoEfficacy of oxycodone in neuropathic painhelliprsquo Neurology 1998501837
OPIOIDS FOR OA PAINbull Osteoarthritis guidelines provide limited guidance on opioid use bull The 1995 ACR guidelines for hip OA suggest opioids be avoided for
long term use but short term use may be helpful without reference to primary data15
bull The 1995 ACR knee OA guidelines do not discuss opioids directly16 bull The 1998 UK guidelines on degenerative arthritis suggest that if
relief is inadequate with 24 grams of ibuprofen and 40 grams of paracetamol a day other antiinflammatories or opioids may be considered18
bull The 2000 update of the ACR OA guidelines suggests that opioids might be used as a medication of last resort17
bull Opioids are effective in OA hip and knee pain and have predictable side effects
bull It would be unwise were physicians to discount an entire class of medications over unfounded fears and incomplete knowledge of their benefits44
USE OF ULTRACET IN OA KNEESbull The efficacy of tramadolacetaminophen combination tablets (Ultracetreg) as add-
on and maintenance therapy in knee osteoarthritis pain inadequately controlled by nonsteroidal anti-inflammatory drug (NSAID)
Park KS Choi JJ Kim WU Min JK Park SH Cho CS
bull TramadolAPAP add-on significantly improved knee OA pain which had been inadequately controlled by NSAIDs In those subjects who showed favorable response to tramadolAPAP and NSAID combination therapy both tramadolAPAP and NSAIDs were effective at maintaining the pain-reduced state and there was no significant difference in efficacy between tramadolAPAP and NSAIDs
Clinical Rheumatology 2011 3 Aug
Opioid Sparing Regimes
bull Multimodal analgesia (Kehlet et al 1999)
bull NSAIDs and COX-2 (Romsing Moiniche 2004)
bull Paracetamol (Romsing 2002)
bull Ketamine (Elia Tramer 2005)
bull Gabapentin and Pregabalin (Dahl et al 2004)
bull Gabapentin and Rofecoxib (Gilron et al 2005)
Opioid reduction 20 ndash 40 Reduction of PONV 30
Clinical effects
Single-modality treatment of a Multi- modality problem is
futile
ldquoTherersquos no pain thatrsquos so easy to bear than that of
someone elserdquo
ndashLeriche
Van Gogh ldquoOld Man in Sorrowrdquo
Events per 100 patient years
Coxib Coxib Placebo Coxib NSAID Percent naproxen
Rofecoxib 17 19 11 08 73
Celecoxib 13 15 11 11 20
Valdecoxib 13 12 13 20 about 50
Etoricoxib 13 12 12 08 67
Lumiracoxib 09 08 52
34
APTC endpoint (cardiovascular haemorrhagic and unknown death and nonfatal myocardial infarction and stroke)
1
MR Weir et al Selective COX-2 inhibition and cardiovascular effects a review of the rofecoxib development program American heart Journal 2003 146 591-604
2
WB White et al Cardiovascular thrombotic events in arthritis trials of the cyclooxygenase-2 inhibitor celecoxib American Journal of cardiology 2003 92 411-418
3
WB White et al Effects of the cyclooxygenase-2 specific inhibitor valdecoxib versus nonsteroidal anti-inflammatory agents and placebo on cardiovascular thrombotic events in patients with arthritis American Journal of Therapeutics 2004 11 244-250
4
S Curtis et al Cardiovascular safety summary associated with the etoricoxib development programme Arthritis amp Rheumatism 2003 48 Suppl S616
5
ME Farkouh et al Comparison of lumiracoxib with naproxen and ibuprofen in the therapeutic arthritis research and gastrointestinal event trial (TARGET) cardiovascular outcomes randomised controlled trial Lancet 2004 364 675-684
RECOMMENDATIONS
NSAIDs COXIBs
bull Use lowest effective dose shortest duration
bull Not for patients who have recently undergone coronary artery bypass graft (CABG) surgery and revascularisation procedures
bull Coxibs should not be prescribed for patients with established ischaemic heart disease stroke or congestive heart failure
bull Caution for Coxibs for patients who have hypertension hyperlipidaemia diabetes and smoking as well as peripheral arterial disease
bull Etoricoxib should not be prescribed for patients with hypertension whose blood pressure has not been adequately controlled
The EU Summit is supported by Pfizer
Tricyclic Agents
bull best documented analgesics here (NNT 22)bull amitriptyline best investigatedbull desipraminenortriptyline less AEs
bull start on low doses increases compliancebullOften adverse effects (NNH 28)bull effect needs timebull SSRIs not as effective (NNT 67)
bull noradrenergic effect necessarybull venlafaxine another option
Antidepressants Compared with Placebo
Condition Number of trials
Antidepressant improvedtotal
Placebo improvedtotal
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 13 180260 73205 19 (16 to
24)30 (24 to 40)
Postherpetic neuralgia 3 4377 868 48 (24 to
94)23 (17 to 33)
Atypical facial pain 2 6288 3085 20 (15 to
28)28 (20 to 47)
Central pain 1 1015 115 10 (15 to 69)
17 (11 to 30)
Bandolier
Anticonvulsants as Membrane Stabilisers
bull pregabalinbull gabapentin bull carbamazepinebull clonazepam pooled NNT 27bull valproatebull lamotriginebull baclofen
Anticonvulsants Compared with Placebo
Condition Number of trials
Anticonvulsant improvedtotal
Placebo improvedtot
al
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 3 5668 2668 19 (14 to 27) 25 (18
to 40)
Trigeminal neuralgia 3 178315 41224 31 (23 to 41) 26 (22
to 33)
Migraine prophylaxis 2 6374 1777 37 (24 to 59) 16 (13
to 20)
Other pain syndromes 1 514 115 54 (07 to 40)
not calculat ed
Bandolier
Relative Activity on Serotonin and Norepinephrine Reuptake Among
Antidepressants
CitalopramFluvoxamineSertralineParoxetineFluoxetine
VenlafaxineDuloxetine
MaprotilineDesipramineNortriptylineReboxetine
AmitriptylineMilnacipranImipramine
Serotonin Mixed Norepinephrine
Antidepressant Analgesic Antidepressant
Fishbain et al Pain Med 20001310-316
Opioidsbull In principle opioids are effective in nociceptive
and some neuropathic pain however not always and not necessarily completely for dynamic pain
bull Possibly preferable opioids here arendash tramadol
bull noradrenergic and serotoninergic effectndash morphine
bull Mu receptor anatagonistmonaminergic effect
ndash oxycodonebull kappa receptor effect
Opioids
bull lsquoLack of analgesic effect of opioids on neuropathic hellip painrsquo Pain 19883311
bull lsquohellip intravenous hellip morphine reduce the pain of Osteoarthritisrsquo Neurology
1991411024bull lsquoA call for more science not more
rhetoric regarding opioids and arthritic painrsquo Pain 2001471
bull lsquoEfficacy of oxycodone in neuropathic painhelliprsquo Neurology 1998501837
OPIOIDS FOR OA PAINbull Osteoarthritis guidelines provide limited guidance on opioid use bull The 1995 ACR guidelines for hip OA suggest opioids be avoided for
long term use but short term use may be helpful without reference to primary data15
bull The 1995 ACR knee OA guidelines do not discuss opioids directly16 bull The 1998 UK guidelines on degenerative arthritis suggest that if
relief is inadequate with 24 grams of ibuprofen and 40 grams of paracetamol a day other antiinflammatories or opioids may be considered18
bull The 2000 update of the ACR OA guidelines suggests that opioids might be used as a medication of last resort17
bull Opioids are effective in OA hip and knee pain and have predictable side effects
bull It would be unwise were physicians to discount an entire class of medications over unfounded fears and incomplete knowledge of their benefits44
USE OF ULTRACET IN OA KNEESbull The efficacy of tramadolacetaminophen combination tablets (Ultracetreg) as add-
on and maintenance therapy in knee osteoarthritis pain inadequately controlled by nonsteroidal anti-inflammatory drug (NSAID)
Park KS Choi JJ Kim WU Min JK Park SH Cho CS
bull TramadolAPAP add-on significantly improved knee OA pain which had been inadequately controlled by NSAIDs In those subjects who showed favorable response to tramadolAPAP and NSAID combination therapy both tramadolAPAP and NSAIDs were effective at maintaining the pain-reduced state and there was no significant difference in efficacy between tramadolAPAP and NSAIDs
Clinical Rheumatology 2011 3 Aug
Opioid Sparing Regimes
bull Multimodal analgesia (Kehlet et al 1999)
bull NSAIDs and COX-2 (Romsing Moiniche 2004)
bull Paracetamol (Romsing 2002)
bull Ketamine (Elia Tramer 2005)
bull Gabapentin and Pregabalin (Dahl et al 2004)
bull Gabapentin and Rofecoxib (Gilron et al 2005)
Opioid reduction 20 ndash 40 Reduction of PONV 30
Clinical effects
Single-modality treatment of a Multi- modality problem is
futile
ldquoTherersquos no pain thatrsquos so easy to bear than that of
someone elserdquo
ndashLeriche
Van Gogh ldquoOld Man in Sorrowrdquo
RECOMMENDATIONS
NSAIDs COXIBs
bull Use lowest effective dose shortest duration
bull Not for patients who have recently undergone coronary artery bypass graft (CABG) surgery and revascularisation procedures
bull Coxibs should not be prescribed for patients with established ischaemic heart disease stroke or congestive heart failure
bull Caution for Coxibs for patients who have hypertension hyperlipidaemia diabetes and smoking as well as peripheral arterial disease
bull Etoricoxib should not be prescribed for patients with hypertension whose blood pressure has not been adequately controlled
The EU Summit is supported by Pfizer
Tricyclic Agents
bull best documented analgesics here (NNT 22)bull amitriptyline best investigatedbull desipraminenortriptyline less AEs
bull start on low doses increases compliancebullOften adverse effects (NNH 28)bull effect needs timebull SSRIs not as effective (NNT 67)
bull noradrenergic effect necessarybull venlafaxine another option
Antidepressants Compared with Placebo
Condition Number of trials
Antidepressant improvedtotal
Placebo improvedtotal
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 13 180260 73205 19 (16 to
24)30 (24 to 40)
Postherpetic neuralgia 3 4377 868 48 (24 to
94)23 (17 to 33)
Atypical facial pain 2 6288 3085 20 (15 to
28)28 (20 to 47)
Central pain 1 1015 115 10 (15 to 69)
17 (11 to 30)
Bandolier
Anticonvulsants as Membrane Stabilisers
bull pregabalinbull gabapentin bull carbamazepinebull clonazepam pooled NNT 27bull valproatebull lamotriginebull baclofen
Anticonvulsants Compared with Placebo
Condition Number of trials
Anticonvulsant improvedtotal
Placebo improvedtot
al
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 3 5668 2668 19 (14 to 27) 25 (18
to 40)
Trigeminal neuralgia 3 178315 41224 31 (23 to 41) 26 (22
to 33)
Migraine prophylaxis 2 6374 1777 37 (24 to 59) 16 (13
to 20)
Other pain syndromes 1 514 115 54 (07 to 40)
not calculat ed
Bandolier
Relative Activity on Serotonin and Norepinephrine Reuptake Among
Antidepressants
CitalopramFluvoxamineSertralineParoxetineFluoxetine
VenlafaxineDuloxetine
MaprotilineDesipramineNortriptylineReboxetine
AmitriptylineMilnacipranImipramine
Serotonin Mixed Norepinephrine
Antidepressant Analgesic Antidepressant
Fishbain et al Pain Med 20001310-316
Opioidsbull In principle opioids are effective in nociceptive
and some neuropathic pain however not always and not necessarily completely for dynamic pain
bull Possibly preferable opioids here arendash tramadol
bull noradrenergic and serotoninergic effectndash morphine
bull Mu receptor anatagonistmonaminergic effect
ndash oxycodonebull kappa receptor effect
Opioids
bull lsquoLack of analgesic effect of opioids on neuropathic hellip painrsquo Pain 19883311
bull lsquohellip intravenous hellip morphine reduce the pain of Osteoarthritisrsquo Neurology
1991411024bull lsquoA call for more science not more
rhetoric regarding opioids and arthritic painrsquo Pain 2001471
bull lsquoEfficacy of oxycodone in neuropathic painhelliprsquo Neurology 1998501837
OPIOIDS FOR OA PAINbull Osteoarthritis guidelines provide limited guidance on opioid use bull The 1995 ACR guidelines for hip OA suggest opioids be avoided for
long term use but short term use may be helpful without reference to primary data15
bull The 1995 ACR knee OA guidelines do not discuss opioids directly16 bull The 1998 UK guidelines on degenerative arthritis suggest that if
relief is inadequate with 24 grams of ibuprofen and 40 grams of paracetamol a day other antiinflammatories or opioids may be considered18
bull The 2000 update of the ACR OA guidelines suggests that opioids might be used as a medication of last resort17
bull Opioids are effective in OA hip and knee pain and have predictable side effects
bull It would be unwise were physicians to discount an entire class of medications over unfounded fears and incomplete knowledge of their benefits44
USE OF ULTRACET IN OA KNEESbull The efficacy of tramadolacetaminophen combination tablets (Ultracetreg) as add-
on and maintenance therapy in knee osteoarthritis pain inadequately controlled by nonsteroidal anti-inflammatory drug (NSAID)
Park KS Choi JJ Kim WU Min JK Park SH Cho CS
bull TramadolAPAP add-on significantly improved knee OA pain which had been inadequately controlled by NSAIDs In those subjects who showed favorable response to tramadolAPAP and NSAID combination therapy both tramadolAPAP and NSAIDs were effective at maintaining the pain-reduced state and there was no significant difference in efficacy between tramadolAPAP and NSAIDs
Clinical Rheumatology 2011 3 Aug
Opioid Sparing Regimes
bull Multimodal analgesia (Kehlet et al 1999)
bull NSAIDs and COX-2 (Romsing Moiniche 2004)
bull Paracetamol (Romsing 2002)
bull Ketamine (Elia Tramer 2005)
bull Gabapentin and Pregabalin (Dahl et al 2004)
bull Gabapentin and Rofecoxib (Gilron et al 2005)
Opioid reduction 20 ndash 40 Reduction of PONV 30
Clinical effects
Single-modality treatment of a Multi- modality problem is
futile
ldquoTherersquos no pain thatrsquos so easy to bear than that of
someone elserdquo
ndashLeriche
Van Gogh ldquoOld Man in Sorrowrdquo
The EU Summit is supported by Pfizer
Tricyclic Agents
bull best documented analgesics here (NNT 22)bull amitriptyline best investigatedbull desipraminenortriptyline less AEs
bull start on low doses increases compliancebullOften adverse effects (NNH 28)bull effect needs timebull SSRIs not as effective (NNT 67)
bull noradrenergic effect necessarybull venlafaxine another option
Antidepressants Compared with Placebo
Condition Number of trials
Antidepressant improvedtotal
Placebo improvedtotal
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 13 180260 73205 19 (16 to
24)30 (24 to 40)
Postherpetic neuralgia 3 4377 868 48 (24 to
94)23 (17 to 33)
Atypical facial pain 2 6288 3085 20 (15 to
28)28 (20 to 47)
Central pain 1 1015 115 10 (15 to 69)
17 (11 to 30)
Bandolier
Anticonvulsants as Membrane Stabilisers
bull pregabalinbull gabapentin bull carbamazepinebull clonazepam pooled NNT 27bull valproatebull lamotriginebull baclofen
Anticonvulsants Compared with Placebo
Condition Number of trials
Anticonvulsant improvedtotal
Placebo improvedtot
al
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 3 5668 2668 19 (14 to 27) 25 (18
to 40)
Trigeminal neuralgia 3 178315 41224 31 (23 to 41) 26 (22
to 33)
Migraine prophylaxis 2 6374 1777 37 (24 to 59) 16 (13
to 20)
Other pain syndromes 1 514 115 54 (07 to 40)
not calculat ed
Bandolier
Relative Activity on Serotonin and Norepinephrine Reuptake Among
Antidepressants
CitalopramFluvoxamineSertralineParoxetineFluoxetine
VenlafaxineDuloxetine
MaprotilineDesipramineNortriptylineReboxetine
AmitriptylineMilnacipranImipramine
Serotonin Mixed Norepinephrine
Antidepressant Analgesic Antidepressant
Fishbain et al Pain Med 20001310-316
Opioidsbull In principle opioids are effective in nociceptive
and some neuropathic pain however not always and not necessarily completely for dynamic pain
bull Possibly preferable opioids here arendash tramadol
bull noradrenergic and serotoninergic effectndash morphine
bull Mu receptor anatagonistmonaminergic effect
ndash oxycodonebull kappa receptor effect
Opioids
bull lsquoLack of analgesic effect of opioids on neuropathic hellip painrsquo Pain 19883311
bull lsquohellip intravenous hellip morphine reduce the pain of Osteoarthritisrsquo Neurology
1991411024bull lsquoA call for more science not more
rhetoric regarding opioids and arthritic painrsquo Pain 2001471
bull lsquoEfficacy of oxycodone in neuropathic painhelliprsquo Neurology 1998501837
OPIOIDS FOR OA PAINbull Osteoarthritis guidelines provide limited guidance on opioid use bull The 1995 ACR guidelines for hip OA suggest opioids be avoided for
long term use but short term use may be helpful without reference to primary data15
bull The 1995 ACR knee OA guidelines do not discuss opioids directly16 bull The 1998 UK guidelines on degenerative arthritis suggest that if
relief is inadequate with 24 grams of ibuprofen and 40 grams of paracetamol a day other antiinflammatories or opioids may be considered18
bull The 2000 update of the ACR OA guidelines suggests that opioids might be used as a medication of last resort17
bull Opioids are effective in OA hip and knee pain and have predictable side effects
bull It would be unwise were physicians to discount an entire class of medications over unfounded fears and incomplete knowledge of their benefits44
USE OF ULTRACET IN OA KNEESbull The efficacy of tramadolacetaminophen combination tablets (Ultracetreg) as add-
on and maintenance therapy in knee osteoarthritis pain inadequately controlled by nonsteroidal anti-inflammatory drug (NSAID)
Park KS Choi JJ Kim WU Min JK Park SH Cho CS
bull TramadolAPAP add-on significantly improved knee OA pain which had been inadequately controlled by NSAIDs In those subjects who showed favorable response to tramadolAPAP and NSAID combination therapy both tramadolAPAP and NSAIDs were effective at maintaining the pain-reduced state and there was no significant difference in efficacy between tramadolAPAP and NSAIDs
Clinical Rheumatology 2011 3 Aug
Opioid Sparing Regimes
bull Multimodal analgesia (Kehlet et al 1999)
bull NSAIDs and COX-2 (Romsing Moiniche 2004)
bull Paracetamol (Romsing 2002)
bull Ketamine (Elia Tramer 2005)
bull Gabapentin and Pregabalin (Dahl et al 2004)
bull Gabapentin and Rofecoxib (Gilron et al 2005)
Opioid reduction 20 ndash 40 Reduction of PONV 30
Clinical effects
Single-modality treatment of a Multi- modality problem is
futile
ldquoTherersquos no pain thatrsquos so easy to bear than that of
someone elserdquo
ndashLeriche
Van Gogh ldquoOld Man in Sorrowrdquo
Tricyclic Agents
bull best documented analgesics here (NNT 22)bull amitriptyline best investigatedbull desipraminenortriptyline less AEs
bull start on low doses increases compliancebullOften adverse effects (NNH 28)bull effect needs timebull SSRIs not as effective (NNT 67)
bull noradrenergic effect necessarybull venlafaxine another option
Antidepressants Compared with Placebo
Condition Number of trials
Antidepressant improvedtotal
Placebo improvedtotal
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 13 180260 73205 19 (16 to
24)30 (24 to 40)
Postherpetic neuralgia 3 4377 868 48 (24 to
94)23 (17 to 33)
Atypical facial pain 2 6288 3085 20 (15 to
28)28 (20 to 47)
Central pain 1 1015 115 10 (15 to 69)
17 (11 to 30)
Bandolier
Anticonvulsants as Membrane Stabilisers
bull pregabalinbull gabapentin bull carbamazepinebull clonazepam pooled NNT 27bull valproatebull lamotriginebull baclofen
Anticonvulsants Compared with Placebo
Condition Number of trials
Anticonvulsant improvedtotal
Placebo improvedtot
al
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 3 5668 2668 19 (14 to 27) 25 (18
to 40)
Trigeminal neuralgia 3 178315 41224 31 (23 to 41) 26 (22
to 33)
Migraine prophylaxis 2 6374 1777 37 (24 to 59) 16 (13
to 20)
Other pain syndromes 1 514 115 54 (07 to 40)
not calculat ed
Bandolier
Relative Activity on Serotonin and Norepinephrine Reuptake Among
Antidepressants
CitalopramFluvoxamineSertralineParoxetineFluoxetine
VenlafaxineDuloxetine
MaprotilineDesipramineNortriptylineReboxetine
AmitriptylineMilnacipranImipramine
Serotonin Mixed Norepinephrine
Antidepressant Analgesic Antidepressant
Fishbain et al Pain Med 20001310-316
Opioidsbull In principle opioids are effective in nociceptive
and some neuropathic pain however not always and not necessarily completely for dynamic pain
bull Possibly preferable opioids here arendash tramadol
bull noradrenergic and serotoninergic effectndash morphine
bull Mu receptor anatagonistmonaminergic effect
ndash oxycodonebull kappa receptor effect
Opioids
bull lsquoLack of analgesic effect of opioids on neuropathic hellip painrsquo Pain 19883311
bull lsquohellip intravenous hellip morphine reduce the pain of Osteoarthritisrsquo Neurology
1991411024bull lsquoA call for more science not more
rhetoric regarding opioids and arthritic painrsquo Pain 2001471
bull lsquoEfficacy of oxycodone in neuropathic painhelliprsquo Neurology 1998501837
OPIOIDS FOR OA PAINbull Osteoarthritis guidelines provide limited guidance on opioid use bull The 1995 ACR guidelines for hip OA suggest opioids be avoided for
long term use but short term use may be helpful without reference to primary data15
bull The 1995 ACR knee OA guidelines do not discuss opioids directly16 bull The 1998 UK guidelines on degenerative arthritis suggest that if
relief is inadequate with 24 grams of ibuprofen and 40 grams of paracetamol a day other antiinflammatories or opioids may be considered18
bull The 2000 update of the ACR OA guidelines suggests that opioids might be used as a medication of last resort17
bull Opioids are effective in OA hip and knee pain and have predictable side effects
bull It would be unwise were physicians to discount an entire class of medications over unfounded fears and incomplete knowledge of their benefits44
USE OF ULTRACET IN OA KNEESbull The efficacy of tramadolacetaminophen combination tablets (Ultracetreg) as add-
on and maintenance therapy in knee osteoarthritis pain inadequately controlled by nonsteroidal anti-inflammatory drug (NSAID)
Park KS Choi JJ Kim WU Min JK Park SH Cho CS
bull TramadolAPAP add-on significantly improved knee OA pain which had been inadequately controlled by NSAIDs In those subjects who showed favorable response to tramadolAPAP and NSAID combination therapy both tramadolAPAP and NSAIDs were effective at maintaining the pain-reduced state and there was no significant difference in efficacy between tramadolAPAP and NSAIDs
Clinical Rheumatology 2011 3 Aug
Opioid Sparing Regimes
bull Multimodal analgesia (Kehlet et al 1999)
bull NSAIDs and COX-2 (Romsing Moiniche 2004)
bull Paracetamol (Romsing 2002)
bull Ketamine (Elia Tramer 2005)
bull Gabapentin and Pregabalin (Dahl et al 2004)
bull Gabapentin and Rofecoxib (Gilron et al 2005)
Opioid reduction 20 ndash 40 Reduction of PONV 30
Clinical effects
Single-modality treatment of a Multi- modality problem is
futile
ldquoTherersquos no pain thatrsquos so easy to bear than that of
someone elserdquo
ndashLeriche
Van Gogh ldquoOld Man in Sorrowrdquo
Antidepressants Compared with Placebo
Condition Number of trials
Antidepressant improvedtotal
Placebo improvedtotal
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 13 180260 73205 19 (16 to
24)30 (24 to 40)
Postherpetic neuralgia 3 4377 868 48 (24 to
94)23 (17 to 33)
Atypical facial pain 2 6288 3085 20 (15 to
28)28 (20 to 47)
Central pain 1 1015 115 10 (15 to 69)
17 (11 to 30)
Bandolier
Anticonvulsants as Membrane Stabilisers
bull pregabalinbull gabapentin bull carbamazepinebull clonazepam pooled NNT 27bull valproatebull lamotriginebull baclofen
Anticonvulsants Compared with Placebo
Condition Number of trials
Anticonvulsant improvedtotal
Placebo improvedtot
al
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 3 5668 2668 19 (14 to 27) 25 (18
to 40)
Trigeminal neuralgia 3 178315 41224 31 (23 to 41) 26 (22
to 33)
Migraine prophylaxis 2 6374 1777 37 (24 to 59) 16 (13
to 20)
Other pain syndromes 1 514 115 54 (07 to 40)
not calculat ed
Bandolier
Relative Activity on Serotonin and Norepinephrine Reuptake Among
Antidepressants
CitalopramFluvoxamineSertralineParoxetineFluoxetine
VenlafaxineDuloxetine
MaprotilineDesipramineNortriptylineReboxetine
AmitriptylineMilnacipranImipramine
Serotonin Mixed Norepinephrine
Antidepressant Analgesic Antidepressant
Fishbain et al Pain Med 20001310-316
Opioidsbull In principle opioids are effective in nociceptive
and some neuropathic pain however not always and not necessarily completely for dynamic pain
bull Possibly preferable opioids here arendash tramadol
bull noradrenergic and serotoninergic effectndash morphine
bull Mu receptor anatagonistmonaminergic effect
ndash oxycodonebull kappa receptor effect
Opioids
bull lsquoLack of analgesic effect of opioids on neuropathic hellip painrsquo Pain 19883311
bull lsquohellip intravenous hellip morphine reduce the pain of Osteoarthritisrsquo Neurology
1991411024bull lsquoA call for more science not more
rhetoric regarding opioids and arthritic painrsquo Pain 2001471
bull lsquoEfficacy of oxycodone in neuropathic painhelliprsquo Neurology 1998501837
OPIOIDS FOR OA PAINbull Osteoarthritis guidelines provide limited guidance on opioid use bull The 1995 ACR guidelines for hip OA suggest opioids be avoided for
long term use but short term use may be helpful without reference to primary data15
bull The 1995 ACR knee OA guidelines do not discuss opioids directly16 bull The 1998 UK guidelines on degenerative arthritis suggest that if
relief is inadequate with 24 grams of ibuprofen and 40 grams of paracetamol a day other antiinflammatories or opioids may be considered18
bull The 2000 update of the ACR OA guidelines suggests that opioids might be used as a medication of last resort17
bull Opioids are effective in OA hip and knee pain and have predictable side effects
bull It would be unwise were physicians to discount an entire class of medications over unfounded fears and incomplete knowledge of their benefits44
USE OF ULTRACET IN OA KNEESbull The efficacy of tramadolacetaminophen combination tablets (Ultracetreg) as add-
on and maintenance therapy in knee osteoarthritis pain inadequately controlled by nonsteroidal anti-inflammatory drug (NSAID)
Park KS Choi JJ Kim WU Min JK Park SH Cho CS
bull TramadolAPAP add-on significantly improved knee OA pain which had been inadequately controlled by NSAIDs In those subjects who showed favorable response to tramadolAPAP and NSAID combination therapy both tramadolAPAP and NSAIDs were effective at maintaining the pain-reduced state and there was no significant difference in efficacy between tramadolAPAP and NSAIDs
Clinical Rheumatology 2011 3 Aug
Opioid Sparing Regimes
bull Multimodal analgesia (Kehlet et al 1999)
bull NSAIDs and COX-2 (Romsing Moiniche 2004)
bull Paracetamol (Romsing 2002)
bull Ketamine (Elia Tramer 2005)
bull Gabapentin and Pregabalin (Dahl et al 2004)
bull Gabapentin and Rofecoxib (Gilron et al 2005)
Opioid reduction 20 ndash 40 Reduction of PONV 30
Clinical effects
Single-modality treatment of a Multi- modality problem is
futile
ldquoTherersquos no pain thatrsquos so easy to bear than that of
someone elserdquo
ndashLeriche
Van Gogh ldquoOld Man in Sorrowrdquo
Anticonvulsants as Membrane Stabilisers
bull pregabalinbull gabapentin bull carbamazepinebull clonazepam pooled NNT 27bull valproatebull lamotriginebull baclofen
Anticonvulsants Compared with Placebo
Condition Number of trials
Anticonvulsant improvedtotal
Placebo improvedtot
al
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 3 5668 2668 19 (14 to 27) 25 (18
to 40)
Trigeminal neuralgia 3 178315 41224 31 (23 to 41) 26 (22
to 33)
Migraine prophylaxis 2 6374 1777 37 (24 to 59) 16 (13
to 20)
Other pain syndromes 1 514 115 54 (07 to 40)
not calculat ed
Bandolier
Relative Activity on Serotonin and Norepinephrine Reuptake Among
Antidepressants
CitalopramFluvoxamineSertralineParoxetineFluoxetine
VenlafaxineDuloxetine
MaprotilineDesipramineNortriptylineReboxetine
AmitriptylineMilnacipranImipramine
Serotonin Mixed Norepinephrine
Antidepressant Analgesic Antidepressant
Fishbain et al Pain Med 20001310-316
Opioidsbull In principle opioids are effective in nociceptive
and some neuropathic pain however not always and not necessarily completely for dynamic pain
bull Possibly preferable opioids here arendash tramadol
bull noradrenergic and serotoninergic effectndash morphine
bull Mu receptor anatagonistmonaminergic effect
ndash oxycodonebull kappa receptor effect
Opioids
bull lsquoLack of analgesic effect of opioids on neuropathic hellip painrsquo Pain 19883311
bull lsquohellip intravenous hellip morphine reduce the pain of Osteoarthritisrsquo Neurology
1991411024bull lsquoA call for more science not more
rhetoric regarding opioids and arthritic painrsquo Pain 2001471
bull lsquoEfficacy of oxycodone in neuropathic painhelliprsquo Neurology 1998501837
OPIOIDS FOR OA PAINbull Osteoarthritis guidelines provide limited guidance on opioid use bull The 1995 ACR guidelines for hip OA suggest opioids be avoided for
long term use but short term use may be helpful without reference to primary data15
bull The 1995 ACR knee OA guidelines do not discuss opioids directly16 bull The 1998 UK guidelines on degenerative arthritis suggest that if
relief is inadequate with 24 grams of ibuprofen and 40 grams of paracetamol a day other antiinflammatories or opioids may be considered18
bull The 2000 update of the ACR OA guidelines suggests that opioids might be used as a medication of last resort17
bull Opioids are effective in OA hip and knee pain and have predictable side effects
bull It would be unwise were physicians to discount an entire class of medications over unfounded fears and incomplete knowledge of their benefits44
USE OF ULTRACET IN OA KNEESbull The efficacy of tramadolacetaminophen combination tablets (Ultracetreg) as add-
on and maintenance therapy in knee osteoarthritis pain inadequately controlled by nonsteroidal anti-inflammatory drug (NSAID)
Park KS Choi JJ Kim WU Min JK Park SH Cho CS
bull TramadolAPAP add-on significantly improved knee OA pain which had been inadequately controlled by NSAIDs In those subjects who showed favorable response to tramadolAPAP and NSAID combination therapy both tramadolAPAP and NSAIDs were effective at maintaining the pain-reduced state and there was no significant difference in efficacy between tramadolAPAP and NSAIDs
Clinical Rheumatology 2011 3 Aug
Opioid Sparing Regimes
bull Multimodal analgesia (Kehlet et al 1999)
bull NSAIDs and COX-2 (Romsing Moiniche 2004)
bull Paracetamol (Romsing 2002)
bull Ketamine (Elia Tramer 2005)
bull Gabapentin and Pregabalin (Dahl et al 2004)
bull Gabapentin and Rofecoxib (Gilron et al 2005)
Opioid reduction 20 ndash 40 Reduction of PONV 30
Clinical effects
Single-modality treatment of a Multi- modality problem is
futile
ldquoTherersquos no pain thatrsquos so easy to bear than that of
someone elserdquo
ndashLeriche
Van Gogh ldquoOld Man in Sorrowrdquo
Anticonvulsants Compared with Placebo
Condition Number of trials
Anticonvulsant improvedtotal
Placebo improvedtot
al
Relative benefit (95CI)
NNT (95CI)
Diabetic neuropathy 3 5668 2668 19 (14 to 27) 25 (18
to 40)
Trigeminal neuralgia 3 178315 41224 31 (23 to 41) 26 (22
to 33)
Migraine prophylaxis 2 6374 1777 37 (24 to 59) 16 (13
to 20)
Other pain syndromes 1 514 115 54 (07 to 40)
not calculat ed
Bandolier
Relative Activity on Serotonin and Norepinephrine Reuptake Among
Antidepressants
CitalopramFluvoxamineSertralineParoxetineFluoxetine
VenlafaxineDuloxetine
MaprotilineDesipramineNortriptylineReboxetine
AmitriptylineMilnacipranImipramine
Serotonin Mixed Norepinephrine
Antidepressant Analgesic Antidepressant
Fishbain et al Pain Med 20001310-316
Opioidsbull In principle opioids are effective in nociceptive
and some neuropathic pain however not always and not necessarily completely for dynamic pain
bull Possibly preferable opioids here arendash tramadol
bull noradrenergic and serotoninergic effectndash morphine
bull Mu receptor anatagonistmonaminergic effect
ndash oxycodonebull kappa receptor effect
Opioids
bull lsquoLack of analgesic effect of opioids on neuropathic hellip painrsquo Pain 19883311
bull lsquohellip intravenous hellip morphine reduce the pain of Osteoarthritisrsquo Neurology
1991411024bull lsquoA call for more science not more
rhetoric regarding opioids and arthritic painrsquo Pain 2001471
bull lsquoEfficacy of oxycodone in neuropathic painhelliprsquo Neurology 1998501837
OPIOIDS FOR OA PAINbull Osteoarthritis guidelines provide limited guidance on opioid use bull The 1995 ACR guidelines for hip OA suggest opioids be avoided for
long term use but short term use may be helpful without reference to primary data15
bull The 1995 ACR knee OA guidelines do not discuss opioids directly16 bull The 1998 UK guidelines on degenerative arthritis suggest that if
relief is inadequate with 24 grams of ibuprofen and 40 grams of paracetamol a day other antiinflammatories or opioids may be considered18
bull The 2000 update of the ACR OA guidelines suggests that opioids might be used as a medication of last resort17
bull Opioids are effective in OA hip and knee pain and have predictable side effects
bull It would be unwise were physicians to discount an entire class of medications over unfounded fears and incomplete knowledge of their benefits44
USE OF ULTRACET IN OA KNEESbull The efficacy of tramadolacetaminophen combination tablets (Ultracetreg) as add-
on and maintenance therapy in knee osteoarthritis pain inadequately controlled by nonsteroidal anti-inflammatory drug (NSAID)
Park KS Choi JJ Kim WU Min JK Park SH Cho CS
bull TramadolAPAP add-on significantly improved knee OA pain which had been inadequately controlled by NSAIDs In those subjects who showed favorable response to tramadolAPAP and NSAID combination therapy both tramadolAPAP and NSAIDs were effective at maintaining the pain-reduced state and there was no significant difference in efficacy between tramadolAPAP and NSAIDs
Clinical Rheumatology 2011 3 Aug
Opioid Sparing Regimes
bull Multimodal analgesia (Kehlet et al 1999)
bull NSAIDs and COX-2 (Romsing Moiniche 2004)
bull Paracetamol (Romsing 2002)
bull Ketamine (Elia Tramer 2005)
bull Gabapentin and Pregabalin (Dahl et al 2004)
bull Gabapentin and Rofecoxib (Gilron et al 2005)
Opioid reduction 20 ndash 40 Reduction of PONV 30
Clinical effects
Single-modality treatment of a Multi- modality problem is
futile
ldquoTherersquos no pain thatrsquos so easy to bear than that of
someone elserdquo
ndashLeriche
Van Gogh ldquoOld Man in Sorrowrdquo
Relative Activity on Serotonin and Norepinephrine Reuptake Among
Antidepressants
CitalopramFluvoxamineSertralineParoxetineFluoxetine
VenlafaxineDuloxetine
MaprotilineDesipramineNortriptylineReboxetine
AmitriptylineMilnacipranImipramine
Serotonin Mixed Norepinephrine
Antidepressant Analgesic Antidepressant
Fishbain et al Pain Med 20001310-316
Opioidsbull In principle opioids are effective in nociceptive
and some neuropathic pain however not always and not necessarily completely for dynamic pain
bull Possibly preferable opioids here arendash tramadol
bull noradrenergic and serotoninergic effectndash morphine
bull Mu receptor anatagonistmonaminergic effect
ndash oxycodonebull kappa receptor effect
Opioids
bull lsquoLack of analgesic effect of opioids on neuropathic hellip painrsquo Pain 19883311
bull lsquohellip intravenous hellip morphine reduce the pain of Osteoarthritisrsquo Neurology
1991411024bull lsquoA call for more science not more
rhetoric regarding opioids and arthritic painrsquo Pain 2001471
bull lsquoEfficacy of oxycodone in neuropathic painhelliprsquo Neurology 1998501837
OPIOIDS FOR OA PAINbull Osteoarthritis guidelines provide limited guidance on opioid use bull The 1995 ACR guidelines for hip OA suggest opioids be avoided for
long term use but short term use may be helpful without reference to primary data15
bull The 1995 ACR knee OA guidelines do not discuss opioids directly16 bull The 1998 UK guidelines on degenerative arthritis suggest that if
relief is inadequate with 24 grams of ibuprofen and 40 grams of paracetamol a day other antiinflammatories or opioids may be considered18
bull The 2000 update of the ACR OA guidelines suggests that opioids might be used as a medication of last resort17
bull Opioids are effective in OA hip and knee pain and have predictable side effects
bull It would be unwise were physicians to discount an entire class of medications over unfounded fears and incomplete knowledge of their benefits44
USE OF ULTRACET IN OA KNEESbull The efficacy of tramadolacetaminophen combination tablets (Ultracetreg) as add-
on and maintenance therapy in knee osteoarthritis pain inadequately controlled by nonsteroidal anti-inflammatory drug (NSAID)
Park KS Choi JJ Kim WU Min JK Park SH Cho CS
bull TramadolAPAP add-on significantly improved knee OA pain which had been inadequately controlled by NSAIDs In those subjects who showed favorable response to tramadolAPAP and NSAID combination therapy both tramadolAPAP and NSAIDs were effective at maintaining the pain-reduced state and there was no significant difference in efficacy between tramadolAPAP and NSAIDs
Clinical Rheumatology 2011 3 Aug
Opioid Sparing Regimes
bull Multimodal analgesia (Kehlet et al 1999)
bull NSAIDs and COX-2 (Romsing Moiniche 2004)
bull Paracetamol (Romsing 2002)
bull Ketamine (Elia Tramer 2005)
bull Gabapentin and Pregabalin (Dahl et al 2004)
bull Gabapentin and Rofecoxib (Gilron et al 2005)
Opioid reduction 20 ndash 40 Reduction of PONV 30
Clinical effects
Single-modality treatment of a Multi- modality problem is
futile
ldquoTherersquos no pain thatrsquos so easy to bear than that of
someone elserdquo
ndashLeriche
Van Gogh ldquoOld Man in Sorrowrdquo
Opioidsbull In principle opioids are effective in nociceptive
and some neuropathic pain however not always and not necessarily completely for dynamic pain
bull Possibly preferable opioids here arendash tramadol
bull noradrenergic and serotoninergic effectndash morphine
bull Mu receptor anatagonistmonaminergic effect
ndash oxycodonebull kappa receptor effect
Opioids
bull lsquoLack of analgesic effect of opioids on neuropathic hellip painrsquo Pain 19883311
bull lsquohellip intravenous hellip morphine reduce the pain of Osteoarthritisrsquo Neurology
1991411024bull lsquoA call for more science not more
rhetoric regarding opioids and arthritic painrsquo Pain 2001471
bull lsquoEfficacy of oxycodone in neuropathic painhelliprsquo Neurology 1998501837
OPIOIDS FOR OA PAINbull Osteoarthritis guidelines provide limited guidance on opioid use bull The 1995 ACR guidelines for hip OA suggest opioids be avoided for
long term use but short term use may be helpful without reference to primary data15
bull The 1995 ACR knee OA guidelines do not discuss opioids directly16 bull The 1998 UK guidelines on degenerative arthritis suggest that if
relief is inadequate with 24 grams of ibuprofen and 40 grams of paracetamol a day other antiinflammatories or opioids may be considered18
bull The 2000 update of the ACR OA guidelines suggests that opioids might be used as a medication of last resort17
bull Opioids are effective in OA hip and knee pain and have predictable side effects
bull It would be unwise were physicians to discount an entire class of medications over unfounded fears and incomplete knowledge of their benefits44
USE OF ULTRACET IN OA KNEESbull The efficacy of tramadolacetaminophen combination tablets (Ultracetreg) as add-
on and maintenance therapy in knee osteoarthritis pain inadequately controlled by nonsteroidal anti-inflammatory drug (NSAID)
Park KS Choi JJ Kim WU Min JK Park SH Cho CS
bull TramadolAPAP add-on significantly improved knee OA pain which had been inadequately controlled by NSAIDs In those subjects who showed favorable response to tramadolAPAP and NSAID combination therapy both tramadolAPAP and NSAIDs were effective at maintaining the pain-reduced state and there was no significant difference in efficacy between tramadolAPAP and NSAIDs
Clinical Rheumatology 2011 3 Aug
Opioid Sparing Regimes
bull Multimodal analgesia (Kehlet et al 1999)
bull NSAIDs and COX-2 (Romsing Moiniche 2004)
bull Paracetamol (Romsing 2002)
bull Ketamine (Elia Tramer 2005)
bull Gabapentin and Pregabalin (Dahl et al 2004)
bull Gabapentin and Rofecoxib (Gilron et al 2005)
Opioid reduction 20 ndash 40 Reduction of PONV 30
Clinical effects
Single-modality treatment of a Multi- modality problem is
futile
ldquoTherersquos no pain thatrsquos so easy to bear than that of
someone elserdquo
ndashLeriche
Van Gogh ldquoOld Man in Sorrowrdquo
Opioids
bull lsquoLack of analgesic effect of opioids on neuropathic hellip painrsquo Pain 19883311
bull lsquohellip intravenous hellip morphine reduce the pain of Osteoarthritisrsquo Neurology
1991411024bull lsquoA call for more science not more
rhetoric regarding opioids and arthritic painrsquo Pain 2001471
bull lsquoEfficacy of oxycodone in neuropathic painhelliprsquo Neurology 1998501837
OPIOIDS FOR OA PAINbull Osteoarthritis guidelines provide limited guidance on opioid use bull The 1995 ACR guidelines for hip OA suggest opioids be avoided for
long term use but short term use may be helpful without reference to primary data15
bull The 1995 ACR knee OA guidelines do not discuss opioids directly16 bull The 1998 UK guidelines on degenerative arthritis suggest that if
relief is inadequate with 24 grams of ibuprofen and 40 grams of paracetamol a day other antiinflammatories or opioids may be considered18
bull The 2000 update of the ACR OA guidelines suggests that opioids might be used as a medication of last resort17
bull Opioids are effective in OA hip and knee pain and have predictable side effects
bull It would be unwise were physicians to discount an entire class of medications over unfounded fears and incomplete knowledge of their benefits44
USE OF ULTRACET IN OA KNEESbull The efficacy of tramadolacetaminophen combination tablets (Ultracetreg) as add-
on and maintenance therapy in knee osteoarthritis pain inadequately controlled by nonsteroidal anti-inflammatory drug (NSAID)
Park KS Choi JJ Kim WU Min JK Park SH Cho CS
bull TramadolAPAP add-on significantly improved knee OA pain which had been inadequately controlled by NSAIDs In those subjects who showed favorable response to tramadolAPAP and NSAID combination therapy both tramadolAPAP and NSAIDs were effective at maintaining the pain-reduced state and there was no significant difference in efficacy between tramadolAPAP and NSAIDs
Clinical Rheumatology 2011 3 Aug
Opioid Sparing Regimes
bull Multimodal analgesia (Kehlet et al 1999)
bull NSAIDs and COX-2 (Romsing Moiniche 2004)
bull Paracetamol (Romsing 2002)
bull Ketamine (Elia Tramer 2005)
bull Gabapentin and Pregabalin (Dahl et al 2004)
bull Gabapentin and Rofecoxib (Gilron et al 2005)
Opioid reduction 20 ndash 40 Reduction of PONV 30
Clinical effects
Single-modality treatment of a Multi- modality problem is
futile
ldquoTherersquos no pain thatrsquos so easy to bear than that of
someone elserdquo
ndashLeriche
Van Gogh ldquoOld Man in Sorrowrdquo
OPIOIDS FOR OA PAINbull Osteoarthritis guidelines provide limited guidance on opioid use bull The 1995 ACR guidelines for hip OA suggest opioids be avoided for
long term use but short term use may be helpful without reference to primary data15
bull The 1995 ACR knee OA guidelines do not discuss opioids directly16 bull The 1998 UK guidelines on degenerative arthritis suggest that if
relief is inadequate with 24 grams of ibuprofen and 40 grams of paracetamol a day other antiinflammatories or opioids may be considered18
bull The 2000 update of the ACR OA guidelines suggests that opioids might be used as a medication of last resort17
bull Opioids are effective in OA hip and knee pain and have predictable side effects
bull It would be unwise were physicians to discount an entire class of medications over unfounded fears and incomplete knowledge of their benefits44
USE OF ULTRACET IN OA KNEESbull The efficacy of tramadolacetaminophen combination tablets (Ultracetreg) as add-
on and maintenance therapy in knee osteoarthritis pain inadequately controlled by nonsteroidal anti-inflammatory drug (NSAID)
Park KS Choi JJ Kim WU Min JK Park SH Cho CS
bull TramadolAPAP add-on significantly improved knee OA pain which had been inadequately controlled by NSAIDs In those subjects who showed favorable response to tramadolAPAP and NSAID combination therapy both tramadolAPAP and NSAIDs were effective at maintaining the pain-reduced state and there was no significant difference in efficacy between tramadolAPAP and NSAIDs
Clinical Rheumatology 2011 3 Aug
Opioid Sparing Regimes
bull Multimodal analgesia (Kehlet et al 1999)
bull NSAIDs and COX-2 (Romsing Moiniche 2004)
bull Paracetamol (Romsing 2002)
bull Ketamine (Elia Tramer 2005)
bull Gabapentin and Pregabalin (Dahl et al 2004)
bull Gabapentin and Rofecoxib (Gilron et al 2005)
Opioid reduction 20 ndash 40 Reduction of PONV 30
Clinical effects
Single-modality treatment of a Multi- modality problem is
futile
ldquoTherersquos no pain thatrsquos so easy to bear than that of
someone elserdquo
ndashLeriche
Van Gogh ldquoOld Man in Sorrowrdquo
USE OF ULTRACET IN OA KNEESbull The efficacy of tramadolacetaminophen combination tablets (Ultracetreg) as add-
on and maintenance therapy in knee osteoarthritis pain inadequately controlled by nonsteroidal anti-inflammatory drug (NSAID)
Park KS Choi JJ Kim WU Min JK Park SH Cho CS
bull TramadolAPAP add-on significantly improved knee OA pain which had been inadequately controlled by NSAIDs In those subjects who showed favorable response to tramadolAPAP and NSAID combination therapy both tramadolAPAP and NSAIDs were effective at maintaining the pain-reduced state and there was no significant difference in efficacy between tramadolAPAP and NSAIDs
Clinical Rheumatology 2011 3 Aug
Opioid Sparing Regimes
bull Multimodal analgesia (Kehlet et al 1999)
bull NSAIDs and COX-2 (Romsing Moiniche 2004)
bull Paracetamol (Romsing 2002)
bull Ketamine (Elia Tramer 2005)
bull Gabapentin and Pregabalin (Dahl et al 2004)
bull Gabapentin and Rofecoxib (Gilron et al 2005)
Opioid reduction 20 ndash 40 Reduction of PONV 30
Clinical effects
Single-modality treatment of a Multi- modality problem is
futile
ldquoTherersquos no pain thatrsquos so easy to bear than that of
someone elserdquo
ndashLeriche
Van Gogh ldquoOld Man in Sorrowrdquo
Opioid Sparing Regimes
bull Multimodal analgesia (Kehlet et al 1999)
bull NSAIDs and COX-2 (Romsing Moiniche 2004)
bull Paracetamol (Romsing 2002)
bull Ketamine (Elia Tramer 2005)
bull Gabapentin and Pregabalin (Dahl et al 2004)
bull Gabapentin and Rofecoxib (Gilron et al 2005)
Opioid reduction 20 ndash 40 Reduction of PONV 30
Clinical effects
Single-modality treatment of a Multi- modality problem is
futile
ldquoTherersquos no pain thatrsquos so easy to bear than that of
someone elserdquo
ndashLeriche
Van Gogh ldquoOld Man in Sorrowrdquo
Single-modality treatment of a Multi- modality problem is
futile
ldquoTherersquos no pain thatrsquos so easy to bear than that of
someone elserdquo
ndashLeriche
Van Gogh ldquoOld Man in Sorrowrdquo
ldquoTherersquos no pain thatrsquos so easy to bear than that of
someone elserdquo
ndashLeriche
Van Gogh ldquoOld Man in Sorrowrdquo
