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Dr Giridhar Panpalia
Clinical definition of pain1
“An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage...
1. IASP Pain Terminology. In Merskey H & Bogduk N eds. Classification of Chronic Pain, Second Edition, IASP Task Force on Taxonomy. IASP Press, Seattle 1994:209-14.
Every one needPain Relief
Nociceptive pain Transient pain in response to noxious stimuli
Inflammatory pain Spontaneous pain and hypersensitivity to pain in response
to tissue damage and inflammation
Neuropathic pain Spontaneous pain and hypersensitivity to pain in
association with damage to or a lesion of the nervous system
Woolf. Ann Intern Med. 2004;140:441-451.
Ref:- Wall and Melzacks text book of pain. 2005
Reuben et al. J Bone Joint Surg. 2000;82:1754-1766.
Myocardialischemia
Increasedsympatheticactivity
Myocardial Myocardial OO2 2
consumptionconsumption
GI effectsSplinting,shallowbreathing
Increasedcatabolicdemands
Anxietyand fear
Peripheral/centralsensitization
GI motilityGI motilityAtelectasis,Atelectasis,hypoxemia,hypoxemia,hypercarbiahypercarbia
Poor woundPoor woundhealing/musclehealing/musclebreakdownbreakdown
Sleeplessness,Sleeplessness,helplessnesshelplessness
AvailableAvailabledrugsdrugs
Delayed recovery Pneumonia
Weaknessand impairedrehabilitation
Psycho-logical
Chronic pain
Acute Pain
20032003 19931993
No. 5:No. 5:Treatment by healthcare Treatment by healthcare professionalsprofessionals 30%30% 30%30%
No. 4: Pain during surgeryNo. 4: Pain during surgery 33%33% 34%34%
No. 3: Full recovery from surgeryNo. 3: Full recovery from surgery 46%46% 42%42%
No. 2: Will surgery improve No. 2: Will surgery improve conditioncondition 51%51% 51%51%
No. 1: Pain after surgeryNo. 1: Pain after surgery 59%59% 57%57%
Warfield et al. Anesthesiology. 1995;83:1090-1094.
Apfelbaum et al. Anesth Analg. 2003;97:534-540..
Patie
nts
(%)
Patie
nts
(%)
*Includes pain in immediate postop period and up to 2 weeks post discharge. *Includes pain in immediate postop period and up to 2 weeks post discharge. Warfield et al. Anesthesiology. 1995;83:1090-1094. Apfelbaum et al. Anesth Analg. 2003;97:534-540..
21%21%
8%8% 19%19%
52%52%
SlightSlight ModerateModerate SevereSevere ExtremeExtremePain IntensityPain Intensity
Apfelbaum et al. Anesth Analg. 2010;97:534-540.
Pain ControlPain Control41%41%
Setting and Route Setting and Route of Administrationof Administration
12%
Side-Effect SeveritySide-Effect Severity19%19%
Side-Effect Type28%
Patients prefer avoiding side effects over complete pain control
47%
Gan et al. Br J Anaesth. 2004;92:681-688.
Postoperative pain management is still sub-optimal
1. Kuhn S et al. BMJ 1990;300(6741):1687-90.2. Poisson-Salomon AS et al. La Presse Médicale 1996;25(22):1013-7.3. Vallano A et al. Br J Clin Pharmacol 1999;47:667-73.4. McHugh GA et al. Anaesthesia 2002;57(3):270-5.5. Rawal N et al. Eur J Anaesth 1998;15:354-63.6. Puig MM et al. Acta Anaesthesiol Scand 2001;45:465-70.
I wantPain relief
Guidelines for optimising POP management1,2,3,4,5,6
Adequate and thorough patient information2,3,4,5,6
Use of written protocols1,3,4,5,6
Regular assessment of pain intensity1,2,3,4,5,6
Adequate medical and nursing staff training1,3,4,5,6
Use of balanced analgesia, PCA, and epidural drug administration1,2,3,4,5,6
1. The Royal College of Surgeons of England and the College of Anaesthetists. Commission on the provision of surgical services, report of the working party on pain after surgery. London, UK, HMSO.1990.2. Agency for Health Care Policy and Research, Public Health Service, US Department of Health and Human Services. Acute Pain Management in Adults: Operative Procedures. Quick Reference Guide for Clinicians. AHCPR Pub. No. 92-0019. Rockville, MD.1992.3. International Association for the Study of Pain, Management of acute pain: a practical guide. In: Ready LB, Edwards WT, eds. Seattle, 1992.4. Wulf H et al. Die Behandlung akuter perioperativer und posttraumatischer Schmerzen Empfehlungen einer interdisziplinaeren Expertenkommision. G. Thieme, Stuttgart, New York. 1997.5. EuroPain. European Minimum Standards for the Management of Postoperative Pain.1998.6. SFAR. Conférence de consensus. Prise en charge de la douleur postopératoire chez l’adulte et l’enfant. Ann Fr Anesth Réanim 1998;17:445-61.
Reduced doses
Improved pain relief
Reduce severityof side effects
Earlier discharge
Decreased costs
OpioidsOpioidsOpioidsOpioids
NSAIDs, coxibs,NSAIDs, coxibs,paracetamol,paracetamol,nerve blocksnerve blocks
NSAIDs, coxibs,NSAIDs, coxibs,paracetamol,paracetamol,nerve blocksnerve blocks
PotentiationPotentiation
Kehlet et al. Anesth Analg. 1993;77:1048-1056 (B).
“Is more effective & has a faster onset than oral paracetamol”
Paracetamol – how does it work?
Paracetamol is a centrally acting agent
It selectively inhibits nervous system PG synthesis2,3 probably via COX-3
Other central mechanisms of action depend on the bulbo-spinal serotoninergic pathway4,5
1. Piguet V et al. Eur J Clin Pharmacol 1998;53:321-4. 2. Carlsson KH et al. Pain 1988;32:313-26. 3. Flower RJ et al. Nature 1972;240:410-1. 4. Tjølsen A et al. Eur J Pharmacol 1991;193:193-201.5. Pélissier T et al. JPET 1996;278:8-14.
Tropisetron blocks the action; not ondansetron and granisetron
Does IV paracetamol have a fast onset and is it effective?1
Single-centre, randomised, double-blind, placebo and active-controlled, single-dose study Oral surgery Onset of analgesia measured by the double click- stopwatch method Pain intensity differences (PID) rated on VAS and VRS
N = 175
n=50 / i.v. paracetamol 1g / 2-min injection
n=50 / i.v. paracetamol 1g / 15-min infusion
n=50 / oral paracetamol 1g
n=25 / placebo
Sindet-Pedersen S. Br Jr Anesth 2005. 94 (5): 642-8
Means of pain intensity differences (VAS)
Onset of action is fast and effective – within 5 minutes
Sindet-Pedersen S. Br Jr Anesth 2005. 94 (5): 642-8
Jarde O et al. Clin Drug Invest 1997;14(6):474-81.
Time-effect curve
(n=109
IV paracetamol 1g is more effective than oral paracetamol 1g
Paracetamol PK/PD relationship in function of the dose
1. Piguet V et al. Eur J Clin Pharmacol 1998;53:321-4.
(n = 11)
No ceiling effect with i.v. paracetamol1
Single-centre, randomised, double-blind, placebo and active-controlled, repeated-dose study Oral surgery Summed pain intensity differences (SPID) and total pain relief (TOTPAR) after 5 and 10 hours
N = 95
n=31 / i.v. paracetamol 1g + i.v. paracetamol 0.5g after 5 hours
n=30 / i.m. morphine 10 mg + i.m. morphine 5 mg after 5 hours
n=34 / placebo
Does Paracetamol 1g compare with Morphine 10mg in terms of analgesic efficacy1
1. Van Aken H. Anesth Analg 2004; 98: 159-65
Time course of pain relief versus initial pain
Comparable analgesic efficacy
Oral surgery
1. Van Aken H. Anesth Analg 2004; 98: 159-65
Multi-centre, randomised, double-blind, placebo- controlled, single-dose study
Total hip or knee replacement surgery
Pain intensity differences (PID) measured on a VAS and a VRS
Pain relief (PR)
1. Zhou TJ et al. Anesth Analg 2001;92:1569-75.
N = 164
n=57 / i.v. paracetamol 1g
n=27 / i.v. ketorolac 30mg
n=28 / i.v. ketorolac 15mg
n=52 / placebo
…and Ketorolac 30mg1
1. Zhou TJ et al. Anesth Analg 2001;92:1569-75.
(n=57)
(n=28)
Total hip or knee replacementPain relief scores at rest
Not dissimilar for the first 5 hours in terms of analgesic efficacy
Single-centre, randomised, double-blind, placebo and active-controlled, double-placebo, repeated-dose study Total hip arthroplasty Total pain relief (TOTPAR) and Pain relief (PR) measured on a VRS
N = 120
n=40 / i.v. paracetamol 1g / 2 times at 5-hour interval
n=40 / i.m. diclofenac 75mg
n=40 / placebo
...and Diclofenac 75mg?
1. Hynes D et al. Acta Anaesthesiol Scand 2006; 50: 374—381
Time course of pain relief versus initial pain
Total hip arthroplasty
The analgesic effect provided by i.v. paracetamol is similar to that provided by a single i.m. injection of diclofenac 75mg.1
1. Hynes D et al. Acta Anaesthesiol Scand 2006; 50: 374—381
Multi-centre, randomised, double-blind, placebo-controlled, repeated-dose study Hip arthroplasty Total doses of PCA morphine over 24 hours, and number of self-administered boluses
Pain intensity assessed on a VRS and VAS
Global efficacy assessed on a VRS
1. Peduto VA et al. Acta Anaesthesiol Scand 1998;42:293-8.
N = 89n=42 / i.v. paracetamol 1g + morphine (PCA)
n=47 / i.v. placebo + morphine (PCA)
Does paracetamol have an opioid-sparing effect1
1. Peduto VA et al. Acta Anaesthesiol Scand 1998;42:293-8.
24-hour morphine consumption in terms of total PCA amountin mg and total number of boluses
Hip arthroplasty
46% less opioid consumed
Paracetamol - Safety
Similar overall incidence of adverse events
Similar incidence of local adverse events
No clinically significant changes in vital signs or laboratory tests
Phase III clinical trials1,2 VS. placebo
IV paracetamol as safe as placebo
1. Lange-Møller P. Anesth Analg 2005;101:90 –6 2. Sinatra RS. Anesthesiology 2005; 102:822–3India Prescribing Information
Paracetamol hepatotoxicity was found to be very rare (<1 / 2,500)1
It was always related to misuse and overdose (>4g / day)1
Hepatic safety at therapeutic doses1
1. Whitcomb DC et al. JAMA 1994;272(23):1845-50.
Good hepatic safety
Can Paracetamol be given in alcoholics?
Paracetamol - Alcohol syndrome
Overdose of Paracetamol in alcoholics results in severe hepatotoxicity
Alcohol induces CYP2E1 but inhibits NAPQI
1. Making paracetamol soluble Use of hydrophilic ingredients (mannitol and disodium phosphate)
2. Ensuring its stability in solution- By controlling hydrolysis Use of a pH buffer (disodium phosphate and sodium hydroxide)
- By preventing oxidation Addition of cysteine hydrochloride
Oxygen-free manufacturing process
What were the challenges?
Up to 4g / day, paracetamol has an excellent renal safety profile1
No evidence exists for the development of chronic nephropathy with paracetamol2
Recommended by the National Kidney Foundation as the non-narcotic analgesic of choice in patients with underlying renal disease 3
1. Whelton A. Am J Therapeut 2000;7(2):63-74.2. Blantz RC. Am J Kidney Dis 1996;28(1):S3-6.3. Henrich WL et al. Am J Kidney Dis 1996;27(1):162-5.
Good renal tolerance
No centrally mediated side-effects1
(e.g. sedation, constipation, nausea, vomiting, respiratory depression) No effect on platelet aggregation, bleeding, or uric acid excretion2
No gastrointestinal Sidé effects3
Good renal4 and hepatic5 safety Few contra-indications and drug interactions
Paracetamol safety benefits in POP
1. Lechat P et al. Thérapie 1989;44:337-54.2. Insel PA. Analgesic-antipyretic and antiinflammatory agents and drugs employed in the treatment of gout. In: Goodman & Gilman eds. The pharmacological basis of therapeutics. McGraw Hill, 9th edition, 1996:617-57.3. Singh G. Am J Therapeut 2000;7(2):115-21.4. Whelton A. Am J Therapeut 2000;7(2):63-74.5. Whitcomb DC et al. JAMA 1994;272(23):1845-50.
.
Where ? First administration in the OR
How?• 15-minute infusion every 4 to 6 hours
Dosing schedule:- Adolescents and adults weighing more than 50kg: 1 g / 4 times a day
Paracetamol infusion
DoseDose Minimum Minimum dosing dosing intervalinterval
Maximum daily Maximum daily dosedose
Adults Adults >50 kg>50 kg 1g qds1g qds 4 hrs4 hrs 4 g4 g
Adults/Adults/Children 33-50 Children 33-50 kgkg
15 mg/kg qds15 mg/kg qds 4 hrs4 hrs 60mg/kg60mg/kg
Not to exceed 3gNot to exceed 3g
Children 10-33 Children 10-33 kgkg
15 mg/kg qds15 mg/kg qds 4 hrs4 hrs 60mg/kg60mg/kg
Not to exceed 2gNot to exceed 2g
Newborn & Newborn & infants infants <10 kg<10 kg
7.5 mg/kg qds7.5 mg/kg qds 4 hrs4 hrs 30mg/kg30mg/kg
Paracetamol - Doses
An opioid An NSAID or a Coxib A local anaesthetic block
Local infiltration Local nerve block Plexus nerve block Neuraxial block
And now……… IV paracetamol