A New Molecule for Post Operative Pain Management Dr.P.Selvakumar M.D.,Senior consultantApollo Specialty Hospitals Madurai

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.

ObjectivesTypes of painPain physiologyMultimodal analgesia Intravenous agents used for postoperative painConclusions

Pain: Clinical TypesNociceptive pain Transient pain in response to noxious stimuli

Inflammatory pain Spontaneous pain and hypersensitivity to pain in response to tissue damage and inflammation

Neuropathic painSpontaneous pain and hypersensitivity to pain in association with damage to or a lesion of the nervous systemWoolf. Ann Intern Med. 2004;140:441-451.

Nociceptive PainSpinal CordBrainPain-Autonomic Response - Withdrawal ReflexNoxious Peripheral StimuliNociceptor Sensory NeuronHeatColdIntenseMechanical ForceChemical IrritantsWoolf. Ann Intern Med. 2004;140:441-451. Is responsive to NSAIDs, coxibs, paracetamol and opiates

Inflammatory PainSpinal CordBrainSpontaneous Pain Pain Hypersensitivity -Allodynia -HyperalgesiaNociceptor Sensory NeuronMacrophageTissue DamageInflammationMast CellNeutrophil GranulocyteWoolf. Ann Intern Med. 2004;140:441-451. Is responsive to NSAIDs,coxibs, paracetamol, and opiates

Neuropathic PainWoolf. Ann Intern Med. 2004;140:441-451. May respond to local anaesthetic anticonvulsants antidepressants

Less responsive to opioids

No response to NSAIDs, coxibs, or paracetamolSpontaneous Pain Pain Hypersensitivity

PerceptionModulationTransductionTransmissionReuben et al. J Bone Joint Surg. 2000;82:1754-1766.Postoperative pain is nociceptiveIs responsive to NSAIDs,coxibs, paracetamol and opiates

Consequences of Unrelieved PainIncreasedsympatheticactivityMyocardial O2 consumptionGI effectsSplinting, shallow breathingIncreased catabolicdemandsAnxiety and fearPeripheral/ central sensitizationGI motilityAtelectasis,hypoxemia,hypercarbiaPoor wound healing/muscle breakdownSleeplessness, helplessnessAvailable drugsChronic painAcute PainCourtesy of Sunil J Panchal, MD

21%8%19%52%Intensity of Pain After Discharge:81% Report Moderate to Extreme Pain SlightModerateSevereExtremePain IntensityApfelbaum et al. Anesth Analg. 2003;97:534-540.

Chart1

20

52

21

8

East

Sheet1

1st Qtr2nd Qtr3rd Qtr4th Qtr

East2052218

West30.638.634.631.6

North45.946.94543.9

Guidelines for optimisingPOP 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. Confrence de consensus. Prise en charge de la douleur postopratoire chez ladulte et lenfant. Ann Fr Anesth Ranim 1998;17:445-61.

Effective pain management may improve outcomes1,2,3Effective analgesia included in a comprehensivepostoperative rehabilitation programme1,2Improved patient comfort and satisfactionDecreased postoperative morbidityFaster recoveryShorter hospital stay1,2,3Very favourablecost/benefit ratio2Low cost of analgesic techniquesand drugs21. Kehlet H. Br J Anaesth 1994;72(4):375-8.2. Jayr C. In Les Aspects Economiques de lAnesthsie. JEPU 2000:131-8.3. DAmours RH et al. JOSPT 1996;24(4):227-36.

Physiology & pharmacological management of postoperative pain

Pain pathway and modulation1Descending inhibitory controls / Diffuse noxious inhibitory controlsInterpretation incerebral cortex: painStimulation of nociceptors(A and C fibers) / Release of neurotransmitters and neuromodulators (i.e. PG)1. Adapted from: Bonica JJ. Postoperative pain. In Bonica JJ, ed. The management of pain. Philadelphia: Lea and Febiger;1990:461-80.

Release of serotonin, noradrenalin and enkephalins at spinal levelActivation of serotoninergic and noradrenergic pathwaysInjuryAscending nociceptive pathways

Modes of action of analgesics1,2,3,41. DAmours RH et al. JOSPT 1996;24(4):227-36. 2. Piguet V et al. Eur J Clin Pharmacol 1998;53:321-4.3. Pini LA et al. JPET 1997;280(2):934-40.4. Chandrasekharan NV et al. PNAS 2002;99(21):13926-31.

OpioidsActivation ofopioid receptorsParacetamolInhibition of central Cox-3 (?)(Inhibition of PG synthesis)ParacetamolInteraction withserotoninergic descending inhibitory pathwayNSAIDs / CoxibsInhibition of peripheral and central Cox-1 / Cox-2 (Inhibition of PG synthesis)

Multimodal and Preemptive Approaches to Managing Postoperative Pain

The concept and benefits of balanced analgesia The rationale for multimodal analgesia is achievement of sufficient analgesia due to additive or synergistic effects between different analgesics, with concomitant reduction of side effects, due to resulting lower doses of analgesics and differences in side -effect profiles

1. Kehlet H et al. Anesth Analg 1993;77:1048-56.

Patients Preferences for Acute Pain TreatmentPain Control 41%Setting and Route of Administration 12%Side-Effect Severity 19%Side-Effect Type 28%Patients prefer avoiding side effects over complete pain controlGan et al. Br J Anaesth. 2004;92:681-688.

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19.0830.645.9

28.1638.646.9

12.0734.645

40.6931.643.9

East

West

North

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1st Qtr2nd Qtr3rd Qtr4th Qtr

East19.0828.1612.0740.69

West30.638.634.631.6

North45.946.94543.9

Proportion of Patients Experiencing Adverse EventsGan et al. Br J Anaesth. 2004;92:1-8.

Adverse Event (AE)Total %Constipation50Mental cloudiness/dizziness82Itching54Nightmares/hallucinations32Mood changes/alterations34Nausea70Sleep disorders48Vomiting32

Preventive Multimodal AnalgesiaSignificant improvement inPain reductionOpioid useOpioid-related AEsRecovery or day ward length of stayUnplanned admission to the hospitalReuben et al. Acute Pain. 2004;6:87-93.

Real World: Multimodal AnalgesiaReduced doses Improved pain relief Reduce severity of AEs

Earlier discharge

Decreased costsOpioidsNSAIDs, coxibs,paracetamol,nerve blocksPotentiationKehlet et al. Anesth Analg. 1993;77:1048-1056 (B).

Intravenous agents for multimodal analgesia

IV morphineIntermittent IV bolus dosesIs best method for acute painOptimal doses and dose intervals not established2-3 mg doses at 5 minute intervals appears effective

Continuous infusionCompared with PCA there is a 5-fold increase in respiratory depression

IV paracetamol - premise

Is more effective & has a faster onset than oral paracetamol

Onset of action is fast and effective within 5 minutes Sindet-Pedersen S. Br Jr Anesth 2005. 94 (5): 642-8

Paracetamol:clinical pharmacology

Paracetamol: a well known analgesic agent First proper account of clinical use in 1894 (Hinsberg and Treupel)1

Analgesic effect formally demonstrated in 1948 (Flinn and Brodie)1

Recommended first-line analgesic therapy:- for the treatment of osteoarthritis since 20002,3 - for musculoskeletal pain in elderly since 20024 - for patients with renal disease since 19965 1. Prescott LF. Am J Therapeut 2000;7(2):143-7.2. EULAR recommendations. Pendleton A et al. Ann Rheum Dis 2000;59(12):936-44.3. American College of Rheumatology Subcommittee on osteoarthritis guidelines. Arthritis Rheum 2000;43(9):1905-15.4. AGS Panel on Persistent Pain in Older Persons. JAGS 2002;50:S205-24.5. Henrich WL et al. Am J Kidney Dis 1996;27(1):162-5.

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. Tjlsen A et al. Eur J Pharmacol 1991;193:193-201.5. Plissier T et al. JPET 1996;278:8-14.

1. Piletta P et al. Clin Pharmacol Ther 1991;49(4):350-4.

Paracetamol clinically demonstrates central activity1

What were the challenges? 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

Indications

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. placeboIV paracetamol as safe as placebo1. Lange-Mller P. Anesth Analg 2005;101:90 6 2. Sinatra RS. Anesthesiology 2005; 102:8223India Prescribing Information

No difference in adverse events vs placeboOral surgeryLange-Mller P. Anesth Analg 2005;101:90 6.

Chart1

60.827.428

4900

33.327.528

Propacetamol 2g (n=51)

Perfalgan 1g (n=51)

Placebo (n=50)

Sheet1

Gen. Anaesth.Epidural anaesth.p

Postop. analgesiaPre-/postop. Analgesia

Duration TI (hrs)81.8 +/- 18.67.1 +/- 1.7< 0.005

ICU stay (days)5.7 +/- 9.32.5 +/- 1.8NS

Hospital stay (days)15.8 +/- 12.311.4 +/- 4.6NS

Hospital cost ($)20380 +/- 2034311218 +/- 57380.02

Mortality4/250/280.04

Morbidity19/259/280.02

Feuil5

BeforeAfter

Moderate to severe pain at rest32%12%

Inadequate pain relief47%21%

No or mild pain30.1%40.2%

Very satisfied patients26%36%

Sheet2

IVOral

ParacetamolParacetamolOpioidsNSAIDsTramadolMetamizol

UK33%46%

Germany6%54%1%35%

Italy2%5%58%35%

Spain18%7%4%4%10%64%

Portugal41%10%12%6%27%16%

Belgium93%23%9%13%14%

Switzerland41%53%32%18%10%

France73%24%22%6%

IVOral

ParacetamolParacetamolOpioidsNSAIDsTramadolMetamizol

UK33%46%

Germany54%35%

Italy58%35%

Spain18%64%

Portugal41%27%

Belgium93%23%

Switzerland41%53%

France73%24%

Feuil1

PropacetamolPerfalganDifferences

Nursing workload cost 1.67 0.79 -0.88 NC

Ancillary items used 0.98 0.40 -0.88 p 1 local AE025 (49.0%)0

> 1 non-local AE14 (27.5%)17 (33.3%)14 (28.0%)

Propacetamol 2g (n=51)Perfalgan 1g (n=51)Placebo (n=50)

Patients with at least one AE60.827.428

Patients with at least one local AE4900

Patients with at least one non-local AE33.327.528

Feuil2

Feuil4

Feuil3

p

%No difference in adverse events vs placeboOrthopaedic surgerySinatra RS. Anesthesiology 2005; 102:8223

Chart1

6665.361.5

4221.9

4863.359.6

Propacetamol 2g (n=50)

Perfalgan 1g (n=49)

Placebo (n=52)

Sheet1

Gen. Anaesth.Epidural anaesth.p

Postop. analgesiaPre-/postop. Analgesia

Duration TI (hrs)81.8 +/- 18.67.1 +/- 1.7< 0.005

ICU stay (days)5.7 +/- 9.32.5 +/- 1.8NS

Hospital stay (days)15.8 +/- 12.311.4 +/- 4.6NS

Hospital cost ($)20380 +/- 2034311218 +/- 57380.02

Mortality4/250/280.04

Morbidity19/259/280.02

Feuil5

BeforeAfter

Moderate to severe pain at rest32%12%

Inadequate pain relief47%21%

No or mild pain30.1%40.2%

Very satisfied patients26%36%

Sheet2

IVOral

ParacetamolParacetamolOpioidsNSAIDsTramadolMetamizol

UK33%46%

Germany6%54%1%35%

Italy2%5%58%35%

Spain18%7%4%4%10%64%

Portugal41%10%12%6%27%16%

Belgium93%23%9%13%14%

Switzerland41%53%32%18%10%

France73%24%22%6%

IVOral

ParacetamolParacetamolOpioidsNSAIDsTramadolMetamizol

UK33%46%

Germany54%35%

Italy58%35%

Spain18%64%

Portugal41%27%

Belgium93%23%

Switzerland41%53%

France73%24%

Feuil1

PropacetamolPerfalganDifferences

Nursing workload cost 1.67 0.79 -0.88 NC

Ancillary items used 0.98 0.40 -0.88 p 1 local AE025 (49.0%)0

> 1 non-local AE14 (27.5%)17 (33.3%)14 (28.0%)

Propacetamol 2g (n=50)Perfalgan 1g (n=49)Placebo (n=52)

Patients with at least one AE6665.361.5

Patients with at least one local AE4221.9

Patients with at least one non-local AE4863.359.6

Feuil2

Feuil4

Feuil3

p

Paracetamol hepatotoxicity was found to be very rare (4g / day)1

Hepatic safety at therapeutic doses11. Whitcomb DC et al. JAMA 1994;272(23):1845-50.

Good hepatic safety

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 toleranceRenal safety

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 side effects3

Good renal4 and hepatic5 safety

Few contra-indications and drug interactions

Paracetamol safety benefits in POP1. Lechat P et al. Thrapie 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.

.

How to use Perfalgan

No reconstitution

Saves nurses time1

Reduces use of ancillary products1

Reduces risk of dosage error1

Reduces risk of contamination1

Perfalgan is ready-to-use

1. Schmitt E et al. Pharm Hosp 2001;36(147):9-18.

1. Take the cap off

2. Link the bottle to a drip with an air intake

3. Hook the bottle with the built-in calliper

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

Perfalgan infusion

Shelf life is 2 years

Do not store above 30C

Do not refrigerate or freezeStorage

Conclusions

Perfalgan is a fast-acting analgesic, as effective as morphine 10mg1

Perfalgan is a proven opioid-sparing agent2

Perfalgan is well tolerated in all types of patients

Perfalgan is ready-to-use and cost-effective31. Van Aken H. 1991. Anesth Analg 2004; 98: 159-65 2. Peduto VA et al. Acta Anaesthesiol Scand 1998;42:293-8.3. Schmitt E et al. Pharm Hosp 2001;36(147):9-18.

**This is the definition of the International Association for the Study of Pain.Notes: Pain is always subjective. Each individual learns the application of the word through experiences related to injury in early life. This definition avoids tying pain to the stimulus. Activity induced in the nociceptor and nociceptive pathways by a noxious stimulus is not pain, which is always a psychological state, even though we may well appreciate that pain most often has a proximate physical cause.1

At least 4 distinct types of pain exist: nociceptive, inflammatory, neuropathic, and functional. Nociceptive pain is a response to noxious peripheral stimuli, such as burning or a surgical incision. The nociceptive pain system serves as a warning system for the body to avoid potentially dangerous stimuli. It should not be turned off except in rare circumstances, such as surgery or dental work. Without nociceptive pain, the body is constantly at risk for injury.Inflammatory pain is a response to tissue damage and inflammation, such as occurs in arthritis or near an infection. It also has a protective function, in that it surrounds and protects injured tissue and helps the healing process by preventing overuse of the injured part. As anyone who has banged a toe can testify, inflammatory pain decreases as the damage resolves. However, we also have degenerative diseases, such as osteoarthritis, that continue to create inflammatory pain because the tissue damage is ongoing.Neuropathic pain results from damage or lesions to the nervous system - such as occur in diabetic peripheral neuropathy or postherpetic neuralgia. It tends to be burning or stabbing in nature and is not responsive to traditional pain agents such as NSAIDs or aspirin. Neuropathic pain can also result from damage to the CNS, such as in patients with MS or spinal cord injury.Functional pain results from a dysfunction in the central processing of pain in the dorsal horn or other regions of the spinal cord. With functional pain, no neurologic deficits or peripheral abnormalities can be detected. Examples of functional pain include fibromyalgia, irritable bowel syndrome, and some forms of noncardiac chest pain.

Woolf CJ. Pain: moving from symptom control toward mechanism-specific pharmacologic management. Ann Intern Med. 2004;140:441-451.

***250 patients who had undergone surgical procedures (in- and outpatient) in the past year completed a questionnaire about their experiences with pain before and after surgery. The most common concern that patients expressed prior to surgery was experiencing pain (59%), which was cited more often than concerns about whether the surgery would improve their condition (51%) or whether they would fully recover (46%).Despite receiving treatment for pain, 82% of all patients reported pain in the immediate postsurgical period (end of surgery up to 2 weeks after discharge); 58% of the sample reported pain prior to discharge and 75% reported pain after discharge.More than two thirds of patients reported pain of moderate to severe intensity, and extreme pain was reported by 18% overall and 8% after discharge.

Apfelbaum JL, Chen C, Mehta SS, Gan TJ. Postoperative pain experience: results from a national survey suggest postoperative pain continues to be undermanaged. Anesth Analg. 2003;97:534-540.*A series of national and international recommendations and guidelines for improving postoperative pain management have been published and progressively implemented since the 1990s in Europe and North America.1,2,3,4,5,6Main directions for improvement are consensual:- Adequate and thorough patient information.2,3,4,5,6- Use of balanced analgesia, PCA, and epidural drug administration.2,3,4,5,6- Regular assessment of pain intensity.2,3,4,5,6- Adequate medical and nursing staff training.3,4,5,6- Use of written protocols.2,3,4,5,6

*Despite the absence of indisputable clinical evidence, it is generally accepted that effective pain management included in a comprehensive postoperative rehabilitation programme may improve patient satisfaction, contribute to lower postoperative morbidity, to faster recovery and rehabilitation, and finally to a shorter hospital stay.1,2,3Moreover, the mean cost of postoperative analgesics is very low compared to the mean cost of a hospital stay. For instance, in a French study, conducted in a major hospital, the cost of postoperative analgesics per patient for the whole length of stay was 7.47 compared to 1,189 for 1 day of hospital stay.2Hence, the choice of an appropriate analgesic technique, integrated in a global pain management strategy, may reduce overall hospital costs based on a very favourable cost/benefit ratio.2

*Surgical operations produce local tissue damage with consequent release of algogenic substances and of a barrage of noxious stimuli, which are transduced by nociceptors into impulses that are transmitted to the neuraxis by A-delta and C fibers. Cortical responses occur in the awake patient. They are provoked by nociceptive impulses that reach the highest parts of the brain, in which they activate complex systems concerned with recognition of the sensation of pain.When the effects of surgical anaesthesia disappear, the patients injury persists and algogenic substances continue to be liberated and sensitise nociceptors.Such pathophysiologic changes are greatly enhanced by sympathetic hyperactivity and by the consequent liberation of noradrenalin, which sensitises nociceptors and damaged nerve membrane.1These processes are partially balanced by the descending control system, which inhibits the recapture of serotonin and noradrenalin at spinal level and generates endorphins that block the opioid receptors.*Opioids provide analgesia by mimicking the effect of endogenous opioids at specific receptors in the central nervous system.1NSAIDs block production of prostaglandins that sensitise peripheral nociceptors after tissue injury.1Paracetamol is a centrally-acting drug that selectively inhibits nervous system cyclo-oxygenase, thus inhibiting prostaglandin synthesis.2 Other central mechanisms dependent on the spinal serotoninergic pathway could also be involved.2,3Moreover, a recent study demonstrated that paracetamol was a potent inhibitor of a NSAID-induced cyclo-oxygenase which could be a third COX (COX-3).4

*N=50 patients undergoing major abdominal surgery; interviewed prior to and 4 weeks after surgery. Patients reported an average of 75% pain relief after surgery. Overall, 82% reported at least one side effect that was moderate or severe. Effective pain control and side effect type/severity ranked about equally in importance, with the combined side effect percentage slightly higher (47%) than that for effective pain control (41%). Setting (eg, at home or in hospital) and route (ie, oral or IV) of administration of pain medications were ranked a distant third at 12%. Gan TJ, Lubarsky DA, Flood EM, et al. Patient preferences for acute pain treatment. Br J Anaesth. 2004;92: 681-688.N4-366 Reuben Periop 5/2/2005 11:29 AM*Fifty patients undergoing major abdominal surgery were enrolled and completed interviews before and after surgery. Measures included an experience with pain questionnaire and an adaptive conjoint analysis interview. The above table represents the proportion of patients experiencing side effect at any time during the study by maximum severity.N4-366 Reuben Periop 5/2/2005 11:29 AM**Paracetamol i.v. is a fast-acting analgesic drug with time-to-onset of analgesia of five minutes or less following oral surgery.Compared to oral paracetamol, i.v. paracetamol has a faster onset of analgesia and is more effective in reducing pain intensity in the first hour of treatment.1*The first proper account of paracetamols clinical use as an antipyretic appeared in 1894 (Hinsberg and Treupel).1The analgesic efficacy of paracetamol was formally demonstrated in 1948 (Flinn and Brodie).1It is now very well documented and paracetamol is recommended as first-line treatment in several painful indications:- In osteoarthritis, paracetamol is recommended by the European League Against Rheumatism and the American College of Rheumatology as the oral analgesic to try first and, if successful, is the preferred long-term oral analgesic.2,3- For musculoskeletal pain in the elderly4 by the American Geriatrics Society.- In patients with underlying renal disease5 by the National Kidney Foundation.

*Paracetamols mechanism of action is not fully understood, but it is generally accepted that it is a centrally-acting drug.1,2Paracetamol selectively inhibits nervous system prostaglandin biosynthesis, while having little effect on enzyme preparations from peripheral sources.2,3Moreover, a recent study demonstrated that paracetamol was a potent inhibitor of a NSAID-induced cyclo-oxygenase which could be a third COX (COX-3).6On the other hand, several studies have demonstrated that activation of spinal serotoninergic system was involved in the antinociceptive effect of paracetamol.4,5

6. Chandrasekharan NV et al. PNAS 2002;99(21):13926-31.

*Intravenous paracetamol and acetylsalicylic acid act at different analgesic levels.Because the RIII reflex investigates the central nervous system impact of drugs, it is very unlikely that acetylsalicylic acid acts at a central level following intravenous administration.Intravenous paracetamol, however, induces manifest central analgesia, and may inhibit prostaglandin synthesis in the central nervous system.Paracetamol-mediated analgesia is therefore probably the result of its ability to cross the blood-brain barrier in high concentrations.1*Although paracetamol is a molecule that has been around for a long time, it took years to develop the innovative formula and manufacturing process that would make a ready-to-use infusible form possible.Specifically, there were two major barriers to overcome:1. Making paracetamol soluble in an aqueous solution.Paracetamol is a hydrophobic molecule. This solubilisation was accomplished through a choice of specific hydrophilic ingredients - mannitol and disodium phosphate - and a special preparation method.2. Ensuring paracetamols stability in solution.This was accomplished by controlling hydrolysis (through adding a pH buffer - disodium phosphate dihydrate/sodium hydroxide - to maintain a stable pH) and oxidation (through adding a powerful antioxidant - cysteine hydrochloride monohydrate - and through an oxygen-free manufacturing process).

* In two phase III studies including 303 patients, in orthopaedic2 and dental1 surgery, no difference was observed between placebo and i.v. paracetamol groups:- for the overall incidence of adverse events- for the incidence of local adverse events.In addition, there were no clinically significant changes in vital signs or laboratory tests.1,2

*Study design:- Multi-centre, randomised, double-blind, placebo and active-controlled, single-dose study after dental surgery.- 152 patients were enrolled.- 51 received a 15-minute i.v. paracetamol 1g (Perfalgan 1g) infusion.- 51 received a 15-minute i.v. propacetamol 2g infusion.- 50 received a 15-minute i.v. placebo infusion.- Safety measures comprised adverse events, vital signs and laboratory tests.Results:No difference was observed between placebo and Perfalgan groups:- for the overall incidence of adverse events- for the incidence of local adverse events (none was observed in either Perfalgan or placebo groups).1

*Study design:- Multi-centre, randomised, double-blind, placebo and active-controlled, repeated-dose study after orthopaedic surgery.- 151 patients were enrolled.- 49 received a 15-minute i.v. paracetamol 1g (Perfalgan 1g) infusion.- 50 received a 15-minute i.v. propacetamol 2g infusion.- 52 received a 15-minute i.v. placebo infusion.- Safety measures comprised adverse events, vital signs and laboratory tests.Results:No difference was observed between placebo and Perfalgan groups:- for the overall incidence of adverse events- for the incidence of non-local adverse events.1

*A retrospective series of 126,779 cases demonstrated that the incidence of paracetamol hepatotoxicity is very low (49 documented cases). All these cases were related to overdose (>4g / day).Most of the time these overdoses were intentional (28/49).1Furthermore, the i.v. formulation makes overdose very unlikely and therefore reduces the risk of hepatotoxicity.*Data show that, at doses up to 4g/day, paracetamol has an excellent renal safety profile and continues to be the preferred first-line analgesic in patients with underlying renal disease, a condition in which the non-selective NSAIDs and specific COX-2 inhibitors may be relatively contraindicated.1,2,3Recent reviews confirmed that there was currently insufficient evidence to conclude that habitual use of paracetamol may be associated with an increased risk of renal disease.*Contrary to opioids, paracetamol is devoid of centrally mediated side effects linked with binding to opioid receptors, and therefore does not lead to nausea, vomiting, sedation, constipation or respiratory depression.1Paracetamol has been shown to have no effect on platelet aggregation, bleeding time, or uric acid excretion.2Paracetamol does not produce gastric irritation, erosion or bleeding which are associated with NSAIDs.3At doses up to 4g/day, paracetamol has good renal4 and hepatic safety.5In addition, Perfalgan has few contra-indications and drug interactions.Hence, it is indicated in all types of patients, including children, pregnant and breast-feeding women, elderly and patients with renal insufficiency.*Perfalgan is supplied in a ready-to-use form providing substantial practical and economic benefits compared to products requiring reconstitution: - Saves nurses time (53% per infusion)- Reduces use of ancillary products- And thus saves cost (1.46 per infusion coming from time saving and fewer ancillary items used).1This study, conducted amongst 100 nurses in 10 French hospitals, also demonstrated that Perfalgan provided valuable safety benefits:- Reduced risk of dosage error- Reduced risk of microbial contamination.1

*Perfalgan is very easy-to-handle thanks to its ready-to-infuse glass bottle. Before administration, the product should be visually inspected for any particulate matter and discolouration. Then proceed as follows:1. Take the aluminium protection off.2. Link the bottle to a drip with an air intake.3. Hook the bottle to the infusion stand with the calliper integrated in the label. *Initial administration should take place in the operating theatre because the analgesic effect peaks one hour after injection.Then administration should be renewed every 4 to 6 hours (minimal interval between infusions = 4 hours).Adolescents and adults weighing more than 50kg: - 1g per administration- i.e. one 100ml vial max. 4g/day.Children weighing more than 33kg (approximately 11 years old), adolescents and adults weighing less than 50kg: - 15mg/kg per administration- i.e. 1.5ml solution per kg max. 60mg/kg/day.

*Perfalgan does not require any specific storage.Its shelf life, under normal conservation conditions, is 2 years.*Perfalgan is a safe and effective i.v. analgesic after all kinds of surgical and anaesthetic procedures.4,5Perfalgan is a fast-acting analgesic, as effective as morphine 10mg.1Perfalgan is a proven opioid-sparing agent.2Perfalgan is well tolerated in all types of patients.Perfalgan is ready-to-use and cost-effective.3

4. Hyllested M et al. Br J Anaesth 2002;88:199-214.5. Rmsing J et al. Br J Anaesth 2002;88:215-26.