Paracetamol - widening the horizon in pain managment
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This document discusses pain and postoperative pain management. It provides definitions of different types of pain and summarizes research on intravenous paracetamol. The research shows that IV paracetamol has a fast onset of action within 5 minutes, comparable analgesic efficacy to opioids like morphine and NSAIDs like diclofenac, and can reduce opioid consumption by 46%. IV paracetamol also has a good safety profile with few drug interactions and contraindications. The document recommends IV paracetamol as an important component of a multimodal regimen for postoperative pain management.
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Paracetamol - widening the horizon in pain managment
- 2. Clinical definition of pain 1 “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 need Pain Relief
- 3. 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.
- 4. Ref:- Wall and Melzacks text book of pain. 2005 Reuben et al. J Bone Joint Surg. 2000;82:1754-1766.
- 5. Acute Pain Increased sympathetic activity GI effects Splinting, shallow breathing Increased catabolic demands Anxiety and fear Peripheral/ central sensitization Myocardial O2 consumption↑ GI motility↓ Atelectasis, hypoxemia, hypercarbia Poor wound healing/muscle breakdown Sleeplessness, helplessness Available drugs Myocardial ischemia Delayed recovery Pneumonia Weakness and impaired rehabilitation Psychological Chronic pain
- 6. 2003 No. 5:Treatment by healthcare professionals No. 4: Pain during surgery No. 3: Full recovery from surgery No. 2: Will surgery improve condition No. 1: Pain after surgery 1993 30% 30% 33% 34% 46% 42% 51% 51% 59% 57% Warfield et al. Anesthesiology. 1995;83:1090-1094. Apfelbaum et al. Anesth Analg. 2003;97:534-540.
- 7. Patients (%) *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.
- 8. 8% 19% 21% 52% Pain Intensity Slight Moderate Severe Extreme Apfelbaum et al. Anesth Analg. 2010;97:534-540.
- 9. Patients prefer avoiding side effects over complete pain control Side-Effect Severity 19% Pain Control 41% 47% Setting and Route of Administration 12% Side-Effect Type 28% Gan et al. Br J Anaesth. 2004;92:681-688.
- 10. Postoperative pain management is still sub-optimal I want Pain relief 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.
- 11. 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.
- 12. NSAIDs, coxibs, NSAIDs, coxibs, paracetamol, paracetamol, nerve blocks nerve blocks Reduce severity of side effects Earlier discharge Potentiation Improved pain relief Opioids Reduced doses Decreased costs Kehlet et al. Anesth Analg. 1993;77:1048-1056 (B ).
- 13. “Is more effective & has a faster onset than oral paracetamol”
- 14. 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 Tropisetron blocks the action; not ondansetron and granisetron 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.
- 15. Does IV paracetamol have a fast onset and is it effective? 1 n=50 / i.v. paracetamol 1g / 2-min injection N = 175 n=50 / i.v. paracetamol 1g / 15-min infusion n=50 / oral paracetamol 1g n=25 / placebo Single-centre, randomised, double-blind, placebo and active-controlled, singledose study Oral surgery Onset of analgesia measured by the double click- stopwatch method Pain intensity differences (PID) rated on VAS and VRS Sindet-Pedersen S. Br Jr Anesth 2005. 94 (5): 642-8
- 16. 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
- 17. Time-effect curve (n=109 IV paracetamol 1g is more effective than oral paracetamol 1g Jarde O et al. Clin Drug Invest 1997;14(6):474-81.
- 18. Paracetamol PK/PD relationship in function of the dose (n = 11) No ceiling effect with i.v. paracetamol1 1. Piguet V et al. Eur J Clin Pharmacol 1998;53:321-4.
- 19. Does Paracetamol 1g compare with Morphine 10mg in terms of analgesic efficacy 1 n=31 / i.v. paracetamol 1g + i.v. paracetamol 0.5g after 5 hours N = 95 n=30 / i.m. morphine 10 mg + i.m. morphine 5 mg after 5 hours n=34 / placebo Single-centre, randomised, double-blind, placebo and active-controlled, repeateddose study Oral surgery Summed pain intensity differences (SPID) and 5 and 10 hours 1. Van Aken H. total pain relief (TOTPAR) after Anesth Analg 2004; 98: 159-65
- 20. Oral surgery Time course of pain relief versus initial pain Comparable analgesic efficacy 1. Van Aken H. Anesth Analg 2004; 98: 159-65
- 21. …and Ketorolac 30mg 1 n=57 / i.v. paracetamol 1g N = 164 n=27 / i.v. ketorolac 30mg n=28 / i.v. ketorolac 15mg n=52 / placebo 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 .
- 22. (n=57) (n=28) Not dissimilar for the first 5 hours in terms of analgesic efficacy Total hip or knee replacement Pain relief scores at rest 1. Zhou TJ et al. Anesth Analg 2001;92:1569-75 .
- 23. ...and Diclofenac 75mg? n=40 / i.v. paracetamol 1g / 2 times at 5-hour interval N = 120 n=40 / i.m. diclofenac 75mg n=40 / placebo 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 1. Hynes D et al. Acta Anaesthesiol Scand 2006; 50: 374—381
- 24. 1. Hynes D et al. Acta Anaesthesiol Scand 2006; 50: 374—381 Time course of pain relief versus initial pain The analgesic effect provided by i.v. paracetamol is similar to that provided by a single i.m. injection of diclofenac 75mg.1 Total hip arthroplasty
- 26. Does paracetamol have an opioid-sparing effect1 N = 89 n=42 / i.v. paracetamol 1g + morphine (PCA) n=47 / i.v. placebo + morphine (PCA) 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.
- 27. 24-hour morphine consumption in terms of total PCA amount in mg and total number of boluses 46% less opioid consumed Hip arthroplasty 1. Peduto VA et al. Acta Anaesthesiol Scand 1998;42:293-8.
- 29. Phase III clinical trials VS. placebo 1,2 Similar overall incidence of adverse events Similar incidence of local adverse events No clinically significant changes in vital signs or tests laboratory IV paracetamol as safe as placebo 1. Lange-Møller P. Anesth Analg 2005;101:90 –6 2. Sinatra RS. Anesthesiology 2005; 102:822–3 India Prescribing Information
- 30. Hepatic safety at therapeutic doses 1 Paracetamol hepatotoxicity was found to be very rare (<1 / 2,500)1 It was always related to misuse and overdose (>4g / day)1 Good hepatic safety 1. Whitcomb DC et al. JAMA 1994;272(23):1845-50.
- 31. Can Paracetamol be given in alcoholics? Paracetamol - Alcohol syndrome Overdose of Paracetamol in alcoholics results in severe hepatotoxicity Alcohol induces CYP2E1 but inhibits NAPQI
- 32. 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
- 33. Up to 4g / day, paracetamol has an excellent renal safety profile 1 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 Good renal tolerance 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.
- 34. Paracetamol safety benefits in POP No centrally mediated side-effects1 (e.g. sedation, constipation, nausea, vomiting, respiratory depression) No effect on platelet aggregation, bleeding, or uric acid excretion 2 No gastrointestinal Sidé effects3 Good renal4 and hepatic5 safety Few contra-indications and drug interactions 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.
- 35. Paracetamol infusion 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
- 36. Paracetamol - Doses Dose Minimum dosing interval Maximum daily dose Adults >50 kg 1g qds 4 hrs 4g Adults/Childre 15 mg/kg qds n 33-50 kg 4 hrs 60mg/kg Not to exceed 3g Children 10-33 15 mg/kg qds kg 4 hrs 60mg/kg Not to exceed 2g Newborn & 7.5 mg/kg qds infants <10 kg 4 hrs 30mg/kg
- 37. 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
Notas do Editor
- 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.
- Are we managing postoperative pain in an adequate way? In 2001, Apfelbaum and colleagues had 250 patients who had undergone surgical procedures (in- and outpatient) in the past year complete 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%). These numbers have not changed much in the past 10 years, as the results from the 1993 data collected by Warfield and Kahn and published in 1995 show. Despite receiving standard postoperative pain care, 43% of patients undergoing outpatient procedures and 73% of patients undergoing inpatient procedures reported experiencing some degree of pain during the immediate postoperative period. Further, 75% of all patients (71% outpatients, 78% inpatients) reported experiencing pain after discharge during the 2 weeks after their surgery. These findings suggest that postoperative pain continues to be undermanaged.
- 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.
- 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.
- 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%.
- Despite considerable advances in the management of POP in recent years, many studies and surveys describe an unacceptably high incidence of significant pain after surgery in Europe. Scores of severe to unbearable pain range from 38% to 46.4%.1,2,3 Outcomes are even worse in day-case surgery, with up to 82% of patients leaving the ward in pain in a survey conducted in the UK.4 This situation is distressing for patients, but it is also unsatisfactory for physicians: In a European survey, conducted in 17 countries, Rawal et al reported that on average 55% of anaesthesiologists were dissatisfied or very dissatisfied with pain management in surgical wards, with scores up to 80% in Austria and Ireland.5 In a similar study conducted in Spain, only 28% of anaesthesiology departments reported being satisfied.6 Notes: - references 1 and 4 = United Kingdom - reference 2 = France - references 3 and 6 = Spain - reference 5 = 17 European countries
- A series of national and international recommendations and guidelines for improving postoperative pain management have been published and progressively implemented since the 1990’s in Europe and North America.1,2,3,4,5,6 Main 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
- Paracetamol’s mechanism of action is not fully understood, but it is generally accepted that it is a centrally-acting drug.1,2 Paracetamol selectively inhibits nervous system prostaglandin biosynthesis, while having little effect on enzyme preparations from peripheral sources.2,3 Moreover, a recent study demonstrated that paracetamol was a potent inhibitor of a NSAID-induced cyclo-oxygenase which could be a third COX (COX-3).6 On 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.
- Study design: - Single-centre, randomised, double-blind, placebo and active- controlled, single-dose study in dental surgery. - 175 patients were enrolled. - 50 received a 2-minute paracetamol 1g (propacetamol 2g) i.v. injection. - 50 received a 15-minute paracetamol 1g (propacetamol 2g) i.v. infusion. - 50 received oral paracetamol 1g. - 25 received a placebo. - Onset of analgesia was measured by the double click-stopwatch method: the evaluation criteria was time to onset of analgesia defined by the time to first perceptible pain relief (first click) if it is confirmed by first meaningful pain relief (second click). - Pain intensity was rated on a 100mm VAS and a 4-point VRS: the evaluation criteria was pain-intensity differences (PID).1
- 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
- This study clearly shows that, after orthopaedic surgery, in comparison with oral paracetamol, i.v. paracetamol: - has a faster onset of action, - is more efficacious, - has a longer duration of action.1
- The study confirms that i.v. paracetamol evokes a central antinociceptive effect. The dose-dependent increase in peak plasma concentrations induced by intravenous administration of paracetamol was accompanied by heightened antinociceptive effects. Thus, the ceiling effect reported by some authors after oral administration was not observed. The analgesic effect of i.v. paracetamol is probably dependent on the rate and amount of active drug reaching the CNS. After short intravenous infusion, the peak plasma concentration is much higher than after oral doses, allowing larger amounts of paracetamol to cross the blood-brain barrier.1
- Study design: - Single-centre, randomised, double-blind, placebo and active-controlled, repeated-dose study in dental surgery. - 95 patients were enrolled. - 31 received a 15-minute paracetamol 1g (propacetamol 2g) i.v. infusion at T0, and a 15-minute paracetamol 0.5g (propacetamol 1g) i.v. infusion after 5 hours. - 30 received a morphine 10mg i.m. injection at T0, and a morphine 5mg i.m. injection after 5 hours. - 34 received identical placebo injections or infusions. - Main efficacy criteria were summed pain intensity differences (SPID) and total pain relief (TOTPAR) after 5 and 10 hours.1
- Single (1g) or repeated (1g followed by 0.5g) i.v. infusions of paracetamol provide analgesia that is not significantly different to that of single (10mg) or repeated (10mg followed by 5mg) i.m. injections of morphine. Repeated administrations of i.v. paracetamol were safe and better tolerated than repeated administrations of morphine. Eight patients reported a total of 9 adverse events with paracetamol, whereas 13 patients reported 24 adverse events with morphine. - No severe adverse event with either paracetamol or placebo. - 3 severe adverse events with morphine 10mg.1
- Study design: - Multi-centre, randomised, double-blind, placebo-controlled, single-dose study after total hip or knee replacement surgery. - 164 patients were enrolled. - 57 received i.v. paracetamol 1g (propacetamol 2g). - 27 received i.v. ketorolac 30mg. - 28 received i.v. ketorolac 15mg. - 52 received a placebo. - Pain intensity differences (PID) were rated using a VAS and a VRS. - Pain relief (PR) .1
- Intravenous paracetamol 1g shows similar analgesic efficacy to ketorolac 15mg or 30mg i.v. with respect to the main analgesic efficacy variables, over 6 hours, after total hip or knee replacement surgery. With respect to pain relief scores at rest, paracetamol i.v. 1g is not different from ketorolac 15mg and 30mg from T0.75h to T5h. Paracetamol i.v., at this dose, may be a useful alternative to ketorolac as a complementary drug to opioids in the treatment of moderate to severe postoperative pain.1
- Study design: - Single-centre, randomised, double-blind, placebo and active-controlled, double-placebo, repeated-dose study after total hip arthroplasty. - 120 patients were enrolled. - 40 received two 15-minute i.v. paracetamol 1g (propacetamol 2g) infusions, five hours apart. - 40 received an i.m. diclofenac 75mg injection. - 40 received identical i.v. infusions or i.m. injection of placebo. - Total pain relief (TOTPAR) and pain relief (PR) were measured on a VRS.1
- In patients with moderate to severe postoperative pain after total hip replacement, the analgesic effect provided by two infusions of i.v. paracetamol 1g is similar to that provided by a single i.m. injection of diclofenac 75mg.1
- Study design: - Multi-centre, randomised, double-blind, placebo-controlled, repeated-dose study after hip arthroplasty. - 89 patients were enrolled. - Following surgery, all patients received four i.v. infusions, at six-hour intervals, of either paracetamol 1g (propacetamol 2g) (n=42) or placebo (n=47). - Morphine was administered using a PCA device set to the following specifications: - initial loading doses of 1mg, at 10-minute intervals until pain relief was obtained - bolus doses of 0.015mg/kg - 15-minute lock-out interval. - The main efficacy criteria were the total doses of PCA morphine requested over 24 hours, and the number of self-administered boluses. - Pain intensity was measured every 1-2 hours, using a 5-point VRS, and 100mm VAS. - After 24 hours, global efficacy was assessed on a five-point VRS.1
- Paracetamol i.v. exerts a very significant opioid-sparing effect after orthopaedic surgery: - 46% in terms of total morphine dose administered (p<0.001) - 43% in terms of the number of boluses requested (p<0.001).1
- 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
- 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).1 Furthermore, 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.1,2,3 Recent 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.1 Paracetamol has been shown to have no effect on platelet aggregation, bleeding time, or uric acid excretion.2 Paracetamol does not produce gastric irritation, erosion or bleeding which are associated with NSAIDs.3 At doses up to 4g/day, paracetamol has good renal4 and hepatic safety.5 In 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.
- 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.