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This is an ongoing section of the PIC website designed to contain abstracts from reviews or informative papers in the medical literature. Permission to reproduce the abstracts has been obtained:
Therapeutic Misadventure with Paracetamol: Fact or Fiction? Laurie F. Prescott American Journal of Therapeutics; 7(2); 99-114 (2000) As a consequence of its consistent safety profile and the low incidence of side effects, paracetamol is one of the most widely used analgesics, both in adults and children. However, paracetamol has the potential for hepatotoxicity, usually as a result of deliberate self-poisoning or, to a much lesser extent, accidental overdose. A variety of factors is thought to influence hepatotoxicity, including dose, concomitant use of microsome-inducing agents and other drugs, underlying disease, malnutrition, fasting, acute and chronic alcohol intake, ethnicity, and age. Unfortunately, none of these factors has been properly studied in humans. From a physiological standpoint, acute paracetamol hepatotoxicity at therapeutic doses is extremely unlikely despite reports of so-called therapeutic misadventure. It is clear that, in many of these cases, grossly excessive doses of paracetamol have been taken. Analysing the various reports is difficult as the data are often incomplete. In summary, although hepatic toxicity is recognised in patients taking a major paracetamol overdose, the incidence of adverse events with its proper use is very low, particularly when considering with the enormous volume of drug used. Therapeutic misadventure is extremely uncommon and the facts are often misrepresented. Keywords: paracetamol, acetaminophen, hepatotoxicity, overdose, therapeutic misadventure. Treatment of Pain or Fever with Paracetamol (Acetaminophen) in the Alcoholic Patient: A Systematic Review Richard C. Dart, Edwin K. Kuffner, and Barry H. Rumack American Journal of Therapeutics; 7(2); 123-134 (2000) An unexpected clinical question has emerged in the treatment of pain or fever in the alcoholic patient: Is paracetamol a safe medication for the alcoholic patient? After decades of use in a variety of patients, sporadic reports suggest a relationship between liver injury and the use of paracetamol by alcoholic patients. We performed a systematic review of the medical literature to answer the question: Can administration of therapeutic doses of paracetamol cause hepatic injury in the alcoholic patient? After extensive data retrieval, each article in any language that involved the use of paracetamol by an alcoholic patient was abstracted and categorised for strength of evidence. Class I data (randomised, controlled trials) show that repeated ingestion of a therapeutic dose of paracetamol over 48 hours by patients with severe alcoholism did not produce an increase in hepatic aminotransferase enzyme levels nor any clinical manifestations compared with a placebo group. Class II data (prospective, nonrandomised trials) reveal that therapeutic doses of paracetamol have been administered to patients and an array of liver diseases (alcoholic, primary biliary, postnecrotic, or unspecified cirrhosis or alcoholic, acute viral, chronic active, or other infectious hepatitis) for periods up to 14 days without adverse effect. Finally in several studies, a 1- to 2-g single dose of paracetamol was administered to alcoholic patients to study metabolism, again without adverse effect. In contrast, Class III data (retrospective case reviews and case reports) describe hepatic injury after repeated paracetamol ingestion with therapeutic intent, although usually not at therapeutic doses. Unfortunately, the information contained in Class III reports is often incomplete and contradictory. The history of ingestion is often unknown or contradicts other clinical information provided. For example, the history may indicate a therapeutic dose, but the serum paracetamol is elevated to levels only produced by ingestion much larger than the history indicates. In summary, all methodologically sound studies available indicate that therapeutic dosing of paracetamol to the alcoholic patient is not associated with hepatic injury. In fact, there is no change at all in hepatic aminotransferase enzymes, prothrombin time, or other biochemical parameters when compared with a placebo group in well-designed trials. Unless stronger evidence of a potentially dangerous interaction emerges, the use of paracetamol in the alcoholic patient is reasonable. During chronic treatment of pain, paracetamol may be preferred in the compliant alcoholic patients owing to the adverse effects associated with long-term use of nonsteroidal anti-inflammatory agents. Keywords: acetaminophen, paracetamol, hepatitis, toxic, liver diseases, alcoholic. Paracetamol Efficacy and Safety in Children: the First 40 Years Noel Cranswick and David Coghlan American Journal of Therapeutics; 7(2); 135-141 (2000) Paracetamol (acetaminophen) has a unique role in children because it is the first-line choice for the treatment of both fever and pain. When used in recommended doses, it has few side effects and is remarkably well tolerated. While fever alone requires no treatment, when associated with discomfort or pain, paracetamol offers relief. Also, for mild to moderate pain, paracetamol, either alone or in combination with another drug, is effective. Even in severe pain, paracetamol offers a significant additive analgesic effect to opiates. Globally, the paediatric dose varies between 10 and 15 mg/kg. In the United Kingdom, 10 mg/kg is given every 4 hours, up to a maximum of four doses per day; in Australia, 15 mg/kg is administered 4-hourly up to a total of 60 mg/kg/day. In overdose, paracetamol is hepatotoxic. Single ingestions of more than ten times the recommended dose are potentially toxic. The development of specific antidotes and the universal availability of the Rumack-Matthew Nomogram have made the early treatment of overdose effective without long-term sequelae. There are sporadic case reports of chronic overdosing resulting in liver failure. Although the specific predictors are still being defined, exposures greater than 140 mg/kg/day for several days carry a risk of serious toxicity. In children, aspirin use almost disappeared with the concurrent decline in Reye Syndrome. Less clinical experience has accumulated with ibuprofen, and it remains the second-line treatment for fever and pain. In conclusion, paracetamol remains the first-choice over-the-counter treatment for analgesia and antipyresis in children. Keywords: paracetamol, acetaminophen, children, pain, fever. Effect of Ibuprofen on Cardioprotective Effect of Aspirin T. M. MacDonald and L. Wei The Lancet Research Letters; 361; 573-574 (2003) Treatment with ibuprofen might limit the cardioprotective effects of aspirin. We aimed to assess whether patients with known cardiovascular disease who take low-dose aspirin and ibuprofen have increased risk of cardiovascular mortality. We studied 7107 patients who were discharged after first admission for cardiovascular disease between April, 1989, and April, 1997, and who were prescribed low-dose aspirin (<325 mg/day) and survived for at least 1 month. Compared with those who used aspirin alone, patients taking aspirin plus ibuprofen had an increased risk of all-cause mortality (adjusted hazard ratio 1.93, 95% CI 1.30-2.87, p=0.0011) and cardiovascular mortality (1.73, 1.05-2.84, p=0.0305). Our finding lends support to the hypothesis that ibuprofen may interact with the cardioprotective effects of aspirin, at least in patients with established cardiovascular disease. Keywords: ibuprofen, aspirin, cardioprotective effects, cardiovascular disease. Exposure to Non-steroidal Anti-inflammatory Drugs During Pregnancy and Risk of Miscarriage: Population Based Cohort Study D-K. Li, L. Liu, and R. Odouli British Medical Journal; 327; 368-372 (2003) Objective: To evaluate whether prenatal use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with increased risk of miscarriage. Keywords: NSAIDs, pregnancy, increased risk of miscarriage, paracetamol. UK Legislation on Analgesic Packs: Before and After Study of Long Term Effect on Poisonings Keith Hawton et al. British Medical Journal; 329; 1076-1080 (2004) Objective: To evaluate the long term effect of legislation
limiting the size of packs of analgesics sold over the counter. Keywords: paracetamol, reduced pack size, suicide. Drug Interactions with Paracetamol M. J. Toes. A. L. Jones and L. Prescott American Journal of Therapeutics; 12(1); 55-66 (2005) National Poisons Information Service, Guy's and St. Thomas' NHS Trust, Medical Toxicology Unit, Avonley Road, London SE14 5ER, United Kingdom. Paracetamol (acetaminophen) is one of the most commonly used analgesic antipyretic drugs worldwide, and it is widely available by prescription and over the counter (OTC). Fortunately, few clinically significant drug interactions have been documented. There is probable potentiation of hepatotoxicity following an overdose from the paracetamol metabolite NAPQI by enzyme-inducing drugs. There is considerable controversy regarding the possible interaction with warfarin in its potential to increase its anticoagulant effects because of discrepancies between observational studies and those in healthy volunteers. Otherwise, no serious adverse drug interactions with therapeutic doses of paracetamol have been confirmed in humans. Because the absorption of paracetamol is so dependent on gastric emptying, other drugs that alter gastric emptying can change its pharmacokinetics; but this would not cause serious adverse effects. Although animal experiments have demonstrated that many compounds can modify paracetamol hepatotoxicity, these are unlikely to be important at therapeutic doses. Keywords: paracetamol, drug interaction. Selecting Nonprescription Analgesics C. J. Nikles, M. Yelland, C. Del Marc, and D. Wilkinson American Journal of Therapeutics; 12(1); 67-79 (2005) Tasmanian School of Pharmacy, Faculty of Health Science, University of Tasmania, Hobart, Tasmania 7001, Australia. G.Peterson@utas.edu.au Worldwide, there has been an emerging patient demand for access to efficient drugs without consulting a doctor and obtaining a prescription. As a result, there has been an expanding movement of prescription-only drugs to over-the-counter (OTC) status. An increasing number of drugs are becoming available OTC, empowering patients to treat themselves. Where the principle of empowering individuals to treat themselves can fail is when consumers lack the knowledge to do so safely. This potentially applies to the self-selection of analgesic drugs by consumers. When used inappropriately, these drugs pose significant risks. The nonsteroidal antiinflammatory drugs (NSAIDs) are associated with many adverse reactions, interactions, and contraindications in a number of patient groups, even at OTC doses. In particular, in the elderly, the high incidence of cardiovascular and gastrointestinal disease, coupled with age-related decline in renal function and multiple medication use, all warrant extra caution with the use of NSAIDs and make paracetamol the simple analgesic drug of first choice. Despite the possibility of hepatotoxicity in overdose, paracetamol represents a better all-round option for most patients requiring OTC analgesic therapy. Keywords: paracetamol, NSAIDs, adverse reactions. The Role of Paracetamol in Chronic Pain: An Evidence-Based Approach C. J. Nikles, M. Yelland, C. Del Marc, and D. Wilkinson American Journal of Therapeutics; 12(1); 80-91 (2005) Discipline of General Practice, The University of Queensland, Herston, Herston, Queensland 4006, Australia. j.nikles@uq.edu.au Chronic pain is a significant public health burden. Several international guidelines and influential reviews recommend the use of paracetamol (acetaminophen) as the first-line analgesic of choice for the management of chronic pain. These recommendations are based largely on the balance of evidence, which favorably demonstrates the efficacy, safety, and low cost of paracetamol relative to other analgesics. A decade ago, March et al suggested that because of the dangers associated with conventional nonsteroidal antiinflammatory (NSAID) use, particularly in the elderly, they should ideally not be used without an individual n-of-1 trial to show that they are more effective than paracetamol. Today, the results of our investigations into the individualization of pain management options continue to support this suggestion. Based on the data available to date, it still seems prudent to use NSAIDs only in those patients in whom there is good evidence of improved efficacy over paracetamol. In patients with chronic pain, paracetamol can play an important role as an NSAID sparer, with resultant benefits in terms of reduced adverse effects and cost savings. Keywords: paracetamol, chronic pain. A Better Acetylcysteine Prescription U. M. Chouhan, E. J. Dubourg, and L. Dodd Pharmaceutical Journal; 279(7464); 157-158 (2007) Pharmacy Department, Glan Clwyd Hospital, Rhyl, Denbighshire LL18 5UJ uttam.chouhan@cd-tr.wales.nhs.uk A paper in the Pharmaceutical Journal reports how two prescribing aids reduce the likelihood of both prescribing and administration errors. Errors can occur, they say, during the writing of the prescription by doctors, and also during administration by nurses. The errors principally concern calculating the correct dosage and making up the correct strength infusion. Pre-printed labels Electronic prescribing An electronic prescription has also been developed for paediatric patients. Keywords: paracetamol, acetylcysteine. Management of Paracetamol Poisoning R. E. Ferner, J. W. Dear, and D. N. Bateman BMJ; 342; 1-9 (2011) Clinical management of patients with paracetamol overdose poisoning is reviewed, and issues surrounding paracetamol overdose deaths are discussed, together with recommendations for avoiding a missed diagnosis and discussion of outcomes. Recommendations for additional educational resources are given. Keywords: paracetamol, management of poisoning.
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