A Reappraisal of Antipyretic and Analgesic Drugs
Dr Anthony Wong, MD, PhD, Medical Director , CEATOX, Instituto da Criança, Department of Paediatrics, Faculty of Medicine, University of São Paulo, Brazil.
Most antipyretics and analgesics are sold as prescription-free, over-the-counter (OTC) drugs in most countries. The main OTC drugs marketed worldwide are acetylsalicylic acid (ASA), meta-mizole, paracetamol and ibuprofen. Metamizole was first marketed in Germany in 1922 and is a member of the phenyl-pyrazolone group of drugs. It has been the center of considerable controversy as regards its safety.
Adverse Drug Reaction (ADR) Reports with Metamizole - Facts & Flaws
An abnormally high incidence of agranulocytosis (0.86%) was reported by Discombe(1) from a retrospective study of four reports totalling 1272 subjects receiving metamizole. A survey by Huguley(2), which added 127 subjects to that report, found an incidence of 0.79%, with a mortality rate of 0.57%. Both papers had two major flaws: 1) positive cases were compiled more than once, resulting in these extraordinary figures, and 2) the ADR figures for metamizole included reports due to aminopyrine and phenyl-butazone, two other drugs also belonging to the phenyl-pyrazolone group. If these numbers were indeed true, it may be surmised that there would have been 102,000 cases of agranulocytosis, with 73,440 deaths among users per year in Germany; 144,300 cases and 103,900 deaths in Spain; and 195,000 cases and 140,400 deaths in France and Italy(3). In other words, the death toll due to agranulocytosis caused by metamizole alone would be several times higher than the deaths from myocardial infarc-tion and cardiac arrhythmias combined. Sir Richard Doll referring to Huguley’s paper stated that the evidence which led to the proscription of metamizole in the UK and the USA, 30 years ago was weak by modern standards(4).
Several subsequent large-scale population studies have re-evaluated the incidence of drug-related agranulocytosis. The International Agranulocytosis and Aplastic Anaemia Study, also known as the Boston Study, surveyed a population of 22.8 million in seven European cities and Jerusalem for over 6½ years, and reported an overall incidence of 1 case per million persons per year(5). Two reports from Brazil, by Sollero(6) and Hamerschlak(7) found an even lower risk for metamizole. In 1998 Andrade et al. conducted a meta-analysis to compare epidemiological studies from 1975 to 1995 and estimated that the excess mortality per million from community acquired cases of agranulocytosis, aplastic an-aemia, anaphylaxis and serious upper gastrointestinal compli-cations was 592 for diclofenac, 185 for ASA, 25 for metamizole, and 20 for paracetamol(8). CIOMS IV in the same year reported the excess mortality risk for the same conditions to be: diclofenac=5.92; ASA=2.03; metamizole=0.20; and para-cetamol=0.25(9). These studies certainly suggest that the risks from adverse reactions to metamizole are similar to those posed by paracetamol, a drug widely reputed to be safe. According to the CIOMS IV conclusion “Newer methods of epidemiological studies have shown that the risk of agranulocytosis (1.7 per million) due to metamizole was exaggerated in the 70’s” (9).
The Ministry of Health in Brazil convened an international panel of experts in July 2001 to evaluate the safety of metamizole and concluded that: “(a) There is consensus that its efficacy as an analgesic and antipyretic is unquestionable; (b) The data presented before this panel allow the participants to conclude that the risks of metamizole are similar, or even lower, than of other analgesic/ antipyretic drugs available on the market; and (c) A change in the present regulatory status of metamizole would incur in negative aspects to the population, increasing the risk from the use of other drugs indicated for the same therapeutic ends”(10).
A randomized, double blind, multinational study involving 555 children showed that metamizole and ibuprofen were significantly more effective than paracetamol in achieving normal body temperatures; metamizole produced a significantly greater temperature reduction than ibuprofen and paracetamol, and helped maintain low tempera-tures for a longer duration(11). An editorial on the report from this study commented that drugs such as metamizole were perhaps unjustly deleted from our pharmacopoeia because of imprecise studies of adverse side effect; some of the older therapeutic agents such as metamizole may be identified as having clinical utility in children(12).
Paracetamol – Some Concerns
Paracetamol has long been heralded as a safe drug and gained wide popularity, more so after Reye’s syndrome was linked to ASA. However, several recent papers have addressed concerns and questioned the drug’s safety following deaths and hepatotoxicity due to intentional and ‘therapeutic’ overdoses, severe drug interactions, nutritional factors and associated diseases. Para-cetamol has been the major cause of drug-related acute liver failure and deaths in the USA and the UK(13). The American Association of Poison Control Centers (AAPCC) lists paracetamol as the single major cause of death reported to the American poison centers since 1994(14,15). In October 2001, the American Academy of Pediatrics issued a Policy Statement with warnings on the risk factors conducive to paracetamol poisoning, and recommendations for its prevention and early diagnosis (16). In addition to hepatotoxicity, paracetamol and other non-steroidal anti-inflammatory drugs (NSAIDs) have been associated with analgesic nephropathy. A recent paper has indicated an odds ratio for chronic renal disease of 5.3 for paracetamol and 3.3 for ASA, with increased risk for pre-existing renal disease. Such an association with renal disease was not observed for propoxyphene or metamizole(17). A recent study has linked chronic use and abuse of paracetamol to a major risk of non-genetic and non-environmental asthma, with the risk increasing with cumulative dosage(18). Altered clotting time, especially when associated with the use of warfarin, has also been well documented.
In conclusion
Generally speaking, it might not be suitable to treat yellow fever, dengue, infectious gastro-enteritis, and other febrile illnesses that require prolonged treatment, with high doses of paracetamol or NSAIDs due to the risk of hepatotoxicity, nephrotoxicity, severe gastro-intestinal irritation and bleeding disorders with chronic use of these drugs. In these instances metamizole might be an alternative choice because of its prolonged action, efficacy, absence of clotting disorders, and low cost. The case presented for metamizole, while open to debate, suggests the need to continuously review evidence for drug safety of all products to reduce the loss of potentially safe, efficacious and cost-effective drugs from the market. It also points to the need for continuing pharmacovigilance in older, more established drugs.
References:
1. Discombe G. Agranulocytosis caused by aminopyrine. An avoidable cause of death. BMJ 1952; 1: 1270-1273.
2. Huguley Jr CM. Agranulocytosis induced by dipyrone, a hazardous antipyretic and analgesic. JAMA 1964; 189: 93d1-941.
3. Pola W. Rare serious side effects following intake of dipyrone (Analgin). In: R. Ovtcharov and W. Pola (eds) Dipyrone - Symposium Moscow 1978 (Proceedings) p. 11-17, Stuttgart, New York, F.K. Schattauer Verlag.
4. Doll R, Lunde PK, Moeschlin S. Analgesics, agranulocytosis and aplastic anaemia. Lancet 1987; 1:101.
5. International Agranulocytosis and Aplastic Anemia Study. Risks of agranulocytosis and aplastic anaemia. A first report of their relation to drug use with special reference to analgesics. JAMA 1986; 256:1749-1757.
6. Sollero L. Incidence of agranulocytosis and the use of dipyrone in Brazil. Rev Bras Pesquisas Med Biol 1976; 9:79-86.
7. Hamerschlak N, Montezuma MPVT, Bacal N et al. Retrospective prevalence and incidence of drug-induced agranulocytosis in the city of São Paulo – Brazil. Rev Paul Med 1993; 111:294-298.
8. Andrade SE, Martinez C, Walker AM. Comparative safety evaluation of non-narcotic analgesics. J Clin Epidemiol 1998; 51: 1357-1365.
9. CCIOMS WORKING GROUP IV – Geneva, 1998 – Benefit-Risk Balance of Marketed Drugs: Evaluating Drug Signals.
10. Oliveira GG. Painel Internacional de Avaliação da Segurança da Dipirona [International Panel for the Evaluation of the Safety of Dipyrone]. Diário Oficial da União, sec. I, p. 201-202, 16 Aug.2001.
11. Wong A, Sibbald A, Ferrero F et al. Antipyretic effects of dipyrone versus ibuprofen versus acetaminophen in children: results of a multinational, randomized, modified double blind study. Clin Pediatr 2001; 40: 313-324.
12. Berlin C. Editorial: Are we losing good drugs? Clin Pediatr 2001; 40: 325-326.
13. Fagan E, Wanna G. Reducing paracetamol overdoses. BMJ 1996; 313: 1417-1418.
14. Litovitz TI, Felberg L, Soloway RA et al. 1994 Annual Report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Amer J Emerg Med 1995; 13: 551-597.
15. Litovitz T, Klein-Schwartz W, White S et al. 1999 Annual Report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Amer J Emerg Med 2000; 18: 517-574.
16. AMERICAN ACADEMY OF PEDIATRICS – COMMITTEE ON DRUGS. Acetaminophen Toxicity in Children. Pediatrics 2001; 108(4): 1020-1024.
17. Fored CM, Ejerblad E, Lindblad P et al. Acetaminophen, aspirin and chronic renal failure. N Engl J Med 2001; 345: 11801-1808.
18. Janson C, Anto J, Burney P et al. The European Community Respiratory Health Survey: what are the results so far? European Community Respiratory Health Survey II. Eur Resp J 2001; 18: 598-611.
16 • WHO Pharmaceuticals Newsletter No. 1, 2002
Sredinom 1970-ih je metamizol (kod nas poznat kao Analgin i Novalgetol) izbacen iz upotrebe u mnogim zemljama, pre svega u SAD, a zatim i u pojedinim zemljama Zapadne Evrope. I danas se mnogi pacijenti, lekari i farmaceuti sa strahom odnose prema ovom leku, pozivajuci se na 30 i vise godina stare statisticke podatke, koji su vise nego pogresni. Na zalost, cesto se cuje da je prisustvo Analgina/Novalgetola u nasim apotekama i ordinacijama samo jos jedan od dokaza koliko smo "zaostali za svetom". U skladu sa takvim "trendom", nedavno je Republicki Zavod za zdravstveno osiguranje zabranio davanje ampula Novalgetola u vanbolnickim uslovima. Lek kojim smo se uspesno decenijama borili protiv bolova i povisene temperature, proteran je iz srpskog zdravstva.
Koliko su pogresne i naduvane bile statisticke procene na osnovu kojih je metamizol izbacen iz upotrebe u SAD i pojedinim zemljama Evrope, govori ovaj odlican clanak, objavljen u casopisu Svetske Zdravstvene Organizacije.
Meta-analize, koje su najvalidnije u savremenoj naucnoj metodologiji, pokazuju da je diklofenak cak 23 puta opasniji, aspirin 7 ipo puta, a paracetamol je opasan skoro isto koliko i metamizol (Novalgetol/Analgin)."In 1998 Andrade et al. conducted a meta-analysis to compare epidemiological studies from 1975 to 1995 and estimated that the excess mortality per million from community acquired cases of agranulocytosis, aplastic an-aemia, anaphylaxis and serious upper gastrointestinal complications was 592 for diclofenac, 185 for ASA, 25 for metamizole, and 20 for paracetamol(8)."
Paracetamol (Febricet, Miralgin, Eferalgan...) - lek koji masovno dajemo deci i odraslima bez ikakvog straha, verujuci da je bezbedan - oznacen je kao glavni uzrok smrti usled trovanja lekovima u Americi. Ipak, taj lek je popularan i medju pacijentima i medju lekarima, dok se metamizol izbacuje sa liste lekova, osudjuje se kao znak nase "nazadnosti" i zanemaruje se da ima pootvrdjeno jace antipireticko dejstvo od Brufena (ibubrofena) i paracetamola."The American Association of Poison Control Centers (AAPCC) lists paracetamol as the single major cause of death reported to the American poison centers since 1994"
Nadam se da ce oni koji donose odluke o povlacenju provereno dobrih lekova sa trzista (i ubacivanju homeopatskih vodica u drzavne apoteke) poceti makar malo da trezveno razmisljaju i da objektivno pristupe podacima na osnovu kojih treba da odlucuju.
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