E-drug: Dipyrone and agranulocytosis
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[Copied as fair use. HH]
Dipyrone and agranulocytosis: what is the risk?
The Lancet 361, 9361, 15 March 2003.
Sir--In reviewing the Swedish study of agranulocytosis,1 Jayne
Edwards and Henry McQuay (Nov 9, p 1438)2 emphasise the small
number of cases, and conclude that the risk of agranulocytosis with
dipyrone is unquantifiable and likely to remain so. We disagree, and
believe that they overlooked important earlier publications.
Sweden and other industrialised countries banned dipyrone because
of blood dyscrasias around 1974. The incidence of blood dyscrasias
was estimated at one in 3000 users. In 1981, the German
Bundesgesundheitsamt (BGA) calculated the risk of agranulocytosis
with dipyrone as one in 20 000 users per year, restricted the
indications for its use, and banned all combinations.
In 1986, the International Agranulocytosis and Aplastic Anemia
Study (IAAAS)3 reported the incidence of dipyrone-induced
agranulocytosis as one case in 1 100 000 user-weeks. The authors
of that study calculated the incidence of agranulocytosis as new
cases per year, dividing this figure by 52 (weeks) to obtain the
denominator "user-week", so converting an estimated incidence of
one in 20 000, based on the annual number of cases and users,
into the widely cited one per million users.
The IAAAS was criticised: centres were lost (Israel, Budapest),
cases were too few (Milan, Sofia), a reference population was
exaggerated (Ulm), and the user-week denominator was seemingly
used to lower the incidence of dipyrone-induced agranulocytosis.4
Both the IAAAS and the BGA calculated the incidence from cases
of agranulocytosis identified by the spontaneous reporting system.
Such systems detect at best only 5% of the adverse reactions that
occur.5 An incidence of one in 20 000 so calculated might thus
represent a true incidence of about one in 1000, as the Swedish
study found.
Offerhaus pointed out that limiting the discussion of risks of
dipyrone to agranulocytosis leads to an underestimation of the
dangers of the drug.4 In 1983, the hospital-based adverse drug
reaction (ADR) monitoring system in Berne had reported serious
hypotension with dipyrone in one per 3000 patients. In 1999, the
hospital-based ADR monitoring system in Bremen reported other
serious immune reactions to dipyrone, such as anaphylaxis, asthma,
serum sickness, hypersensitivity vasculitis, alveolitis, pneumonitis,
hepatitis, or haemolytic-uraemic syndrome about four times more
often than agranulocytosis.
The Cochrane reviews by McQuay's team confirm that one dose of
dipyrone is effective for postoperative pain and acute renal colic
pain. Such treatment causes few adverse reactions, since it takes
about 2 weeks to trigger immune reactions in patients new to the
drug and to manifest infection due to dipyrone-induced
agranulocytosis. Therefore short-term studies miss the drug's
dangerous effects.
The frequency of serious ADRs, not lack of efficacy, makes
dipyrone unacceptable for therapeutic use.
A full version of this letter appears at
http://image.thelancet.com/extras/ 02cor12094web.pdf
*Peter Sch�nh�fer, Leo Offerhaus, Andrew Herxheimer
---------------------------------
*R�tenh�fe 7B, 28355 Bremen, Germany (PS); Koedijklaan 1a,
1406 KW Bussum, Netherlands (LO); and 9 Park Crescent, London
N3 2NL, UK (AH) (e-mail:pschoenhoefer@t-online.de)
1. Hedenmalm K, Spigset O. Agranulocytosis and other blood
dyscrasias associated with dipyrone (metamizole). Eur J Clin
Pharmacol 2002; 58: 265-74. [PubMed]
2. Edwards JE, McQuay HJ. Dipyrone and agranulocytosis: what is
the risk? Lancet 2002; 360: 1438.
3. The International Agranulocytosis and Aplastic Anemia Study
Group. Risks of agranulocytosis and aplastic anemia: a first report
of their relation to drug use with special reference to analgesics.
JAMA 1986; 256: 1749-57. [PubMed]
4. Offerhaus L. Metamizol: een honderdjarige treurnis. Ned Tijdschr
Geneeskd 1987; 131: 479-81. [PubMed]
5. B�gaud B, Martin K, Haramburu F, Moore N. Rates of
spontaneous reporting of adverse drug reactions in France. JAMA
2002; 288: 1588.
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