[e-drug] Dipyrone (metamizole) and risk of agranulocytosis

["Kirsten Myhr" <kirsten.myhr@relis.ulleval.no>]

E-drug: Dipyrone (metamizole) and risk of agranulocytosis
---------------------------------------------

Recently, Leo Offerhaus posted reference to a Swedish study on dipyrone
(metamizole, Analgin and more....) (E-drug 28 August). This week's Lancet
carries a commentary on the study. Neither these authors nor Offerhaus have
commented on a second Swedish study on utilization pattern of metamizole in
northern Sweden and risk of agranulocytosis, abstract copied at the end of
my message. The advantage of this study is that they have been able to look
at both inpatient and outpatient use and the duration of treatment compared
to the approved indication of short term use for specific indications. The
Swedish authors found that ''Regardless of the mechanism (KM: type of
agranulocytosis), from our data it appears that the patient has to be
exposed to the drug and/or its metabolites for at least 4 days.'' I would
also like to add that the study was sponsored by Hoechst Marion Roussel.

For the sake of completeness, it should also be mentioned that there are two
Cochrane reviews:
http://www.cochrane.org/cochrane/revabstr/ab003227.htm
Edwards JE, Meseguer F, Faura CC, Moore RA, McQuay HJ. Single-dose dipyrone
for postoperative pain (Cochrane review. In: The Cochrane Library, 1, 2002.
Oxford: Update Software.
Reviewers' conclusions: Single-dose dipyrone appears to be of similar
efficacy to ibuprofen 400 mg and other analgesics frequently used in the
treatment of moderate to severe postoperative pain. The commonest adverse
effects were somnolence, gastric discomfort and nausea.

http://www.cochrane.org/cochrane/revabstr/ab003867.htm
Edwards JE, Meseguer F, Faura C, Moore RA, McQuay HJ. Single dose dipyrone
for acute renal colic pain (Cochrane Review). In: The Cochrane Library, 4,
2002. Oxford: Update Software.
Reviewers' conclusions: Limited available data indicated that single dose
dipyrone was of similar efficacy to other analgesics used in renal colic
pain, although intramuscular dipyrone was less effective than diclofenac 75
mg. Combining dipyrone with antispasmolytic agents did not appear to improve
its efficacy. Intravenous dipyrone was more effective than intramuscular
dipyrone. Dry mouth and somnolence were commonly reported with intravenous
dipyrone. None of the studies reported agranulocytosis.

As few data, if any, points to any advantage compared to other painkillers,
I suppose there is no reason for promoting it until more is known about the
risk. Though many alternatives carry a risk of gastric bleeding.

Lancet 2002; 360: 1438 (9 November) [Copied as fair use. KM]
Commentary
Dipyrone and agranulocytosis: what is the risk?

Dipyrone is widely used in some parts of the world as an analgesic,
including in Europe and South America. In other regions it has been banned
because of its controversial association with agranulocytosis. The balance
between the benefit and harm associated with this drug is particularly
important for developing countries where dipyrone may be the first-line
analgesic, and where other drugs may not be readily available. Media
pressure caused recent debate in Brazil, with the outcome that dipyrone
remains an over-the-counter medication.1

Recently, Karin Hedenmalm and Olav Spigset2 described Swedish cases of
agranulocytosis. These investigators report on cases recorded before the
original ban of dipyrone in 1974, and those occurring after its
re-introduction as a prescription-only medicine in 1995 until its withdrawal
from the market in 1999. Only the cases after the re-introduction are
considered here to avoid confusion and to reflect recent trends in
treatment.

Since 1995, 14 cases occurred; eight resulted from outpatient prescriptions
data, and five occurred in hospitalised patients or in people who used
dipyrone while travelling abroad. All had taken dipyrone for pain
(postoperative or back pain, arthralgia, post-herpetic neuralgia, headache).
Doses varied between 0.5 and 6 g daily, with most taking 1.5-3 g daily.
Duration of use ranged between 1 and 40 days, with onset of symptoms
occurring within 15 days in nine cases. Symptoms on diagnosis were fever and
pharyngitis in most. Five had previously taken dipyrone. Treatment included
rapid withdrawal of dipyrone, use of antibiotics, and, in nine more severely
affected cases, administration of granulocyte-colony stimulating factor. All
cases resolved and there were no deaths. Current treatments help prevent the
30% mortality occurring in cases reported before 1974 and reflected in
published case reports from 1930 to 1980.

Hedenmalm and Spigset based their incidence of 1 case per 1431 prescriptions
on eight cases resulting from 10,892 outpatient prescriptions between 1995
and 1999. In two of these cases other drugs were also suspected as causal
agents; these should have been excluded from the calculation, but this would
have made little difference to the risk estimate.

Despite rigour in Hedenmalm and Spigset's definition of agranulocytosis,
collection of data, and attribution, the Swedish data are based on a small
number of events. If these were reflected in populations in which dipyrone
is commonly used, as in Spain or Brazil, many individuals would succumb to
agranulocytosis every year. Yet the literature and clinical experience do
not readily support this. Under-reporting is one explanation for low
reported event-rates in countries with high use of dipyrone, but would not
alone account for the short-fall if the Swedish rates are to be applied.
Increased susceptibility in naive populations is another possibility
discussed by Hedenmalm and Spigset, but several of the cases had used
dipyrone before. The widely criticised2,3 International Agranulocytosis and
Aplastic Anemia Study (IAAS)4 found vastly varying risks in different
countries. Methodological issues aside, different incidences could be
related to several factors. Consumption and frequency of use of dipyrone
differs from country to country, and some populations may have increased
genetic susceptibility to agranulocytosis.

Dipyrone clearly causes agranulocytosis, but there is insufficient useful
information to adequately quantify the risk. The association has been
extensively studied over the years with case reports and series, hospital
record review, and case-control and cohort studies. None inform us, since
most are old, methodologically weak, small, and use different definitions of
agranulocytosis. The studies do not reflect current practice. More recent
studies have also failed to quantify the risk.5,6 To date, the Swedish data2
are the best we have.

It is absolute risks that are important when determining harm. Absolute
risks of rare events for some treatments have been determined in
high-quality systematic reviews.7,8 Such quantification is not possible for
determining the risk of agranulocytosis with dipyrone. The uncertainty
remains, and is likely to do so. The worst-case scenario reported in the
IAAS4 was 9.0 cases per million per year. The Swedish estimates are many
orders of magnitude greater. Which do we believe? If we assume both are
correct, then there must be some genetic involvement to explain the
differences. The only way to settle the argument would be to do a large
study in countries which are heavy users of dipyrone.
*Jayne E Edwards, Henry J McQuay
----------------------------------------------------------------------------
----
Pain Research and Nuffield Department of Anaesthetics, University of Oxford,
Oxford Radcliffe Hospital NHS Trust, The Churchill, Oxford OX3 7LJ, UK
(e-mail:jayne.edwards@pru.oxa.c.uk)

References
1 Bensenor IM. To use or not to use dipyrone? Or maybe, Central Station
versus ER? That is the question.  Sao Paulo Med J 2001; 119: 190-91.
2 Hedenmalm K, Spigset O. Agranulocytosis and other blood dyscrasias
associated with dipyrone (metamizole).  Eur J Clin Pharmacol 2002; 58:
265-74.
3 Kramer MS, Lane DA, Hutchinson TA. Analgesic use, blood dyscrasias, and
case-control pharmacoepidemiology: a critique of the International
Agranulocytosis and Aplastic Anemia Study.  J Chronic Dis 1987; 40: 1073-85.
4 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. The International
Agranulocytosis and Aplastic Anemia Study.  JAMA 1986; 256: 1749-57.
5 van der Klauw MM, Goudsmit R, Halie MR, et al. A population-based
case-cohort study of drug-associated agranulocytosis.  Arch Intern Med 1999;
159: 369-74.
6 Shapiro S, Issaragrisil S, Kaufman DW, et al. Agranulocytosis in Bangkok,
Thailand: a predominantly drug-induced disease with an unusually low
incidence. Aplastic Anemia Study Group.  Am J Trop Med Hyg 1999; 60: 573-77.
7 Tram�r M, Moore RA, McQuay HJ. Propofol and bradycardia: causation,
frequency and severity.  Br J Anaesth 1997; 78: 642-51.
8 Tramer MR, Moore RA, Reynolds DJ, McQuay HJ. Quantitative estimation of
rare adverse events which follow a biological progression: a new model
applied to chronic NSAID use.  Pain 2000; 85: 169-82.

---------------------
Backstrom M, Hagg S, Mjorndal T, Dahlqvist R. Utilization pattern of
metamizole in northern Sweden and risk estimates of agranulocytosis.
Pharmacoepidemiol Drug Saf 2002 Apr-May;11(3):239-45.
Division of Clinical Pharmacology, Norrland University Hospital, S-901 85
Umea, Sweden. martin.backstrom@pharm.umu.se

OBJECTIVE: This study was carried out in order to investigate the
utilization pattern of metamizole to better estimate the quantitative risk
of agranulocytosis since a cluster of such cases have been observed in
Sweden. METHODS: Cases of agranulocytosis submitted to the Swedish Adverse
Drug Reactions Advisory Committee (SADRAC) between 1996 and 1999 were
identified. Based on the utilization pattern of metamizole in inpatients at
three hospitals and in outpatients in two counties in northern Sweden risk
estimates of agranulocytosis during metamizole treatment were estimated. The
utilization of metamizole was investigated by scanning 3567 case records at
10 hospital departments as well as stored prescriptions at six pharmacies
during a 3-month study period. RESULTS: Ten cases of agranulocytosis during
treatment with metamizole have been reported to SADRAC over the period 1996
to 1999. During the 3-month study period metamizole was prescribed to 666
(19%) inpatients. Of these, approximately 96% received the drug for less
than 1 week, 7.2% had used the drug previously. At the participating
pharmacies 112 metamizole prescriptions for outpatients were found. The drug
was prescribed in 34% for less than 1 week, in 28% for 7-15 days, and in 38%
for more than 15 days. The mean prescribed daily dose was 2.7 g. Given
certain assumptions including the actual amounts prescribed the calculated
risks of agranulocytosis would be approximately one out of every 31,000
metamizole-treated inpatients and one of every 1400 metamizole-treated
outpatients.
CONCLUSION: This study indicates that in most inpatients the use of
metamizole in northern Sweden was within the approved indications for the
drug. However, a considerable number of outpatients received the drug for a
longer time than recommended and this may carry an increased risk for
developing agranulocytosis.


Kirsten Myhr, MScPharm, MPH
Head, RELIS Ost Drug Information Centre
Ulleval University Hospital
0407 OSLO, Norway
Tel: +47 23 01 64 11  Fax: +47 23 01 64 10
kirsten.myhr@relis.ulleval.no
www.relis.no
[One of the early 'whistle blowers' was Mike Muller in 1982.  He 
included case studies of reactions to diyprone in 'The Health of 
Nations' London; Faber and Faber. Much of his information came from 
Mozambique where dipyrone was available OTC as an analgesic and used 
over long periods, much the same way that paracetamol is used today, 
supporting the conclusion above.   BS]

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