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Review
. 2015 Apr 13;10(4):e0122918.
doi: 10.1371/journal.pone.0122918. eCollection 2015.

Metamizole-associated adverse events: a systematic review and meta-analysis

Thomas Kötter  1 , Bruno R da Costa  2 , Margrit Fässler  3 , Eva Blozik  4 , Klaus Linde  5 , Peter Jüni  2 , Stephan Reichenbach  6 , Martin Scherer  4
Affiliations
Review

Metamizole-associated adverse events: a systematic review and meta-analysis

Thomas Kötter et al. PLoS One. .

Abstract

Background: Metamizole is used to treat pain in many parts of the world. Information on the safety profile of metamizole is scarce; no conclusive summary of the literature exists.

Objective: To determine whether metamizole is clinically safe compared to placebo and other analgesics.

Methods: We searched CENTRAL, MEDLINE, EMBASE, CINAHL, and several clinical trial registries. We screened the reference lists of included trials and previous systematic reviews. We included randomized controlled trials that compared the effects of metamizole, administered to adults in any form and for any indication, to other analgesics or to placebo. Two authors extracted data regarding trial design and size, indications for pain medication, patient characteristics, treatment regimens, and methodological characteristics. Adverse events (AEs), serious adverse events (SAEs), and dropouts were assessed. We conducted separate meta-analyses for each metamizole comparator, using standard inverse-variance random effects meta-analysis to pool the estimates across trials, reported as risk ratios (RRs). We calculated the DerSimonian and Laird variance estimate T2 to measure heterogeneity between trials. The pre-specified primary end point was any AE during the trial period.

Results: Of the 696 potentially eligible trials, 79 trials including almost 4000 patients with short-term metamizole use of less than two weeks met our inclusion criteria. Fewer AEs were reported for metamizole compared to opioids, RR = 0.79 (confidence interval 0.79 to 0.96). We found no differences between metamizole and placebo, paracetamol and NSAIDs. Only a few SAEs were reported, with no difference between metamizole and other analgesics. No agranulocytosis or deaths were reported. Our results were limited by the mediocre overall quality of the reports.

Conclusion: For short-term use in the hospital setting, metamizole seems to be a safe choice when compared to other widely used analgesics. High-quality, adequately sized trials assessing the intermediate- and long-term safety of metamizole are needed.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. PRISMA flowchart.
The 79 randomized controlled trials [–95] assessed mainly short-term use of common analgesics. Forty-two trials (53%) investigated the use of only a single dose of metamizole. In addition, 18 trials (23%) had a maximum treatment duration of only one day, while in 17 trials treatment lasted from two days up to one week (22%) and only two trials (2%) had a treatment duration of two weeks. Average length of follow-up ranged from 0.33 to 366 hours (median: 24 hours). Four trials (5%) had sample sizes of at least 100 patients per randomized group (median: 30 patients).
Fig 2
Fig 2. Forest plot—Metamizole versus Placebo.
Categories according to the International Classification of Primary Care (see Methods section and [13]). Results from single studies are of limited interpretability but are displayed for the sake of completeness. RR = risk ratio. AE = adverse events. SAE = serious adverse events.
Fig 3
Fig 3. Forest plot—Metamizole versus Paracetamol.
Categories according to the International Classification of Primary Care (see Methods section and [13]). Results from single studies are of limited interpretability but are displayed for the sake of completeness. RR = risk ratio. AE = adverse events. SAE = serious adverse events.
Fig 4
Fig 4. Forest plot—Metamizole versus Aspirin.
Categories according to the International Classification of Primary Care (see Methods section and [13]). Results from single studies are of limited interpretability but are displayed for the sake of completeness. RR = risk ratio. AE = adverse events. SAE = serious adverse events.
Fig 5
Fig 5. Forest plot—Metamizole versus NSAIDs.
Categories according to the International Classification of Primary Care (see Methods section and [13]). Results from single studies are of limited interpretability but are displayed for the sake of completeness. RR = risk ratio. AE = adverse events. SAE = serious adverse events.
Fig 6
Fig 6. Forest plot—Metamizole versus Opioids.
Categories according to the International Classification of Primary Care (see Methods section and [13]). Results from single studies are of limited interpretability but are displayed for the sake of completeness. RR = risk ratio. AE = adverse events. SAE = serious adverse events.
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Grants and funding

The study was funded by the German Federal Ministry of Research and Education (Grant-No. 01KG1017). The funding source did not play a role in the design, conduct or reporting of the study, or the decision to submit the manuscript for publication.