Safety Profile of Metamizole – A Systematic Review
Metamizole is a long-established non-steroidal analgesic used for acute and chronic pain management. A systematic review of the literature published in the Journal of Clinical Pharmacy and Therapeutics focused on the safety profile of this drug. Here, we present a summary of the most important findings.
Effect and Indications of Metamizole
Metamizole is a non-addictive pyrazolone analgesic that also has antipyretic and spasmolytic effects. It is indicated for severe acute pain, including colicky pain, as well as chronic pain and fevers unresponsive to treatment.
Treatment of Severe Postoperative Pain
In terms of efficacy and safety, metamizole has been compared, for example, to the opioid analgesic tramadol in patients after hysterectomy. In a multicenter randomized double-blind study (Torres et al.), analgesia was assessed in 151 patients (ages 18–60) in the first 24 hours after abdominal hysterectomy. Both drugs attained comparable analgesic efficacy, but significantly higher gastrointestinal side effects were observed in the tramadol group (42.1% vs. 20.2%; p < 0.05). Tramadol treatment was also associated with more frequent administration of antiemetics (ondansetron) within the first 24 hours postoperatively (46% vs. 29%; p < 0.05).
Safety Profile
In the early 1970s, metamizole was withdrawn from the market in several European countries and the USA following reports of fatal agranulocytosis cases. Consequently, several non-interventional epidemiological studies were performed to quantify the risk of agranulocytosis and other adverse effects associated with metamizole and other non-opioid analgesics.
Andrade et al. published a systematic review of metamizole safety in 2016, based on epidemiological studies published between 1980 and 2014. The review included epidemiological studies comparing the safety of metamizole to control groups, describing adverse effects such as hematological abnormalities, gastrointestinal bleeding, anaphylaxis, and hepatotoxicity. A total of 22 publications were included in the review.
Hematological Adverse Effects
The risk of agranulocytosis was assessed by 5 case-control studies and 1 cohort study. Individual estimates of the relative risk associated with metamizole use were highly heterogeneous, with odds ratios (OR) ranging from 1.5 (95% confidence interval [CI] 0.8–2.7) to 40.2 (95% CI 14.7–113.3). These studies also observed associations between agranulocytosis and the use of paracetamol, salicylates, diclofenac, and other non-steroidal anti-inflammatory drugs (NSAIDs), with highly inconsistent results.
Findings in 3 case-control studies did not suggest a link between metamizole and aplastic anemia.
Gastrointestinal Safety
Of the 5 case-control studies assessing the risk of upper gastrointestinal bleeding, 4 found a statistically significant increased risk associated with metamizole use (estimated OR ranging from 1.4 to 2.7), which was generally lower than the risk associated with other NSAIDs (estimated ORs for: paracetamol 0.6–1.5; acetylsalicylic acid 1.8–8.0; ibuprofen 1.3–4.1; naproxen 2.1–10.0; diclofenac 1.3–7.9).
There was insufficient evidence to establish a causal relationship between metamizole use and the risk of other adverse effects (hepatotoxicity, anaphylaxis, congenital anomalies).
Conclusion
The results of published studies are highly heterogeneous, with significant variations in risk estimates for adverse effects associated with metamizole and other NSAIDs. Due to small sample sizes and other limitations, potential biases may distort the results. To accurately quantify the potential risks associated with NSAID use, well-designed epidemiological studies are required.
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Sources:
1. Torres L. M., Rodríguez M. J., Montero A. et al. Efficacy and safety of dipyrone versus tramadol in the management of pain after hysterectomy: a randomized, double-blind, multicenter study Reg Anesth Pain Med 2001; 26 (2): 118–124, doi: 10.1053/rapm.2001.21437.
2. Andrade S., Bartels D. B., Lang R. et al. Safety of metamizole: a systematic review of the literature. J Clin Pharm Ther 2016; 41 (5): 459–477, doi: 10.1111/jcpt.12422.
3. SPC Novalgin. Available at: www.sukl.cz/modules/medication/detail.php?code=0221112&tab=texts
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