Metamizole as an Analgesic with a Favorable Benefit-Risk Ratio
Metamizole is a well-established and widely used molecule in many countries worldwide, suitable as an alternative to opioids for patients with moderate to severe acute or chronic pain. The popularity of this drug is associated not only with its efficacy but also with its safety, with no contraindications for patients with cardiovascular, renal, or gastrointestinal comorbidities.
Introduction
Metamizole was first introduced over 100 years ago and has become widely used in Europe and South America for its advantageous analgesic, antipyretic, and spasmolytic properties. However, the mechanism of its action remains not entirely explained. Initially classified among non-steroidal anti-inflammatory drugs (NSAIDs), it is now classified as a non-opioid analgesic.
NNT Indicator
A meta-analysis by the Cochrane Collaboration confirmed that metamizole shows a high success rate in relieving dental pain, with 62% of patients achieving at least 50% of the maximum possible relief within 4-6 hours of administration compared to placebo. Compared to other monitored drugs (NSAIDs, paracetamol), it performed best.
The NNT (number needed to treat) for acute pain after oral administration of 500 mg metamizole was 2.3 (95% confidence interval [CI] 1.8–3.1), which is in the upper half of the range for common cyclooxygenase (COX) inhibitors. Among single-drug preparations, metamizole was among the best according to NNT values. Only fast-acting ibuprofen in doses of 200 or 400 mg and diclofenac 50 mg achieved better values.
Pharmacokinetics Independent of Administration Route
Key pharmacokinetic characteristics of metamizole are similar for both oral and parenteral administration. The peak analgesic effect is achieved approximately 1 hour after oral administration, regardless of the dose. In dental pain induced by electrical stimulation of the dental pulp, an increase in maximum effect was observed depending on the dose, but this increase was less pronounced at doses above 1500 mg, and the time to onset of effect was independent of the dose given.
Indications and Tolerance
For moderate to severe pain, metamizole is used alone or in combination with opioids or other analgesics, leading to increased analgesic effects and potentially reduced opioid consumption.
A meta-analysis of randomized studies with nearly 4,000 patients conducted in the past highlighted a significantly lower incidence of adverse effects with metamizole compared to opioids. Several studies have demonstrated the favorable gastrointestinal, cardiovascular, and cerebrovascular profiles of metamizole compared to NSAIDs.
The most serious and feared complication of treatment is agranulocytosis, which led to its withdrawal from the market in some countries in the 1960s. However, agranulocytosis occurs only rarely or very rarely, with an estimated incidence ranging from 1: 1500 to > 1: 1,000,000. The median latency between the initiation of treatment and the occurrence of hematological adverse reactions is 7 days, with agranulocytosis potentially occurring 2 days after the start of treatment. In 96% of cases, these reactions occur within the first 2 months of treatment, after which the risk of hematological reactions quickly decreases.
Metamizole in Practice
Metamizole is available in many countries, both on prescription and as an OTC medication. The choice of appropriate analgesic is influenced by the increasing number of comorbidities and the risk of interactions. Although metamizole, via its main metabolite 4-methylaminoantipyrine, acts as an inducer of CYP and an inhibitor of CYP1A2, interaction with the constitutive androstane receptor (CAR) is necessary for the mentioned induction.
The analgesic and antipyretic effects of metamizole are comparable to COX inhibitors in prostaglandin-mediated inflammations. Unlike metamizole, non-selective COX inhibitors more often lead to gastrointestinal complications (bleeding and ulcers) and are more often associated with cardiovascular events and renal dysfunction. The incidence of these events is statistically significantly higher than the risk associated with agranulocytosis from metamizole.
Summary and Conclusion
The comprehensive analgesic action of metamizole is at least comparable to most other non-opioid analgesics, with wide applicability according to current recommendations of the European Medicines Agency (EMA). Compared to COX inhibitors, its favorable safety profile in terms of gastrointestinal and cardiovascular events makes it more suitable for patients with renal dysfunction or increased bleeding risk. The risk of agranulocytosis is statistically very low and can be further reduced by monitoring the blood count during treatment. Metamizole appears to be a drug with an acceptable and favorable benefit-risk profile.
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Sources:
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1. Stromer W., Palladini M. Metamizole: A comprehensive approach to its benefit-risk profile. EFSM 2022 Nov 2; 2: 220153, doi: 10.52778/efsm.22.0153
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2. Moore R. A., Wiffen P. J., Derry S. et al. Non-prescription (OTC) oral analgesics for acute pain - an overview of Cochrane reviews. Cochrane Database Syst Rev 2015; 2015 (11): CD010794, doi: 10.1002/14651858.CD010794.pub2.
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3. SPC Novalgin. Available at: www.sukl.cz/modules/medication/detail.php?code=0221112&tab=texts
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