The Uncertainties of Metamizole Use
Ingolf Cascorbi
Abstract
The potent analgesic and antipyretic drug metamizole (dipyrone) is widely used in many countries but was banned in others due to severe safety concerns regarding the risk of agranulocytosis. In this issue of Clinical Pharmacology and Therapeutics, a further so-far-not-described characteristic of metamizole to induce cytochrome P450 enzymes is reported, potentially decreasing the bioavailability of quite a number of drugs.1 Is such an interaction an additional aspect of concern in prescribing metamizole? The pyrazolone derivative metamizole belongs to the group of nonacid nonopioids that was introduced into the market already in 1922. Due to its comparably high analgesic and antipyretic potency but also spasmolytic properties, it is indicated in various countries for adults and adolescents above the age of 14 years for acute severe pain after injuries or surgeries, colic, tumor pain, and other acute or severe pain symptoms, if other therapeutic measures are not indicated, as well as for high fever if other measures are unsuccessful. It is available as a prescribed drug in certain European countries as well as in Asia and South America, or even as an over-the-counter medication, but was banned in some European countries like the United Kingdom, France, Sweden, and Norway, and in the United States, Canada, Australia, and others due to severe safety concerns regarding the risk of agranulocytosis. The discussion on the benefits and risks of this potent analgesic drug is ongoing. In Germany, metamizole/dipyrone still belongs to the most frequently prescribed drugs. From 1991 to 2018 the number of daily defined doses increased from 15 million to 225 million. In a cross-sectional study in elderly community-dwelling adults (mean age 74.5 years), half of the subjects suffering from high-intensity or disabling pain took analgesics, from which 16.1% took metamizole. It was reportedly the second-most frequent analgesic after occasional nonsteroidal anti-inflammatory drugs (NSAIDs).2 Metamizole has weak anti-inflammatory or antithrombotic properties. Although the mode of action has not yet been entirely elucidated, the main analgesic effects of metamizole are attributed to the inhibition of prostaglandin E2 (PGE2) formation by its metabolite 4-methyl-amino-antipyrene. This is not due to competitive inhibition of arachidonic acid metabolism like conventional NSAIDs, but through reducing the higher oxidation states of both COX1 and COX2 enzymes, or sequestering activating peroxides. Moreover, it may block PGE2-inhibitor–induced hyperalgesia.3 Therefore, it was suggested that metamizole may have direct effects upon the excitability of primary sensory neurons. Recent experimental findings indicate an association of the phosphatidylinositol 3 kinase/serine/threonine protein kinase B (PI3K__/AKT) pathway with peripheral metamizole-derived antinociceptive effects (Cecilio 2020). Further it was shown that the metabolite 4-aminoantipyrine reduces PGE2-induced pain-related behavior through cannabinoid CB1 receptor–mediated desensitization of the heat receptor TRPV1 (transient receptor potential cation channel subfamily V member 1) (Goncalves dos Santos 2020). As mentioned above, significant safety concerns have led to the decision of a number of regulatory authorities to ban metamizole due to the rare but life-threatening event of agranulocytosis that is characterized by a neutrophil count of less than 500 cells per microliter. A recent report from the EudraVigilance pharmacovigilance database identified 1,478 cases within the time period of 1985–2017, the majority coming from Germany and Switzerland.4 The event was not dose-dependent, the median doses were 1,500 mg/day and in the recommended range, and occurred with a median latency of 13 days after starting metamizole. Forty-three percent of cases were reported as life-threatening, and 16.2% (222 cases) were fatal. The authors stated that the proportion of cases with fatal outcome decreased from 20.9% reported before 1998 to 15% reported after 2007.4 Data on prescription rates in Germany from statutory health insurance funds revealed that among 68.4 million insured persons 8.1% received a least one metamizole prescription per year. The true incidence rate of this very rare event is difficult to estimate as there is assumingly also a high number of unreported cases. Based on ~ 44 reported cases of agranulocytosis per year from 2015 to 2017 and at least 5.5 million yearly prescriptions in Germany,5 these data suggest an incidence rate of 7.9 per million prescriptions. Other data from various European studies on incidence rates within 7–10 days of exposure vary from 0.6 to 1.4 per million as summarized by Andrade et al.,6 opposing data from Sweden that estimated 1 case per 1,400 outpatients based on 10 spontaneous reports and pharmacy sales data.7 As clozapine-induced agranulocytosis was shown to be associated with the presence of specific HLA-alleles,8 similar attempts have been made in three European populations for metamizole-induced agranulocytosis, however without revealing strong results. The most promising single-nucleotide polymorphisms that met marginal significance in a joint meta-analysis were rs55898176 and rs4427239, the latter located in SVEP1 (Sushi, von Willebrand factor type A, EGF and pentraxin domain-containing protein 1), a gene previously implicated in hematopoiesis.9 Aside from the life-threatening risk of agranulocytosis, anaphylaxis is a feared risk of metamizole. The estimates of incidence are 8.1 (3.5–19) per 10,000 exposed patients and are thus much higher compared with the risk of agranulocytosis, but in a range similar to diclofenac's incidence of 7.2 (2.6–20) cases of anaphylaxis per 10,000.6 The risk of drug-induced liver injury (DILI) seems to be underestimated so far, as various studies outlined that the risk is lower as compared with analgesics like acetaminophen or some NSAIDs. A recent study from Germany, however, showed that after the anticoagulant phenprocoumon, metamizole was the second-most frequent agent, putatively causing DILI, contributing to 14.9% of 154 DILI cases retrospectively analyzed at the Hamburg University Medical Center Hamburg-Eppendorf.10 Concerning drug-interactions, metamizole—similar to ibuprofen—impairs the acetylation of COX1 by aspirin through blocking the serine residue at position 529 that may subsequently result in a diminished platelet inhibition when low-dose aspirin is given as platelet inhibitor, e.g., in coronary artery disease. Such information has been already inserted in the product information, and recommendations have been made suggesting to take aspirin 30 minutes prior to dipyrone or reduced metamizole doses should be applied to avoid such pharmacodynamic interactions.11 Of novel knowledge is the observation on pharmacokinetic drug interactions reported in this issue.1 Bachmann et al. showed that metamizole is a moderate inducer of cytochrome P450 2B6 (CYP2B6), CYP3A4, and CYP2C19, reducing the area under the concentration-time curve (AUC) of the probe drug efavirenz by 79%, the AUC of midazolam by 68%, and the AUC of omeprazole by 66% in a clinical study in healthy volunteers. Moreover, it was a weak inducer of CYP2C9 and weak inhibitor of CYP1A2. The findings were confirmed in in vitro assays, and the induction could be attributed to the constitutive androstane receptor (CAR). It should be mentioned that volunteers took a relatively high dose of 3 g metamizole per day for 7 consecutive days. One week is usually considered to cause stable inductions mediated by the pregnane X receptor (PXR) or CAR. What is the consequence? If metamizole is prescribed for more than only a few days, it could lead to substantial loss of efficacy of comedicated drugs metabolized by P450 enzymes. This could be of therapeutic relevance in particular for those having a narrow therapeutic index, such as immunosuppressants like cyclosporine or tacrolimus. Could metamizole (dipyrone) still be considered as safe? Although this potent analgesic drug has been banned in many countries due to the discussion on agranulocytosis risk, according to a questionnaire to anesthesiologists in German-speaking countries, metamizole is still the preferred nonopioid analgesic in Central Europe for the treatment of acute pain in particular before the end of surgery and in the recovery room.12 There are also recommendations for the treatment of cancer pain as an alternative to other nonopioids either alone or in combination with opioids. As compared with NSAIDs, metamizole is considered to be more potent, as well tolerated, and to have a lack of contra-indications such as cardiovascular or gastrointestinal comorbidities so that benefits are considered to outweigh the risks.13 Moreover, for short-term use, the novel facts on pharmacokinetic interactions could possibly be neglected. Since there are no biomarkers available to predict the risk of agranulocytosis, however, careful clinical monitoring is a prerequisite of prescribing metamizole. It should be considered that—though very rare—agranulocytosis is not only a deadly risk, but may cause long-lasting health impairments. With respect to the new data on the risk of liver injury but also the potential risk of drug–drug interactions, additional caution is warranted and long-term use should be performed with caution. Due to the different prescription patterns in various countries and still ongoing discussion on safety issues, metamizole/dipyrone will remain a drug with ambiguous properties of its potential benefits and risks. No funding was received for this work. The author declared no competing interests for this work.