The Uncertainties of Metamizole Use

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 sofarnotdescribed characteristic of metamizole to induce cytochrome P450 enzymes is reported, potentially decreasing the bioavailability of quite a number of drugs. 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 overthecounter 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 crosssectional study in elderly communitydwelling adults (mean age 74.5 years), half of the subjects suffering from highintensity or disabling pain took analgesics, from which 16.1% took metamizole. It was reportedly the secondmost frequent analgesic after occasional nonsteroidal antiinflammatory drugs (NSAIDs). Metamizole has weak antiinflammatory 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 4methylaminoantipyrene. 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 PGE2inhibitor– induced hyperalgesia. 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 (PI3Kγ/AKT) pathway with peripheral metamizolederived antinociceptive effects (Cecilio 2020). Further it was shown that the metabolite 4aminoantipyrine reduces PGE2induced painrelated 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