Metamizole (Dipyrone) and the Liver: A Review of the Literature

Abstract

Metamizole, also known as dipyrone, was introduced to the market nearly a century ago. Due to its excellent analgesic, antipyretic, and spasmolytic properties combined with its mostly favorable gastrointestinal tolerability, the drug was extensively applied worldwide during the first decades after its market introduction. Although rare, agranulocytosis is a well‐known adverse event of metamizole and led to its withdrawal from the market in a number of countries beginning in the 1960s. Nevertheless, metamizole is still a frequently used drug worldwide either legally (by prescription in some countries, over the counter in other countries) or without official approval (especially by immigrants knowing the drug from their home countries) or even illegally (due to its growing application as an adulterant in illicit drugs). Metamizole undergoes extensive metabolism in the liver and cases of potential metamizole‐associated hepatotoxicity have been described. Here, the literature is extensively reviewed for the first time regarding hepatic effects associated with the use of metamizole.

Acute intermittent porphyria: analgesia can be dangerous

“…Metamizole (also known as dipyrone) is a pyrazolone derivative that due to its chemical structure and its analgesic, antipyretic and anti-inflammatory effects, is classified as a nonsteroidal anti-inflammatory drug. Additionally, metamizole offers spasmolytic properties 6 7. In combination with its mostly favourable gastrointestinal tolerability, his profile led to an extensive clinical application.…”

“…Metamizole has several active metabolites with an extensive hepatic metabolism mediated, not only, by cytochrome P450 (CYP) 3A4 system, but also, by CYP2B6, CYP2C8 and CYP2C9. This gives him a certain potential for interactions with other substances metabolised via these CYP systems as well as a hepatotoxic potential of metamizole seems to be possible 6 7 14…”

“…However, potential risks associated with metamizole administration are not yet clear in the latest published studies and some also consider that in the past the risk of metamizole-induced agranulocytosis was exaggerated and may depend on dose, duration and concomitant medication 15 17–20. However, an increasing number of side effects of metamizole have been reported affecting the cardiovascular system (ie, hypotension and arrhythmia), the respiratory system (ie, bronchospasm, especially in asthmatic patients) and the skin (ie, maculopapular rash), among others 6 14 19…”

Arylamine N-acetyltransferase acetylation polymorphisms: paradigm for pharmacogenomic-guided therapy- a focused review

“…As described in a comprehensive review [73], metamizole is a non-steroidal antinflammatory in use for nearly a century for its analgesic, antipyretic, and spasmolytic properties. Metamizole was extensively applied worldwide until incidences of hypersensitivity leading to agranulocytosis led to its ban in a number of countries including the USA.…”

Further evidence for the hepatotoxic potential of metamizole

“…3 However, despite its extensive hepatic metabolism, the potential of metamizole to cause drug-induced liver injury (DILI) has been disregarded for many years, and only few cases have been reported. 4 Björnsson emphasizes 1 that including recently published cases by Sebode et al, 5 approximately 40 patients with metamizoleinduced liver injury have been reported worldwide, which qualifies metamizole as a Category B drug causing DILI according to the categorization system of LiverTox (http://livertox.nih.gov). 6 As stated by the LiverTox "likelihood score," Category A drugs are considered to have a definite hepatotoxic potential with a positive rechallenge reported for almost 90% of the drugs, while Category B drugs are highly likely to cause DILI.…”