Keep in Mind TRPA1 When Prescribing Metamizole!

To the Editor: We have read a paper by Konijnenbelt-Peters et al., recently published in Pain Practice, with much interest. The authors have reviewed the efficacy and safety profile of metamizole and performed a safety analysis using WHO data to define the current placement of metamizole in pain management. The authors conclude that metamizole might be an effective and safe alternative to nonsteroidal antiinflammatory drugs (NSAIDs) for postoperative pain, but repeatedly underline the absence of an explanation for the better safety profile of metamizole in comparison with NSAIDs. In the introduction, the authors refer to metamizole as a strong, nonselective cyclooxygenase (COX) inhibitor, thus including it within the NSAID pharmacological class. However, evidence corroborating the ability of metamizole to inhibit COX has never been conclusive, whereas, in sharp contrast with indomethacin, a clear dissociation between the antihyperalgesic and anti-inflammatory actions of metamizole has been reported. In line with these findings, we recently provided robust evidence that metamizole and other pyrazolone derivatives (propyphenazone and antipyrine) selectively antagonize the transient receptor potential ankyrin 1 (TRPA1) channel, and indicate such action as the underlying mechanism of the analgesic effect of these drugs. TRPA1, which belongs to the larger family of TRP channels and is expressed by a subpopulation of nociceptors, has recently been identified as a major pain transducer in different models of nociceptive and neuropathic pain. Thus, TRPA1 is currently considered an innovative and druggable target for a new class of analgesic medicines. We reported that the three pyrazolone derivatives, metamizole, propyphenazone, and antipyrine, selectively inhibit TRPA1 signaling in rodent nociceptors and in human cells that express the channel. More importantly, nocifensor responses evoked in mice by selective channel agonists (allyl isothiocyanate, acrolein, and H2O2), or mechanical allodynia produced in classical models of inflammatory pain (formalin, carrageenan) and in models of neuropathic pain (bortezomib, partial sciatic nerve ligation), were abated by metamizole in a TRPA1-dependent fashion. It is noteworthy that, as opposed to indomethacin, metamizole attenuated carrageenan-evoked mechanical allodynia without affecting increases in prostaglandin E2 in the inflamed paw. These results strongly suggest that COX inhibition is not the primary mechanism of action of metamizole, thus justifying the better gastroenterological and renal safety profile of metamizole vs. NSAIDs. It should also be underlined that concentrations/doses of metamizole that completely inhibited TRPA1 in vitro and in vivo in rodents are fully compatible with those regarded as effective in human plasma. All together, these findings would explain the efficacy of metamizole in reducing postoperative pain, a prototypical condition of mixed pain, characterized by the simultaneous presence of inflammatory and neuropathic features. The novel finding that old medicines, such as metamizole and propyphenazone (originally synthetized more than 100 years ago, and still in use in a vast majority of countries worldwide) inhibit the pain transducer TRPA1, rejuvenates such drugs, provided that, as indicated by Konijnenbelt-Peters et al., they are prescribed appropriately.