Prevention of the cytokine storm in COVID-19.

The Comment by Marc Feldman and colleagues, published recently in The Lancet, discussed the potential of anti-tumor necrosis factor (TNF) therapy to inhibit development of a cytokine storm in patients with coronavirus disease 2019 (COVID-19). Following this Comment, I write to propose that the opioid, meptazinol, might be a possible alternative or addition to anti-TNF therapy, particularly in the UK, where meptazinol is a licensed drug (current licenced supplier Almirall, Barcelona, Spain) and thus could be easily prescribed.

The basis of this suggestion is a study I led with Bayu Teklu and colleagues, in which we studied the Jarisch-Herxheimer (JH) reaction in louse-borne relapsing fever. The JH reaction appeared to be a transient manifestation of a cytokine storm, induced by treatment of relapsing fever with antibiotics, and only lasting for around 2 h after a single curative injection of tetracycline. Notably, concentrations of interleukins 6 and 8 and TNF are increased during this reaction. Meptazinol, an opioid antagonist–agonist or sometimes termed a partial opioid agonist, but not naloxone, supressed the JH reaction, similar to the effect of anti-TNF. Meptazinol reduced high temperature, pulse rate, and breathing rate during the JH reaction. An effect of the JH reaction is exacerbation of any local lesions (in this case, the lungs). The theoretical basis of the action of opioid antagonists was elucidated in an animal model of relapsing fever and described in detail previously. However, a disadvantage of meptazinol is that it is short acting (half-life of about 2 h) and causes nausea and occasional vomiting.

A trial of meptazinol for COVID-19 in patients presenting with a cytokine storm and in those without, to provide proof of effectiveness, might indicate its efficacy in ameliorating symptoms. The results of such a trial might prove especially useful, given that antipyretics, such as paracetamol and aspirin, have become less favoured by clinicians. Building on this approach, a range of opioids should be tested, particularly in the context of the COVID-19 cytokine storm, to establish if a longer acting and more palatable opioid than meptazinol can be used (eg, buprenorphine, half-life 24 h) or even synthesised.