Nicotinic acid in erythromelalgia associated with Clitocybe acromelalga intoxication: Theories and therapy

To the Editor:

The case report by Nakajima and his colleagues was both interesting and informative.¹ This report is a great contribution in the management of erythromelalgia and we would like to mention the probable mechanisms for the pain and role of nicotinic acid in pain relief. Though the exact pathophysiology of erythromelalgia in Clitocybe acromelalga poisoning is not clear, it is likely that the toxin might have caused small-fiber neuropathy through dysregulation of blood flow to small fibers, resulting in microvascular ischemia. Further, stimulated sensory neurons might have initiated its action via calcitonin gene-related peptide (CGRP), which in turn deregulate the vascular tone² and contribute to ischemic neuropathy. This neurovascular dysfunction is clearly manifested as oxidative–nitrosative stress in the peripheral nerve and vasa nervorum.

Nicotinic acid mitigates pain, not only by its vasodilatory effects, but also through multiple mechanisms such as induction of PGD2 in the skin and subsequent increase of its metabolite in the plasma which might down-regulate the output of CGRP, and halt the neurogenic inflammation and normalize the vascular tone.³ Clitocybe acromelalga also contains clitidine, a toxic nucleoside, which increases the conversion of tryptophan to niacin. Therefore, with an adequate supplement of nicotinic acid it would facilitate the conversion of tryptophan to serotonin via its negative feedback on the kynurenine pathway diverting more tryptophan to serotonin. Moreover, nicotinic acid counteracts oxidative–nitrosative stress which regulates the vasa nervorum, and also maintains adequate mitochondrial energy metabolism by increasing substrate availability to complex I.⁴ It has also been found to stimulate GABA receptors, without binding to the receptor sites, thus creating a benzodiazepine-like effect. Additionally, due to its inhibition of ADP-ribosylation, nicotinic acid has been shown to suppress cytokine-mediated induction of nitric oxide synthase resulting in decreased inflammation.⁵ Thus, it might mitigate the pain response. Kamerath and De Luigi had reported the analgesic benefit of niacin for shrapnel wound pain in war veteran.⁶

Though the therapeutic spectrum of nicotinic acid has expanded, the adverse effects are experienced by many including the case reported. These symptoms can frequently be minimized by mid-meal dosing or gradual titration. Sustained-release preparations have higher chances of producing hepatic toxicity in doses comparable to the immediate-release preparations. We have used analgesic formulation of nicotinic acid with oxycodon in those with severe arthritis, and found it to be more effective than oxycodon alone due to possible synergistic effect.⁷ Despite this the usefulness of nicotinic acid as an adjuvant in pain relief has not been discussed in educational programs, has not reached the minds of practitioners, and has not attracted the research scholars. Hence, there is a need to explore the analgesic effects of nicotinic acid through controlled clinical trials.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.