Differential medication overuse risk of novel anti-migraine therapeutics

Abstract

Medication overuse headache is estimated to affect 2% of the population, and is ranked in the top 20 most disabling disorders due to its high level of disability. Several therapies used in the treatment of acute migraine are thought to be associated with medication overuse headache, including opioids and triptans. With limited treatment options, it is critical to determine the risk profile of novel therapies prior to their widespread use. The current study explores the potential medication overuse risk of two novel therapeutic drug classes, namely the ditans: 5-HT1F receptor agonists, and the gepants: calcitonin gene-related peptide receptor antagonists, in a preclinical model of medication overuse. Persistent exposure of mice to the 5-HT1F agonist LY344864, but not olcegepant produced a significant reduction in hind paw and orofacial mechanical withdrawal thresholds as a surrogate readout of allodynia. In agreement, only LY344864 induced neuroplastic changes in trigeminal sensory afferents, increasing calcitonin gene-related peptide expression and basal trigeminal nociception. Our data highlight a differential medication overuse headache risk profile for the ditan and gepant classes of drugs that has important implications for their clinical use and patient education to help reduce the burden of medication overuse headache.

Medication overuse headache: Divergent effects of new acute antimigraine drugs

“…The level of sensitisation was comparable to that observed with sumatriptan, suggesting a similar risk profile that needs to be considered with respect to avoiding their overuse clinically. In agreement, with a similar mechanism of action, both sumatriptan and lasmiditan induced a state of "latent sensitisation" to presumed migraine triggers in rats following their withdrawal out to 28 days (6) and sumatriptan and LY344864 induced increased expression of CGRP and activation of trigeminal nociceptive pathways (8).…”

“…The triptans and ditans, both agonists to the G i/o -coupled 5-HT 1B/1D and 5-HT 1F receptors, respectively act to decrease the production of cAMP (12). A similar cAMP-dependent mechanism is proposed for the acute effects of morphine (13); however, persistent exposure leads to upregulation of cAMP, and increased CGRP release (14,15), suggesting a similar converse relationship may exist following persistent activation of 5-HT 1B/1D/1F receptors that is supported by increased CGRP expression (8). Further, prolonged agonist exposure decreases receptor expression, whereas receptor antogonists classically increase receptor expression (16,17).…”

“…In comparison, persistent exposure to either ubrogepant or olcegepant for an equivalent duration induced no MOH-like phenotypes in rats and mice, no "latent sensitisation" and no alteration in CGRP expression or trigeminal nociceptive activity (7,8), suggesting a proportionally safer MOH-risk profile. This data is in agreement with preliminary clinical data suggesting that persistent exposure to gepants for migraine prevention is effective with no evidence of MOH development (9,10), while clinical and preclinical data highlight a potential therapeutic efficacy for targeting CGRP signalling to treat MOH (10,11).…”

“…The important question now is: What is the MOH-risk profile of these novel therapies? While convincing clinical evidence is not yet available, two recent publications in Cephalalgia (6,7) and one in Brain (8) have started to address this question in a preclinical setting, with complimentary results. The research suggests that 5-HT 1F receptor agonist ditans, including lasmiditan and LY344864, share a similar MOH-risk profile to the related 5-HT 1B/1D receptor agonist triptan drugs, independent of the route of administration.…”

“…The research suggests that 5-HT 1F receptor agonist ditans, including lasmiditan and LY344864, share a similar MOH-risk profile to the related 5-HT 1B/1D receptor agonist triptan drugs, independent of the route of administration. Rats and mice persistently exposed to either ditan (6,8) developed decreased orofacial and hindpaw mechanical withdrawal thresholds that are considered a preclinical readout of cutaneous allodynia. The level of sensitisation was comparable to that observed with sumatriptan, suggesting a similar risk profile that needs to be considered with respect to avoiding their overuse clinically.…”