Medication overuse headache: Divergent effects of new acute antimigraine drugs

For every person living with disabling primary headaches, recent translational success has heralded a welcome advance in therapeutic options. After years of research and some wrong turns along the way, it is reassuring that a number of promising targets have advanced the journey from bench to bedside. The first approval was monoclonal antibodies to target calcitonin gene-related peptide (CGRP) or its receptor (erenumab, fremanezumab and galcanezumab) for migraine prevention. In terms of acute therapy, both the serotonin (5-HT) 5-HT_1F receptor agonist (lasmiditan) and small molecule CGRP receptor antagonists (ubrogepant and rimegepant) received FDA approval. Despite this success, there is little time to rest on our laurels, as there remains a need to generate a greater understanding of all anti-migraine therapies, to include their clinical mechanisms of action and their potential unwanted side effects/risk factors. Unfortunately, a common theme has emerged for several drugs including triptans, ergotamine, caffeine, paracetamol (acetaminophen) and opioids (1–3), whereby their excessive use leads to an increased risk of increasing migraine frequency and the development of a chronic state termed medication overuse headache (MOH) (4). Importantly, MOH appears a particular characteristic of headache disorders, with people who have a personal or family history of headaches most vulnerable, suggesting a potential genetic component (5).

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. 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. 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).

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).

Taken together, the results highlight an extremely interesting differential MOH risk-profile for these novel therapies. 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). Finally, triptans and ditans both act presynaptically on the trigeminal afferents to reduce CGRP release (18,19), which is in keeping with the neuroplastic changes identified in trigeminal afferents following their persistent exposure (8,20). CGRP receptor antagonists or monoclonal antibodies targeting CGRP or the CGRP receptor act postsynaptically to dampen receptor activation and, as such, have limited impact on the underlying signalling if the system is not in an active state.

Irrespective of the potential differential mechanisms, the results highlight an important divergent MOH risk that can immediately influence clinical practice and inform patient education, when combined with drug efficacy (21). The preclinical and preliminary clinical evidence supporting a lower MOH-risk profile with the small molecule CGRP receptor antagonists offers an interesting tool to explore these potential shared and divergent mechanisms underlying variable MOH-risk profiles. The exploration of this will be boosted by several studies that have aided in our understanding of the underlying mechanisms of MOH, with a clear focus on reducing the burden of this highly disabling condition in those already blighted by primary headache disorders.