Migraine is a common disabling primary headache disorder with high socio-economic burden and personal impact. It typically occurs with recurrent attacks of pulsating quality and unilateral location, associated with autonomic symptoms, such as nausea, photophobia, and phonophobia, as defined by the International Classification of Headache Disorders, 3rd edition (ICHD-III) (1). Migraine etiology and pathophysiological mechanisms are complex and not fully understood. It is well-known that various triggers may precipitate migraine attacks, such as changes in lifestyle, physical activity, diet, and hormones and sleep disturbances (1, 2).

Increasing evidence suggests that sleep and migraine share a multifaceted and bidirectional relationship. Patients with migraine frequently report poor sleep quality and excessive daytime sleepiness (EDS). On the other hand, sleep disruption can be a trigger of migraine attacks, which often benefit of sufficient restful sleep (3–6). In clinical settings, physicians ordinarily consider sleep as one aspect of migraine treatment, selecting medications with sedative side effects, in an attempt to improve sleep as a protective factor against migraine attacks.

Several polysomnographic studies identified a decreased sleep efficiency (SE) and alterations in sleep architecture in patients with migraine when compared to healthy subjects (7–9). Furthermore, among adult patients with migraine, a high prevalence of sleep disorders has been found and can range from insomnia to more specific disorders, such as Restless Legs Syndrome (RLS) and parasomnias (10–15). Together, these findings suggest to consider migraine and sleep problems as conditions with common pathophysiologic elements that still are partly obscure. Few previous studies evaluated sleep changes in patients treated with migraine-preventive treatments by means of questionnaires (16–19). For example, a recent study investigated possible sleep changes in patients with chronic migraine effectively treated with a greater occipital nerve block, showing a significant improvement in scores of different clinical questionnaires evaluating sleep after 3 months of treatment (19). However, more extensive clinical and polysomnographic trials for this purpose are not currently available.

In the last years, the development of new monoclonal antibodies toward calcitonin gene-related peptide (CGRP) or its receptor has opened an innovative therapeutic scenario. Erenumab, in particular, was the first anti-CGRP receptor antibody employed in the clinical practice for migraine prevention (20).

The aim of the present study was to investigate possible sleep changes in patients with episodic and chronic migraine treated with erenumab, assessed with validated sleep questionnaires and polysomnography (PSG) performed at baseline, after 3 and 12 months of treatment.

To our knowledge, this is the first polysomnographic study that evaluated objective sleep changes in patients who were treated with MPMs. A recent meta-analysis that includes trials based on PSQI and PSG demonstrated poorer sleep quality and a lower percentage of REM sleep in patients with migraine when compared to healthy controls (9). In our patients, we found a higher SE after the treatment with erenumab. This result was obtained through a significant reduction of wake time duration, WASO, and number of awakenings per hour, with unaltered TST and duration of different sleep stages, indicating a higher sleep stability after erenumab treatment. Particularly, we observed a weak positive relationship between the improvement in objective SE and a better response to the treatment with erenumab. This association, however, did not reach a clear statistical significance probably due to the limited sample size. Subjective measures of sleep quality (PSQI and ESS questionnaires) corroborated home-PSG data. Our patients reported to sleep better after only 3 months of treatment, reaching a significant decrease in EDS and daytime dysfunction after 12 months.

Duman et al. used for the first time the PSQI questionnaire and testing the subjective effects of migraine prophylaxis on sleep (16). In that study, patients were treated with propranolol or amitriptyline for 12 weeks, after which a significant improvement in sleep quality was observed in both groups, with greater results in those with initial PSQI scores ≥6 taking amitriptyline. These molecules exert central effects on sleep architecture by reducing REM sleep. In particular, it is well-known the sleep-promoting role of amitriptyline by modulating sleep-wake cycle neurotransmitters (36–38). Erenumab, in contrast, does not cross the blood-brain barrier (BBB) (39, 40), and thus a direct action on sleep central pathways is not expected. For this reason, the observed sleep changes can be attributed to migraine improvement itself. In fact, our PSG results occurred concurrently with erenumab effectiveness in reducing migraine frequency, severity, duration of attacks and improving the response to symptomatic medications and the disability related to migraine attacks. We also observed a significant improvement in patients' mood and self-reported quality of life. In this respect, our data are consistent with the increasing amount of literature demonstrating erenumab success in migraine prevention, with concurrent benefits on living standards and mood (17, 18, 20, 41–44). Real-life data support erenumab safety and tolerability. We detected infrequent and mild AEs, obtaining full adherence to the treatment. Compared to information in the Summary of Product Characteristics (45), we found a higher frequency of constipation (20.7%); however, none of the patients dropped out by reason of side effects, and constipation tended to dissipate over time, as described elsewhere (41, 42, 46).

Erenumab was the first monoclonal antibody approved by the U.S. Food Drug Administration and the European Medicines Agency in May 2018 for the treatment of chronic and episodic migraine (45, 47). Its efficacy is mainly attributed to the blockage of CGRP receptors expressed in the trigeminal system. CGRP is a vasoactive neuropeptide released from trigeminal ganglia cells at the level of intracranial cerebral and dural blood vessels, causing vasodilation and neurogenic inflammation and playing an important role in sustaining a state of central sensitization during migraine attacks (39, 40, 48).

Migraine and sleep share a complex bidirectional relationship, which still remains poorly understood. At least in part, they have common anatomic structures, neural pathways, signaling neurotransmitters, and neuropeptides. Both the brainstem and the hypothalamus play a central role in migraine and sleep-wake cycle regulation, particularly involving dopamine, serotonin, adenosine, melatonin, orexin, and pituitary adenylate cyclase-activating polypeptide (PACAP) as possible mediators of this relationship (49–51).

Patients with migraine were found with low serotonin levels during interictal periods and high mobilization of serotonin intracellular stores in the early phase of the attack, promoting wakefulness, disrupted sleep, and REM sleep reduction (52, 53). Instead, inhibition of serotoninergic neurons of the dorsal raphe nucleus in the brainstem is essential for the transition from NREM to REM sleep (54). Dopaminergic A11 hypothalamic nucleus, implicated in the prodromal symptoms of migraine, facilitates arousals and wakefulness and could explain the high prevalence of RLS in migraine patients (51). The dopamine neurons of the periaqueductal gray are also involved in wake promotion by inhibiting the hypothalamus, and in pain signaling between the trigeminocervical complex (TCC), the hypothalamus, and the thalamus. Noradrenergic neurons in the locus coeruleus work in concert with dopaminergic and serotoninergic systems of the brainstem as pain modulators and facilitate wakefulness (50, 55–57). Moreover, a possible association between the therapeutic effect of sleep in migraine and the glymphatic system (a little-known waste removal mechanism working during sleep in the central nervous system) has been hypothesized; its dysfunction has been also proposed as a possible mechanism in the development of chronic migraine (49, 58).

Finally, PACAP is emerging as an important molecular target in the pathophysiology of migraine. Similar to CGRP, it works on the nociceptive neurons of the TCC promoting vasodilation and increased cerebral blood flow during migraine attacks (59, 60). Recent evidence suggests that PACAP also plays an important role in the hypothalamus for sleep homeostasis. In animal models, it seems to act on sleep-related neuroendocrine changes, through the modulation of sleep-wake cycle pathway, clock genes expression, and melatonin synthesis (61–65). Despite current knowledge, the pathogenic correlation between regulation of sleep, migraine, and circadian rhythm remains largely unclear. PACAP and CGRP represent significant migraine triggers, but little is known about their circadian variability. Again, nothing is known about possible indirect central effects due to peripheral modulation of CGRP with erenumab or other anti-CGRP monoclonal antibodies.

This study has several limitations. The first one is represented by the small size of the sample, due to the strict enrollment criteria, and the even smaller size of the group that completed the 12-month follow-up. Sample reduction at 12 months was determined randomly, mainly because of limited hospital access during the COVID-19 pandemic and, rather, it was not influenced by factors such as patients' sleep quality or therapeutic response to erenumab. Despite some disadvantages when compared to laboratory recordings, home-PSG was a more cost-effective alternative, easy to perform during the COVID-19 pandemic, and enabled patients to sleep in their habitual setting. Another issue is the absence of a control group in the study design, although it has to be considered that since erenumab does not pass the BBB, we studied the impact of migraine improvement on sleep, rather than the direct effect of the drug on patients' sleep. Moreover, we are aware of the fact that a subgroup of patients continued to take other MPMs with a potential influence on sleep during the treatment with erenumab (i.e., antidepressants, antihistamines, and beta-blockers). In order to prevent a possible interference of these drugs on our results, however, other MPMs were not modified during the 2 months preceding the enrollment and for the following 3 months. Interestingly, during the second study period, we confirmed a global improvement in sleep quality although antidepressants had been discontinued in several cases. This gives more strength to the positive effect of erenumab on sleep, since this effect was obtained despite the withdrawal of other sleep-promoting drugs. One last point to consider is that most of the patients selected, due to the enrollment criteria, already had a quite normal SE at baseline. This precondition explains the mild but significant extent of results, since an impressive change in sleep quality was not expected.

Future studies on larger groups will be needed in order to perform further analyses, for instance, to evaluate whether there is a linear correlation between migraine improvement and sleep changes, or whether results are influenced by the treatment dose or the type of monoclonal antibody used. Explaining common pathophysiologic mechanisms between migraine, sleep homeostasis, and sleep disorders still remains very challenging.

In conclusion, erenumab is effective and safe in migraine prevention, demonstrating consequent benefits on both subjective sleep quality and sleep architecture. After starting the treatment, our patients significantly increased their SE, resulting in better life quality, improved daytime functioning, and reduced somnolence levels. Our findings support the growing body of evidence suggesting a common undelying pathophysiology for migraine and sleep disorders. Basic research into neuropeptides and their pathways appear to be crucial to improve our understanding of this fascinating relationship and developing new therapeutic solutions.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Comitato Etico Unico Regionale, Friuli Venezia Giulia (CEUR FVG), Italy. The patients/participants provided their written informed consent to participate in this study.

GP, SP, and MV conceived the study and its design. GP, SP, and AS performed the acquisition and interpretation of data. GP and SP drafted the manuscript. AN contributed to the analysis and interpretation of data. AN, AS, GG, and MV substantively revised the manuscript. All authors made substantial contributions to conception, study design, data collection, and approved the final manuscript.

GP and SP received travel grants from Novartis and Eli Lilly. AS received travel grants from Novartis. MV received travel grants, honoraria for scientific contributions or clinical investigation studies from Novartis, Teva Pharmaceuticals, and Eli Lilly. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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