Non-invasive Vagus Nerve Stimulation (nVNS) as mini-prophylaxis for menstrual/menstrually related migraine: an open-label study

Menstrual migraine (MM) without aura is defined as the exclusive occurrence of attacks on days −2 to +3 of menstruation in at least 2 of 3 consecutive menstrual cycles according to the International Classification of Headache Disorders, 3rd edition (beta version) (ICHD-III beta) appendix (i.e., requires further validation), and menstrually related migraine (MRM) without aura is also characterized by the occurrence of attacks on other days of the cycle [1]. More than 90 % of women with migraine attacks during menstruation have MRM [2]; the estimated prevalence among migraineurs has varied from 0.85 to 14.1 % for MM and from 3 to 71.4 % for MRM [3]. These conditions are believed to be a result of fluctuating oestrogen levels; steady or elevating levels are associated with a protective effect, whereas abrupt oestrogen withdrawals are associated with precipitation of migraine attacks [2, 4]. In the late luteal phase of the menstrual cycle, decreased oestrogen levels have been observed, which lead to serotonin declines and are likely responsible for the triggering of MM/MRM attacks just prior to menses [2, 4].

No acute or prophylactic therapies are currently approved specifically for the treatment of MM/MRM in the European Union or the United States [5, 6]. Acute treatments used for these conditions are the same as those used for non-menstrual migraine and include triptans, non-steroidal anti-inflammatory drugs (NSAIDs), and ergot derivatives [2, 6]. Prophylaxis comprises short-term and continuous treatments [2]. Short-term prophylactic therapies are administered only during the time of need (e.g., perimenstrually) and include triptans, oestrogen, and naproxen, whereas continuous prophylactic options such as hormonal contraceptives provide ongoing exposure to the treatment [2]. A systematic review of MM/MRM clinical trials indicated that evidence supporting most categories of prophylactic MM/MRM treatments is generally weak [6]. Clinical studies of triptans represent the strongest evidence to date for acute and preventive MM/MRM treatment, which supports almotriptan, naratriptan, sumatriptan, and zolmitriptan as acute therapies and frovatriptan, naratriptan, and zolmitriptan as preventive therapies [6].

Despite the general safety and tolerability of triptans with appropriate patient selection [2, 7, 8], the MM/MRM population may have unique challenges related to the adverse events (AEs) associated with these treatments. Compared with non-menstrual migraine attacks, MM/MRM attacks are generally longer lasting, more debilitating, more prone to recurrence, and less responsive to therapies such as triptans [9, 10]. Results from a large study showed that 44 % and 48 % of migraineurs were dissatisfied with triptan-associated tolerability and general/work-related functional ability, respectively [7], and these concerns may be even more prominent in the relatively treatment-refractory MM/MRM population [10]. Menses is generally considered to be a period of inherent discomfort [11], and the repeated treatments required to mitigate the effects of MM/MRM could further exacerbate the level of discomfort while providing only minimal response [10, 12]. Evidence-based guidelines for migraine suggest limiting the use of triptans to 2 headache days per week to reduce the risk of rebound or medication-overuse headache [8], and frequent use of these agents may lead to misuse/overuse and has been significantly associated with the development of chronic migraine [13, 14]. Thus, the prophylactic administration of triptans over the course of several days during menstruation coupled with the potential need for acute triptan therapy in women with MM/MRM could complicate the condition [12, 13]. Patients may be unwilling to accept the AE burden and/or potential complications of adhering to monthly prophylactic MM/MRM therapies [15], defining a need for alternative treatment options among this population.

Non-invasive vagus nerve stimulation (nVNS) (gammaCore®; electroCore, LLC; Basking Ridge, NJ, USA) provides neuromodulation that transfers electrical impulses transcutaneously to the cervical branch of the vagus nerve. In 4 open-label ≤ 12-week studies, nVNS demonstrated efficacy, safety, and tolerability as an acute/prophylactic therapy for migraine and chronic cluster headache [16‐19]. Based on the treatment benefits observed in previous studies and the potential for reducing medication overuse and medication-associated AEs [16], we evaluated nVNS used as mini-prophylaxis for MM/MRM in this 24-week study of 56 subjects.

To our knowledge, this study is the first to evaluate the effects of a neuromodulation device for the treatment of MM/MRM without aura. Primary end point results demonstrated that prophylactic nVNS administered from −3 days before estimated onset of menstruation through +3 days after the end of menstruation (a total of 10 to 14 days of treatment per month) for 3 cycles provided an average decrease of 2.4 MM/MRM days per month (~33 %), which exceeds the MID of 1 headache day established for this end point [24, 25]. The change in number of headache days from baseline is among the few headache-symptom measures with an established MID, and this MID has been associated with significant effects on health-related quality of life [24, 25]. The assessment of MM/MRM days for the primary end point is clinically relevant to patients and treating physicians, acknowledging that we did not concurrently assess the frequency of individual attacks in this initial study of MM/MRM prophylaxis. The reduction in MM/MRM days was accompanied by significant and clinically meaningful reductions in analgesic use and functional disability. Although this prophylactic study was not intended to evaluate the efficacy of nVNS in the acute treatment of attacks, a modest decrease in pain intensity was observed for the attacks that were not prevented. As several end points in this study represent monthly averages during each 3-month study period, the possibility for improvements in actual monthly MM/MRM outcomes with nVNS treatment over time warrants further evaluation.

Study limitations include the open-label, single-arm study design and the potential for inaccurate subject predictions of menses onset. The open-label study design likely contributed a placebo response to the treatment, as seen in other therapeutic migraine studies [18, 26]. In this study, the actual treatment effect of nVNS cannot be separated from the potential placebo effect because of the lack of a sham control group. On the basis of the ease of use and lack of AE concerns associated with nVNS in the current study, the device appears to have a favourable risk-benefit profile in MM/MRM that is appropriate for further evaluation. As in any MM/MRM study of prophylaxis, imprecise treatment initiation due to inaccurate predictions of the start of menses may have affected the observed results [12] but is likely reflective of real-world use; nVNS has the flexibility to be used outside the perimenstrual period (e.g., before or after menstruation) without increasing the potential for medication-related AEs and complications.

The relative refractoriness of MM/MRM attacks to pharmacologic treatments currently available (but not specifically approved) for the condition [10] may be related to the complexity of the relationship between migraine and oestrogen and the brain’s sensitivity to fluctuations in hormones that cross the blood–brain barrier [27]. Chronic exposure to oestrogen has been suggested to enhance susceptibility to migraine by promoting increased numbers and excitation of glutamatergic neurons [28]. Paradoxically, oestrogen withdrawal is associated with the occurrence of MM/MRM attacks [27]. The efficacy of nVNS in the treatment of migraine may be related to the suppression of excessive extracellular levels of glutamate [29]. In MM/MRM, prophylactic nVNS may exert its anti-glutamatergic mechanistic actions directly via the trigeminal nociceptive pathways of women who are susceptible to oestrogen-related attacks.

The efficacy of prophylactic medications used for MM/MRM has been demonstrated in clinical trials [30, 31] but may be limited by oestrogen level declines and by concerns related to rebound headaches, practicality, and safety. Managing optimal oestrogen levels is challenging for many clinicians, especially in the context of orally administered drugs, because of the complex changes that occur throughout the menstrual cycle [27]. Randomised, double-blind, placebo-controlled MM/MRM studies have suggested that prophylactic triptan and perimenstrual oestrogen therapy may lead to post-treatment or rebound migraine attacks [32‐34], possibly reflecting a delayed abrupt decrease in oestrogen levels upon medication discontinuation or a nonhormonal occurrence of end-menstrual migraine (i.e., related to blood loss and transient relative anaemia) [35]. Rebound attacks were not observed after nVNS discontinuation in the current trial or in previous studies of primary headache conditions [16‐19], but additional studies are needed to rule out the potential for post-nVNS migraines. Patients with MM/MRM may be reluctant to accept these and other AE-related consequences of preventive triptans given the potentially modest therapeutic gain [12, 15, 32]. The oral anticonvulsant topiramate has been shown to be effective in the prevention of MM attacks but does not appear to reduce attack severity or duration [36]. In addition, topiramate may require several months of daily administration to achieve its potential benefits and may increase the risk for serious adverse events [36, 37]. Non-invasive vagus nerve stimulation is a practical nonpharmacologic option that does not affect oestrogen levels, interact with acute medications, or increase cardiovascular disease risk. Results of the current study suggest that prophylactic nVNS reduces medication use in women with MM/MRM, thereby possibly mitigating the future risk of medication overuse headache and chronic migraine [13, 16, 38].

Non-invasive vagus nerve stimulation may serve as an effective therapeutic option with no safety or tolerability concerns for MM/MRM prevention and may mitigate the risk of medication-related AEs and complications, rebound headaches, and potential drug interactions that are highly relevant among this population. Prophylactic use of nVNS for up to 14 days per month is practical and appears to provide a clinical benefit in MM/MRM while decreasing the need for analgesic medications, consistent with results of previous nVNS studies of other primary headache disorders [16‐19].

This study suggests that mini-prophylaxis with nVNS is an effective treatment that reduces the number of MM/MRM days and acute analgesic use for subjects with MM/MRM without adding any treatment-related safety or tolerability concerns. The current study also expands the body of evidence regarding this condition, for which there are no specifically approved therapies. As the first neuromodulation technique evaluated in patients with MM/MRM, nVNS may offer an important new option for effectively treating the condition while mitigating the monthly perimenstrual AE burden and potential complications of pharmacologic medications. Randomised controlled studies are needed to validate these results.