Abstract and Introduction
Objective: To evaluate the efficacy and safety of concurrent non-invasive stimulation of occipital and trigeminal nerves in acute treatment of migraine with or without aura.
Background: Non-invasive neuromodulation devices stimulating a single peripheral nerve or anatomic distribution are routinely used by patients with migraine refractory to the first-line drugs or those who opt out of pharmaceutical treatment. Concurrent occipital and trigeminal stimulation was described in an invasive setting, and its safety cost outweighed its efficacy gain. This study evaluated the efficacy and safety of an external concurrent occipital and trigeminal device in acute treatment of migraine.
Design and Methods: This was a randomized, sham-controlled, double-blind, multi-center trial. Patients 18 years of age or older who met the International Classification of Headache Disorders (2018) diagnostic criteria for migraine with or without aura, reported 1–6 migraine attacks per month, and other headaches no more than 6 days per month were enrolled. Of 131 intention-to-treat participants (67 and 64 in the active and sham groups, respectively), 109 (50 and 59 in the active and sham groups, respectively) treated at least one migraine episode. Reduction of migraine headache (pain relief) 2 h after treatment initiation was the primary efficacy endpoint. Pain relief at 1 h, and pain freedom and relief in most bothersome symptom at 2 h after treatment initiation were the secondary endpoints. Freedom from most bothersome symptom at 2 h and sustained pain freedom 24 h after treatment initiation were among the exploratory endpoints.
Results: Sixty percent of participants (30/50) in the active arm reported pain relief at 2 h after initiation of the first eligible treatment (primary outcome) compared to 37% (22/59) in the control arm (difference, 23%; 95% confidence interval [CI], 2%–41%; p = 0.018). Pain freedom at 2 h without rescue medication was reported by 46% (23/50) of participants in the active arm and by 12% (7/59) of participants in the sham arm (p < 0.001). Pain freedom 2 h after the treatment and, subsequently, at 24 h, was reported by 4.25 times more participants in the active arm (36%; 18/50) than in the sham arm (8%; 5/59). The 28% difference was statistically significant (95% CI, 1%–43%; p < 0.001). A 4.25-fold difference was also observed comparing the proportion of participants free from pain and most bothersome symptom 2 h after the stimulation (47% [17/36] and 11% [5/45] in the active and sham arms, respectively; 95% CI, 14%–54%; p < 0.001). Adverse events were not serious or severe. All study-related events resolved without treatment.
Conclusion: External concurrent occipital and trigeminal neurostimulation is a well-tolerated, safe, and effective migraine treatment that provided a fast and durable relief and freedom from migraine pain and associated symptoms in a randomized setting. The observed safety and performance suggest external concurrent occipital and trigeminal neurostimulation is a viable alternative to the currently available acute migraine treatments.
Trial Registration: clinicaltrials.gov identifier NCT03631550.
Migraine is the second most common neurologic disorder affecting more than 1 billion people worldwide.[1,2] It is two to three times more likely to be experienced by women, with prevalence peaking at 35–39 years of age in both sexes.
Migraine spares no aspect of everyday life, and substantial impairment is registered in professional, academic, and social activities of people with migraine.[5,6] Often a debilitating condition, migraine is a prominent contributor to the global neurological disability-adjusted life years, second only to stroke. It is also the seventh highest cause worldwide of years lost due to disability, third in both sexes under 50.
The underlying biology and pathophysiology pathways of migraine are complex, which may explain the considerable rate of failure of the current first-line acute therapy agents, such as triptans, to provide relief of headache, the main migraine symptom. Severe baseline headache as well as photophobia, nausea, and phonophobia, the three most bothersome symptoms (MBS) of migraine, predict poor response to triptans, and nausea may be further exacerbated by these agents.[12–14] Switching to a different drug, class, or formulation may benefit some people. However, a large fraction of patients remain refractory to pharmacological treatment, contraindications prevent use of certain agents in some people, and a minority of patients may experience uncommon but potentially harmful treatment intolerance.[15–17] Treatment alternatives are warranted.
Use of unifocal non-invasive neuromodulation devices is gaining acceptance in migraine care[18–27] and a non-invasive supraorbital trigeminal stimulation device (external trigeminal nerve stimulator [e-TNS])[18–20] was cleared by the US Food and Drug Administration (US FDA) for acute and preventive migraine treatment. Concurrent trigeminal and occipital stimulation was described only in an invasive setting.[28,29] Although the potential gain in efficacy was evident in the early clinical work and seemed to hold promise for further research, the discouragingly high rate of complications associated with the invasive nature of the procedure may have dampened the enthusiasm of the technology developers.
The non-invasive Relivion MG system (Figure 1), US FDA cleared and CE-marked following the study described below, applies non-invasive external concurrent occipital and trigeminal neurostimulation (eCOT-NS) in a bid to harness the potential strengths of multifocal neural action and to mitigate the weaknesses of the invasive approach. In this, randomized, double-blind, sham-controlled, multi-center Relivion in Migraine (RIME) study, efficacy and safety of the eCOT-NS device were evaluated in adults with migraine with or without aura. The primary endpoint was pain relief 2 h after treatment initiation. We hypothesized that the proportion of patients reporting pain relief level 2 h after treatment initiation will be higher in the active arm. The trial also assessed pain freedom and MBS absence 2 h after treatment initiation[32–34] in secondary and exploratory analyses, respectively. Sustained response was evaluated at 24 h after treatment initiation. This publication contains the primary analysis of data collected in the trial.
External combined occipital and trigeminal neurostimulation (eCOT-NS) system. TCC, trigeminocervical complex; Channel 1, occipital stimulation channel; Channel 2 and Channel 3, trigeminal (supraorbital/supratrochlear) stimulation channels; numbers 1–6 represent the six electrodes. [Color figure can be viewed at wileyonlinelibrary.com]
Headache. 2022;62(8):989-1001. © 2022 Blackwell Publishing