Introduction
Migraine is a highly prevalent chronic neurological condition, characterized by attacks of headache and associated symptoms including photophobia, phonophobia, nausea, and/or vomiting [
1,
2]. A recent epidemiological study suggests that approximately 21% of women and 11% of men in the USA currently suffer from migraine headaches, affecting about 40 million people in the USA, including 5 million children and adolescents [
3]. More than 4 million emergency department visits [
2], 50,000 inpatient hospitalizations [
4], and 4.3 million office visits [
3] are attributable to migraine each year in the USA. Migraine experiences vary substantially by person, with costs and burden of illness concentrated in patients with the most frequent and intense attacks (high-frequency episodic and chronic migraine).
Migraine affects individuals from their childhood or youth, through their most productive adult years, until around retirement age or even beyond, causing significant disruptions in daily activities and work performance [
5]. While various pharmacological treatments are available in the USA, many patients struggle with adherence as a result of intolerance of side effects, lack of efficacy, risk of chronification, and/or high cost [
6‐
10].
The American Headache Society (AHS) consensus statement suggests over-the-counter drugs such as nonsteroidal anti-inflammatory drugs (NSAIDs) and a few families of prescribed drugs including generic oral triptans as first-line acute treatments of migraine [
11]. However, these current first-line acute treatments do not provide a sustainable solution for many patients with migraine for several reasons. First, they are not universally effective in managing headache and associated symptoms. About 30–50% of patients prescribed triptans have insufficient response [
12,
13]. Second, first-line treatments can have intolerable adverse effects [
14]. Third, these medications are not appropriate for all patients with migraine because of contraindications from other diseases or medications [
15]. Fourth, triptans, some NSAIDs, and other acute medications may cause chronification of migraine and/or medication overuse headaches (MOH) [
16,
17], which results in more frequent headaches and may result in the need for detoxification from the overused medications [
18]. Therefore, their usage is limited and patients may require additional acute treatments [
19]. Fifth, some patients prefer not to take medications [
20]. Sixth, not all treatments are approved or desirable for children and adolescents [
21] and other sensitive populations (e.g., pregnancy) (see references in [
22,
23]). On the basis of these factors, many patients struggle with adherence to pharmacological acute migraine treatments, and up to 60% of triptan users discontinue treatment within the first year of usage [
24]. Insufficient adherence to treatment also increases the risk for disease complications [
25]. Given the chronic nature of migraine over many years of patients’ lives, there is a pressing need for tolerable, safe, and effective treatments that can be used for long durations (years) to help individuals regain daily function and relief from pain.
Remote electrical neuromodulation (REN) is a smartphone-controlled wearable technology, US Food and Drug Administration (FDA)-cleared for the acute and/or preventive treatment of migraine in patients 12 years of age or older. By stimulating arm nociceptive receptors, the device turns on an endogenous pain mechanism called conditioned pain modulation (CPM), which initiates a global pain inhibition process generated by the brainstem.
REN was shown in numerous studies to be a safe and effective treatment for the acute treatment of migraine in adults with episodic migraine [
26‐
28] or chronic migraine [
29,
30], and in adolescents [
31]. Recently, its safety, efficacy, and cost-effectiveness were shown in preventing migraine [
32,
33]. Moreover, previous real-world studies show that when using REN many adult patients with migraine [
34,
35] and adolescent patients with migraine [
22] reported a reduction in their utilization of acute medications.
REN presents several potential advantages as a treatment option for the acute treatment of migraine compared to pharmacological treatment. It is a non-invasive, targeted treatment. Unlike pharmacological treatments, REN does not have any systemic side effects and has a very low risk of adverse events. Additionally, REN can be customized to meet the individual needs of each patient by personally modifying treatment intensity and has no risk of drug–drug interactions or abuse. REN can be used either as a standalone treatment or in combination with other treatments according to patients’ needs. These factors highlight the potential benefits of REN as a safe and effective treatment option for acute treatment of migraine.
Given the chronic nature of migraine disease and that most patients with migraine require long-term treatment over years, the evaluation of treatments over an extended period of time is crucial. This study aims to examine REN’s long-term safety, efficacy, and usage. The hypothesis is that REN provides a safe, efficacious, and stable treatment over 1 year of consecutive use.
Discussion
The real-world evidence presented in this study shows that remote electrical neuromodulation (REN) is safe, effective, and has a high level of patient adherence and tolerance for the treatment of migraine over the long-term course of 12 months of consecutive use, confirming the stated study hypothesis.
First, this study shows that REN is a safe long-term treatment option, having a low incidence of device-related adverse events (1.96%) and no severe dAEs. The most common side effects were local paresthesia or skin sensitivity in the area of the device, without any systemic events. All of the patients who reported dAEs continued treating with REN after their reports, and the dAEs were distributed over the year indicating that even in the case of dAEs, the users found the treatment tolerable, with treatment benefits overcoming the discomfort from the dAEs.
Second, patient compliance with REN therapy remained consistent over 1 year, with a substantial number of patients utilizing the device throughout a year. While inclusion criteria required consecutive treatment over 12 months, there was no selection criterion on the actual number of treatments per month beyond the constraint of at least one treatment per month for each of the 12 consecutive months. Maintaining a stable level of treatment utilization and thus adhering to treatment over time is a complicated issue in migraine, for both acute treatment and preventive treatment.
Third, REN was effective in providing long-term benefits for the majority of patients over 1 year, in all efficacy endpoints measured. Nearly two-thirds of patients experienced consistent efficacy in at least 50% of their treatment, including reduction in pain 2 h following REN treatments (74.1%), functional disability relief (70.2%), and disappearance of least one associated symptom (73.5%) over the course of a year. The most common associated symptom is photophobia, reported by 46 to 114 patients per month over 12 months, while the least common associated symptom is nausea/vomiting, reported by 29–78 patients per month. While nausea/vomiting is less common, it is the associated symptom most benefiting from REN treatment with an annual average of 70.8% reporting its disappearance at 2 h post treatment, followed by phonophobia (52.7%), and photophobia (43.2%).
Moreover, 26.0% of the patients achieved consistent pain freedom during REN treatments and 33.7% achieved functional disability freedom. These results are clinically meaningful, given that pain, associated symptoms, and functional disability are key factors in the overall burden of migraine and significantly impact patients’ quality of life and ability to function [
36].
Commonly used migraine medications for the acute treatment of migraines include NSAIDs and triptans. The latter constitute the most common first-line physician-prescribed acute treatment for migraine, yet up to 60% of users abandon their triptan treatment within the first year of usage [
24], due to lack of adherence caused by intolerability to AEs and/or lack of efficacy [
37]. On the other hand, those who do continue using triptans frequently and for long time periods are at risk for medication overuse headache (MOH) and migraine chronification [
9,
16]. Widespread adverse effects of triptans include nausea, vomiting, dizziness, somnolence, and chest tightness [
38,
39]. Long-term use of NSAIDs can lead to gastrointestinal bleeding [
40], renal dysfunction, and cardiovascular events. In the past, opioids were sometimes used for the acute treatment of migraines, but their long-term use is generally discouraged because of the risk of dependence and addiction [
41]. Other reported adverse effects of opioids include nausea, vomiting, constipation, respiratory depression, and overdose leading to death.
Open-label post-marketing surveillance studies on long-term effects of treatment with new migraine drugs are recently emerging, reporting treatment-emergent adverse events (TEAEs). TEAEs from 12-month treatment with lasmiditan [
42,
43] include dizziness, paresthesia, fatigue, nausea, vertigo, somnolence, and asthenia (ranging between 5.8% and 35.7% of patients, and 0.8% and 9.5% of attacks). Most TEAEs were mild or moderate in severity, with 0.9% of participants experiencing serious TEAE. Nearly a third of the study participants did not complete the open-label extension, mostly because of study withdrawal, lack of efficacy, and adverse events. While the authors report no new safety concerns during this long-term study, patients are not allowed to drive for 8 h after lasmiditan dosing based on previous trials [
44], and the results from this 1-year study add to the existing safety concerns and intolerability associated with lasmiditan (dizziness, somnolence and paresthesia, and rare cases of serotonin syndrome [
45,
46]).
The long-term safety, tolerability, and efficacy of small-molecule antagonists of calcitonin gene-related peptide (CGRP) receptor called gepants were assessed in open-label studies of 52 weeks in adults with migraine. Both rimegepant 75 mg every other day for preventive treatment of migraine plus as-needed for acute treatment of migraine in adults [
43], and once-daily orally administered atogepant 60 mg [
47] were associated with consistent reductions in monthly migraine days (MMDs). However, TEAEs were not rare during the 52 weeks of treatments, including upper respiratory tract infection, nasopharyngitis, and back pain (4.3–7.1% of patients) from rimegepant, and upper respiratory tract infection, constipation, nausea, and urinary tract infection from atogepant (6.3–10.3% of patients). Serious TEAEs were reported in 4.4% for atogepant. Discontinuation rate due to AEs/TEAEs was 2.8% and 5.7% for rimegepant and atogepant, respectively [
43,
48].
Evidence for long-term effects of monthly injectable monoclonal antibody preventive medications (mAbs) targeting CGRP are also emerging. Spontaneous adverse events reported to the US FDA Event Reporting System (FAERS) included disproportionate reporting of significant alopecia signals, with 3.26% cases of alopecia [
49‐
51].
Participants in the current study performed an average of 8.05 ± 0.44 (mean ± SD) REN treatments per month, suggesting they should be offered migraine prevention treatment, as per the consensus statement of the American Headache Society (AHS) in 2021 [
13]. The long-term evidence presented here on REN from 12 consecutive months should therefore be interpreted in light of, and compared to, evidence from other treatments for the acute and/or preventive treatment of migraine, according to the current indication of the Nerivio
® REN device.
While this is the first study to assess long-term treatments with REN, there are some study limitations that should be acknowledged. First, the users included in this analysis constitute a subset of all REN device users. As in any sub-analysis, there is a concern for selection bias. In this case, users who did not treat consecutively for 1 year were not included in the study. We therefore excluded users who did treat for at least 1 year; however, they did not treat in each and every calendar month of the year. Such a scenario could result from either infrequent attacks or from using a combination of treatments (having a “migraine toolbox”) and deciding which treatment(s) to use for each attack. Some users excluded from this analysis are also those who discontinued treating with REN, and therefore did not meet the 12 consecutive treatment months criterion. Discontinuation of REN could result from lack of efficacy for some patients. Pain relief from various acute migraine treatments is around 60%, and despite REN being on the higher end with 66.7% of the patients reporting pain relief in the pivotal REN randomized controlled study of acute treatment of migraine, by Yarnitsky et al. [
28], there is no one treatment that works for all patients with migraine. However, our only selection criterion was at least one treatment per month, for 12 consecutive months, without any additional constraint on the number of monthly treatments, safety, or efficacy.
Second, the current study did not incorporate additional outcomes such as standardized migraine questionnaires to measure the effects of REN on patients’ quality-of-life, which could show a wider effect than focusing mainly on measures of effectivity. However, since this is a real-world evidence study and not a clinical trial, there is a limit to the number of questions patients can be asked and expected to answer on a regular basis via a commercial app (i.e., every treatment). Standardized migraine questionnaires can be embedded in the app and users may be prompted to answer them periodically to explore associations of REN long-term use with quality of life and with psychiatric comorbidities in future studies.
Third, although 1-year consecutive use is considered a long period to track patients, studies looking at longer durations could benefit the medical and patient communities. This is true for all types and families of migraine treatments, pharmacological and devices alike. However, REN has the benefit that usability information regarding each and every treatment performed is automatically registered into the Nerivio® app and database, even without the need for patients to actively record this data, making it more accurate than information from patient or pharmacy-reported drug usage. Having validated data provides a strong benefit, and future studies can be conducted to track patients over even longer time periods.