Introduction
Migraine is one of the most prevalent and disabling neurologic diseases [
1], characterized by recurrent, often disabling, headache attacks associated with nausea, vomiting, photophobia, and phonophobia [
2]. Migraine attacks are frequently treated symptomatically with nonsteroidal anti-inflammatory drugs (NSAIDs), simple analgesics such as acetaminophen or aspirin, at times combined with caffeine, or with specific migraine treatments such as triptans and ergots [
3]; however, these pharmacological treatments may be ineffective, poorly tolerated, contraindicated, and if used to excess, may lead to medication overuse headache [
4,
5], migraine chronification [
6] and significant medical complications. Thus, there is a significant unmet need for new, effective and well tolerated non-pharmacological acute migraine therapies.
Remote electrical neuromodulation (REN) is a novel acute migraine treatment [
7], in which upper arm peripheral nerves (median and musculocutaneous) are stimulated to induce conditioned pain modulation (CPM) – a descending endogenous analgesic mechanism in which sub-threshold conditioning stimulation inhibits pain in remote body regions [
8]. A recent randomized, double-blind, sham-controlled, multicenter study has demonstrated that REN provides superior, clinically meaningful relief of migraine pain and complete pain freedom at 2 h post-treatment compared to sham stimulation. Specifically, active stimulation was more effective than sham stimulation in achieving pain relief (66.7% vs. 38.8%,
p < 0.001), pain freedom (37.4% vs. 18.4%,
p < 0.005) and relief of most bothersome symptom (MBS) (46.3% vs. 22.2%,
p < 0.001) at 2 h post-treatment. The pain relief and pain freedom superiorities of the active treatment were sustained for 48 h post-treatment [
9]. This study also demonstrated a low incidence of device-related adverse events which was similar between treatment groups (4.8% vs. 2.4%,
p = 0.49). All device-related adverse events, mainly reports of sensation of warmth and redness of the arm/hand, were mild, resolved within 24 h and did not require medical treatment [
9].
The current report describes an exploratory, within-subject, post-hoc analysis of the aforementioned study, aiming to examine whether REN is as effective as usual care and pharmacotherapies in the acute treatment of migraine. The effect of preventative medication on REN effectiveness was also assessed.
Discussion
The overall results demonstrate that REN is an effective acute treatment for migraine with non-inferior efficacy to usual care in general and to acute migraine pharmacological treatments specifically. REN, when compared to usual care or pharmacological treatments, proved to be as effective for pain relief and pain-free at 2 h post-treatment both in a single attack and across two attacks. Importantly, the efficacy of REN treatment did not depend on preventive medications use.
The significant need for new effective and safe acute treatments of migraine has led to the development of REN [
7]. A recent study has demonstrated favorable efficacy and safety outcomes of REN [
9], with a superior efficacy compared to other neuromodulation devices for acute migraine treatment [
10,
14]. This study has also shown that REN has a favorable tolerability profile compared with triptans [
15] and with new pharmacological agents, such as centrally acting serotonin (5-HT
1F) agonists that lack vasoconstrictor activity [
16]. The within-subject pos-hoc analysis presented in this paper extends these findings by providing direct evidence that the efficacy of REN is non-inferior to individual usual care and to current acute migraine pharmacological treatments. It appears that, at least in some patients, REN treatment may be even more efficacious than usual treatment in terms of pain relief at 2 h post-treatment. Further investigation is necessary to better characterize this population.
The current analysis also suggests that the efficacy of REN does not depend on whether or not patients are taking preventive medications. Therefore, REN may be effective for a wide range of people with migraine, as opposed to the single-pulse transcranial magnetic acute migraine neuromodulation device in which use of concomitant preventive drugs could affect its effectiveness [
14].
In the context of this study, usual care (which included either no pharmacological treatment or migraine specific and non-specific pharmacological treatments) and pharmacological treatment (which included any type of acute medication) provided a window into real-life management and experiences without producing expectations about the efficacy of a particular treatment approach. Although direct comparisons between this exploratory post-hoc analysis and randomized clinical trials must be made cautiously, pain relief and pain-free response rates across pharmacological treatments in the current study are in the same range as those reported in previous studies [
17,
18]. This suggests that our data reflects the clinical efficacy of pharmacological treatments observed in other randomized trials and that the results of the current study could be generalizable. A prospective head to head trial is required to further investigate this.
The current study has several limitations. First, this paper presents a post-hoc analysis and not a prospective head to head trial. Second, the small sample size precludes the comparison between different classes of pharmacological treatments (e.g. NSAIDS, acetaminophen, triptans) and thus all drugs were classified to one group of pharmacological treatments. This approach is supported by a review of comparative clinical trials of acute migraine treatments, indicating that in a clinical trial setting, the efficacy of migraine specific and non-specific acute mediations is comparable [
17]. Finally, our dataset of multiple attacks included different pharmacological treatments (or no treatment) for a single person, which decreases its scientific purity; however, this intra-individual variability encompasses real-life migraine management, varying across attacks within the same patient, thus empowering our findings. Notably, while the post-hoc analysis presented in the current paper focused on a comparison between current pharmacological treatments versus REN, in real life, it is highly likely that a combined pharmacological and REN therapy will have an added benefit since the two treatment modalities are independent and should be compatible.
Conclusions
REN is an effective acute treatment of migraine attacks, with non-inferior efficacy compared with usual care and various pharmacological treatments in this analysis. Along with its favorable safety and tolerability profiles and its non-pharmacological nature that alleviates the adverse events and medical risks associated with some current migraine pharmacological treatments, our findings suggest that REN may be useful as an alternative or adjunctive acute migraine treatment.
Acknowledgements
We thank the participants who volunteered for this trial and the investigators and site personnel. We also acknowledge BioStats Statistical Consulting (Modi’in, Israel) for statistical consultation and analyses and FlaskData.IO (Modi’in, Israel) for the electronic data collection system used in this study.
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