Study Design and Participants
This was a retrospective, observational survey study in which users of the REN device (Nerivio®, Theranica Bio-Electronics Ltd., Netanya, Israel) were contacted by an in-app notification and/or e-mail (provided by the users, during the sign-up process to the Nerivio app) and offered to participate. The study protocol (ClinicalTrial.Gov registration number NCT04600388) was reviewed and approved by the Western Institutional Review Board (WIRB) and was conducted according to Good Clinical Practice (GCP) and the Declaration of Helsinki guidelines.
The survey was sent to 455 female patients aged 18–55 across the United States who used Nerivio between October 1, 2019, and October 18, 2020, and completed at least four REN treatment sessions. The study sample represents a randomly selected sub-sample of Nerivio users who met the admission criteria. The sample size was calculated to achieve an approximate number of 100 completed surveys. Data were then excluded from the analysis if a patient’s report indicated that she was not menstruating, did not have menstrual migraines, or did not use the device to treat menstrual migraines (see Fig. 2 disposition chart). Menstrual migraine was defined according to the International Classification of Headache Disorders, third edition (ICHD-3; ), and reported as a yes/no question by the participants (Question text: “Do you usually experience migraines that occur 2 days before you get your period or during the first 3 days of your period (menstrual migraines)?”). Additionally, all participants were prescribed a migraine therapy by a neurologist.
Before taking the survey, patients provided informed consent. The consent form appeared as the first page of the survey, and participants clicked either "agree" or "disagree" to the consent statement (those who clicked “agree” proceeded to the survey, and those who clicked “disagree” were brought to an exit page). Patients received a $10 gift card for participating in this survey. The first patient completed the survey on September 14, 2020, and the last patient completed the survey on October 20, 2020.
The REN Device
The REN device (Nerivio, Theranica Bio-Electronics Ltd., Netanya, Israel) and its mechanism of action have been described in detail elsewhere [17, 18]. Briefly, this is a wearable device worn on the upper arm upon the onset of migraine symptoms, the device is controlled by a smartphone application (the Nerivio app). It stimulates mainly C and Aδ noxious fibers for 45 min to activate an endogenous analgesic mechanism termed conditioned pain modulation (CPM) [13,14,15,16]. The stimulus pulse frequency is set at 100–120 Hz (modulated), with a pulse width of 400 μs, and the output current is up to 40 mA that can be adjusted by the patient. The stimulus is a modulated, symmetrical, biphasic square pulse.
Data Collection and Outcome Measures
Participants were asked to complete a 5-min online survey assessing satisfaction, effectiveness, and safety—using multiple-choice questions, open-ended questions, and rating questions. The primary endpoints were: effectiveness of REN for menstrual migraine and user satisfaction. Secondary endpoints included reported tolerability of the treatment, side-effect prevalence, effectiveness for menstrual cramps, and effectiveness for pelvic pain.
Continuous variables were analyzed using mean and standard deviation. Ordinal and nominal variables are presented as the total number and percentage of patients in each category, per question. The multiple-choice questions concerning effectiveness and tolerability (Q3, Q6, Q8, Q9) were rated from least to most, and for those questions we present results ranging from moderate to extreme together (i.e., answers 3–5), along with separate rates of each of the answers. Question 2 (satisfaction) was rated on a five-point Likert scale (i.e., the middle answer was neutral), and thus results are presented separately for negative answers (1, 2), neutral answer (3), and positive answers (4, 5), along with rates of each of the five answers.
Data were analyzed using Microsoft Office Excel version 16 (Microsoft Inc., USA), and IBM SPSS statistics software version 23.0. (SPSS Inc., USA).