Erik Greb
June 08, 2021
A non-invasive, self-administered neurostimulation device recently approved by the US Food and Drug Administration (FDA) is safe, tolerable, and offers “highly effective” pain relief in acute migraine, new research shows.
Results of a randomized, sham-controlled trial show 46% of patients with acute migraine achieved complete freedom from pain 2 hours after treatment with combined occipital and trigeminal nerve stimulation (COT-NS) versus 11.8% of those assigned to sham stimulation.
“This multicenter, pivotal, regulatory, sham-controlled study provides evidence that self-administered, noninvasive, combined occipital and trigeminal neurostimulation is a safe and highly effective acute treatment for migraine,” Stewart J. Tepper, MD, professor of neurology at the Geisel School of Medicine at Dartmouth College in Lebanon, New Hampshire, told Medscape Medical News.
The findings were presented at the virtual American Headache Society (AHS) Annual Meeting 2021.
No Concurrent Medication
Previous research has shown COT-NS (Relivion, Neurolief) is beneficial in treating migraines. However, until recently it was only available via implanted systems.
The new device enables patients to noninvasively self-administer COT-NS.
The front of the device provides bilateral stimulation of the supraorbital and supratrochlear nerves, which reach the brain through the first division of the trigeminal nerve. The back of the device has two channels that activate the greater occipital nerve.
To assess the safety and efficacy of the device in treating acute migraine, investigators conducted a multicenter, prospective, double-blind study. Eligible patients were at least 18 years old and had migraines with or without aura.
Investigators randomly assigned participants to active or sham stimulation. Participants self-administered treatment for 1 hour within 30 minutes of migraine onset.
In the active group, the intensity of treatment was as high as 12 mA for the occipital nerve and as high as 6 mA for the trigeminal nerve. The frequency was 80 Hz. In the sham group, the intensity was as high as 10 mA for the occipital nerve and as high as 5 mA for the trigeminal nerve at a frequency of 0.3 Hz.
Using a four-point scale, participants recorded their pain level before treatment and at 1, 2, and 24 hours after treatment initiation. They recorded their most bothersome symptom, such as phonophobia, photophobia, or nausea, with the same scale before treatment and at 1 and 2 hours after initiating treatment. Participants were asked not to take medication for at least 2 hours after starting COT-NS treatment.
The primary endpoint was the proportion of patients with reduced migraine headache pain at 2 hours after the first treated attack. Pain reduction was defined as a decrease from severe or moderate to mild or no pain, or from mild to no pain. Participants who used rescue medication were considered to have had no reduction in pain.
Researchers randomly assigned 131 participants to treatment. They excluded 22 participants because of protocol deviations. Of the 131 participants, 109 (83%) were women. The patients’ mean age was 40.3 years. Approximately 63% had migraine without aura and 27% had migraine with aura. There were no significant differences between groups at baseline.
Effective Pain Relief
The proportion of patients with reduced pain 2 hours after treatment was 60% in the active group and 37% in the sham stimulation group (P = .018). The therapeutic gain associated with the device was 23%.
The secondary endpoint was the proportion of participants with complete pain freedom 2 hours after treatment. Approximately 46% of patients in the active group and 11.8% of patients in the control group achieved this outcome (P < .0001).
Investigators also examined several exploratory endpoints. Two hours after treatment, 75% of patients in the active group achieved complete freedom from their most bothersome symptom. In the sham group, 46.7% of patients achieved this outcome (P = .009).
The proportion of participants who achieved pain relief at 2 hours in at least 50% of their treated episodes across five attacks (the 50% responder rate) was 70% in the active arm and 42% in the sham arm (P = .0039). Approximately 36% of active and 8% of sham participants achieved sustained pain freedom at 24 hours (P = .0004).
No serious adverse events were reported during the study. Adverse events consisted of “trivial, transient, mild buzzing,” said Tepper.
Participants appeared to have been successfully blinded to their treatment assignment. More than two-thirds were unable to tell whether they had received active or sham stimulation.
These results were the basis for the FDA’s recent approval of the Relivion device for the treatment of acute migraine in adults with and without aura. The device may become available within the next year.
“Patients who request this type of treatment include those early on in migraine natural history who do not want medications, patients contemplating pregnancy who do not want medications, and patients who have experienced multiple medications fail for acute treatment or who have contraindications to multiple acute medications,” said Tepper.
Relivion is the first non-invasive neuromodulation device for the acute treatment of migraine designed to simultaneously modulate the first division of the trigeminal nerve through supraorbital and supratrochlear nerves, as well as the cervically derived greater occipital nerves, he added.
“These data are encouraging because the active device resulted in statistically and clinically significant 2-hour pain freedom and freedom from most bothersome symptom after 1 hour of treatment,” Tepper noted.
Need for Comparison With Active Devices
Commenting on the findings for Medscape Medical News, Jean Schoenen, MD, Ph.D., said: “At first sight, the Relivion results are slightly superior to those of the two acute migraine trials performed with the Cefaly device [which provides noninvasive stimulation of the trigeminal nerve], but because of methodological differences, comparisons between the two may not be reliable.” Schoenen is the leader of the Headache and Neuronal Regeneration Research Unit and Headache Clinic at Liège University in Belgium.
For example, in the in-hospital, sham-controlled trial of Cefaly, which was applied for 1 hour for one attack, the rate of pain freedom was 17% at 2 hours. The rate of 50% or greater pain relief at 2 hours was 54%.
However, he noted, some patients do not tolerate neurostimulation during a migraine attack.
“In the expanded publication of the Relivion trial, this will most likely be mentioned, and it would be of interest to know which device is better tolerated, although this depends on the stimulation parameters,” said Schoenen.
The Relivion device would provide an advantage for patients if it proved more efficacious and better tolerated than other available noninvasive neurostimulation devices.
These devices stimulate the trigeminal nerve, provide remote electrical neuromodulation, stimulate the cervical vagus nerve, or provide transcranial direct current or magnetic stimulation. A direct trial comparing these devices is necessary to evaluate their effects reliably, said Schoenen.
“In theory, combining trigeminal and occipital stimulation should be superior to either one alone, but in medicine, one plus one is not necessarily two,” said Schoenen.
The precise mechanism of action of these devices has not been settled, he added. The current investigators suggest that the stimulation might act on the trigemino-cervical complex to block afferents.
“This remains to be proven and does not explain why remote electrical neurostimulation on the upper limb is equally effective for migraine attack treatment,” said Schoenen. “The effect of trigeminal and occipital stimulation could chiefly be due to modulation of the descending pain control pathways.”
In addition, in the context of novel effective drug therapies for migraine attacks and migraine prevention, such as drugs that block calcitonin gene-related peptide transmission, the benefit and cost-effectiveness of noninvasive neurostimulation devices remain to be determined, Schoenen added. One advantage is that they can be used with drug treatment.
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