A 38-year-old female individual with a past medical history significant for migraine with and without aura presented to the clinic for routine follow-up regarding her headaches. She had previously tried topiramate, gabapentin, and amitriptyline for chronic migraine management, but suffered from side effects or lack of efficacy from these medications. She was started on propranolol ~1 year prior, and uptitrated to a dose of 160 mg, and more recently occipital nerve blocks and Botulinum toxin injections were added. For acute treatment, she had been taking zolmitriptan and compazine as-needed. However, despite the above therapies, she continued to suffer from 3 to 4 migraine attacks per month. During her appointment, she inquired about the newer noninvasive neurostimulation devices for migraine control she saw reported in the news, and whether or not she could benefit from them. Discussion arose as to whether or not this patient could benefit from using noninvasive neuromodulation for treatment of acute migraine attacks, with minimal associated side effects.
The first study involving implantable neuromodulation devices in headache began in 1999, when 13 patients were implanted with subcutaneous electrodes at the C1 level for intractable occipital neuralgia.1 Since then, there have been various implantable and noninvasive devices tested and marketed for headache disorders, such as cluster headache and migraine. Implantable options include occipital, supraorbital, and sphenopalatine ganglion nerve stimulations, and deep brain stimulation. More recently, a number of noninvasive options have been utilized in clinical trials and cleared by the Federal Drug Administration (FDA) for headache disorders, including single pulse transcranial magnetic stimulation, noninvasive vagus nerve stimulator (nVNS), and external trigeminal nerve stimulators, all with various proposed mechanisms of action and levels of efficacy.2,3
The nVNS device is a small, handheld electronic stimulator that is placed on the anterolateral area of the neck, at which point an electrical discharge is produced, designed to stimulate the vagus nerve. Stimulation of this nerve, which is a major parasympathetic component of the autonomic nervous system, can regulate inflammatory responses through its afferent projections through the nucleus tractus solitarius, which has been implicated in the pathophysiology of migraine.4 The FDA initially cleared the nVNS device known as gammaCore (manufactured by electroCore, Inc.) for the management of episodic cluster headache, based on 2 sham-controlled randomized trials, the Non-Invasive Vagus Nerve Stimulation for the ACute Treatment of Cluster Headache (ACT1) trial, and the Non-Invasive Vagus Nerve Stimulation for the ACute Treatment of Episodic and Chronic Cluster Headache (ACT2) trial.5,6 Neither of these trials met their primary endpoints, but did demonstrate superiority of gammaCore when compared with sham on various secondary endpoints.7 The Non-Invasive Vagus Nerve Stimulation for PREVention and Acute Treatment of Chronic Cluster Headache (PREVA) study, a prospective, open-label, randomized trial, compared gammaCore with standard of care for use in chronic cluster headache as a prophylactic device, and found gammaCore to be superior to standard of care in its primary endpoint, which was reduction in cluster attacks per week.8 In 2018, gammaCore was FDA-cleared for the use of acute treatment of pain associated with migraine through the label expansion process, based on the results of the Noninvasive Vagus Nerve Stimulation as Acute Therapy For Migraine (PRESTO) clinical trial.9
In patients with migraine with or without aura, does the addition of a noninvasive vagus nerve stimulation device provide improved acute migraine attack control, in terms of attack length and severity, when compared with placebo?
The search was conducted using the Ovid MEDLINE database. The following MeSH terms were used and all were exploded: migraine disorders and vagus nerve stimulation. The text words used included: acute migraine, noninvasive vagus nerve stimulation, and non-invasive vagus nerve stimulation. The MeSH terms and text words were combined using the Boolean operators “OR” and “AND” resulting in 26 citations. The title term “PRESTO study” was searched, resulting in 3 citations then “OR”d with the original 26 resulting in a total of 29 citations. Of the 29 reference, 1 was selected for critical appraisal and evaluation authored by Tassorelli et al,9 on the PRESTO Study. This article was selected as it represented the highest level of evidence available to answer the clinical question.
EVIDENCE AND RESULTS
The Prospective Study of nVNS for the Acute Treatment of Migraine (PRESTO trial) published in 2018, was a multicenter, randomized, double-blinded, parallel-group, sham-controlled clinical trial that recruited patients from 10 Italian centers between January 2016 and March 2017. The trial compared the use of nVNS (gammaCore) with a sham device designed to be physically perceived by the participant, but not provide actual vagal nerve stimulation. Inclusion criteria included the following: patients who were 18 to 75 years old with previous diagnosis of migraine with or without aura per ICHD-3 beta criteria, below 50 years old at migraine onset, and attack frequency of 3 to 8 migraine attacks per month with <15 headache days per month over the last 6 months (ie, episodic migraine). Exclusion criteria consisted of the following: history of secondary headache, aneurysm, ICH, brain tumors, significant head trauma, substance abuse, addiction, syncope, or seizure; another significant pain disorder; cardiovascular/cerebrovascular disease; uncontrolled hypertension; psychiatric/cognitive disorders; pregnancy; medical condition requiring oral/injectable steroids; botulinum toxin injections in the past 6 months; head or neck nerve blocks in the past 2 months; previous migraine prevention surgery, cervical vagotomy, electrical device, or metal cervical spine hardware implantation; current use of opioids for >2 days per month; current use of simple analgesics or NSAIDs for >15 days per month; current use of triptans, ergots, or combined analgesics for >10 days per month, and initiation of preventive migraine medications in the past 2 months. Those on preventative medications had to have a stable dose 2 months before the study, and throughout the study; no new preventative medications were allowed during the study itself. Eligible patients were randomized 1:1 to either nVNS or sham by an independent, statistician-generated randomization schedule. A site unblinded trainer provided training for each participant in the use of their particular device.
The study design consisted of three 4-week periods including a run-in period, a double-blind period, and an open-label period. During the run-in period, participants treated migraine attacks per individual scripts; during the double-blind period, participants treated up to 5 attacks with either the nVNS or sham device, with only 1 attack allowed to be treated in a 48-hour period; during the open-label period, participants were allowed to treat up to 5 additional attacks with nVNS, with only 1 attack to be treated in a 48-hour period. In terms of treatment instructions, participants were instructed to do the following within 20 minutes of migraine attack onset: immediately administer 120 seconds of treatment to each side of the neck, then record post-treatment assessments at 15, 30, 60, and 120 minutes, and at 24 and 48 hours. If there was no improvement in pain at 15 minutes post-treatment, they were instructed to administer another 120 seconds of treatment to both sides of the neck. If not pain-free at 120 minutes, they were allowed to administer a second set of bilateral treatment. However, subjects were asked to wait 120 minutes before using acute rescue medications. The primary endpoint was pain freedom at 120 minutes after intervention. Secondary endpoints included pain freedom at 30 and 60 minutes; pain relief at 30, 60, and 120 minutes; mean percentage change in pain score from baseline at 30, 60, and 120 minutes; absence of associated symptoms (such as nausea, vomiting, photophobia, and phonophobia) at 120 minutes. Pain relief was defined as a reduction in pain from moderate (2), or severe (3), to no pain (0), or mild pain (1), on a 4-point scale. Consistency of response was defined as participants who had ≥50% rates of either pain relief or pain freedom (at 120 min) in at least 2 treated migraine attacks during the double-blind period. Safety endpoints compared rates of adverse events (AEs), adverse device effects, and serious adverse events among nVNS and controls.
Among 285 participants who were enrolled, 248 were randomized and 243 formed the intention-to-treat population. A total of 237 participants completed the open-label period, with 219 treating at least 1 migraine attack during the open-label period. Baseline demographics were similar between the 2 groups. There were slightly higher numbers of participants in the nVNS group that used preventative medications (35% vs. 28.5%) and treated their headaches when they were more severe (first attack: 23.5% vs. 15.1%, all attacks: 25.1% vs. 17.5%), but these differences were not statistically significant. When looking at rates of pain freedom, statistically significant differences were found favoring the nVNS group at 30 minutes (12.7% vs. 4.2%; P=0.012) and at 60 minutes (21% vs. 10%; P=0.023), but not at 120 minutes, which was the primary endpoint (30.4% vs. 19.7%; P=0.067). A repeated measures test was performed to examine the inconsistencies found in the pain-free rates at 30, 60, and 120 minutes, and found nVNS to be superior to sham for pain freedom at 30, 60, and 120 minutes (odds ratio, 2.3; 95% confidence interval, 1.2-4.4; P=0.012). In terms of pain relief, a statistically significant difference favoring nVNS was found at the 120-minute time point (40.8% vs. 27.6%; P=0.030]), but not at 30 or 60 minutes. nVNS was found to have greater mean percentage pain score reductions when compared with sham at 60 minutes (−25.4% vs. −7.7%; P=0.033) and at 120 minutes (−34.8 vs. −5.4; P=0.004). Consistency of response was greater for nVNS when compared with sham for pain freedom (32.4% vs. 18.2%; P=0.020) and pain relief (47.6% vs. 32.3%; P=0.026). Overall, a low percentage of study participants had associated symptoms at the commencement of treatment (vomiting, 6.6%; nausea, 30.5%; photophobia, 46.9%; and phonophobia, 43.2%). More participants from the nVNS group had no vomiting at 120 minutes versus sham (6/8, 75% vs. 3/8, 36.5%), but this was not statistically significant. The proportion of subjects who became free of nausea, photophobia and phonophobia after the first treated attack were similar between groups. Although 98% of participants administered at least 1 set of stimulations, most did not repeat stimulations at 15 minutes (nVNS, 60.8%; sham, 60.2%), or optionally at 120 minutes (nVNS, 95.8%; sham, 93.5%), and there was nostatistically significant difference between groups. Only 2 participants discontinued the study due to AEs (both controls), with an overall low rate of AEs including application site discomfort, erythema, nasopharyngitis, dizziness and pain. No serious AEs were reported in either group.
The PRESTO clinical trial was the largest study of its kind, and tested a novel, nonpharmacologic method of headache control with the nVNS device that can be used with existing medication regimes with minimal side effects. Other strengths included the fact that this was a well-designed trial with clearly defined eligibility criteria, and 3 distinct study periods including a run-in period, a double-blind period, and an open-label period. Blinding was completed appropriately, and recruitment was adequate, with investigators estimating they would require a sample size of 232 participants to demonstrate statistical significance for the primary endpoint with 90% power. In the end, the study was able to enroll 285 subjects, 243 of which were included in the intention-to-treat population. Very low numbers were lost to follow-up (1 in the nVNS group, 3 in the sham group). Study designers used accepted International Headache Society (IHS) guidelines with regards to the formulation of the study protocol, and used the recommended primary endpoint (pain freedom at 120 min for first-treated attack).10
One of the limitations of the study is that it recruited from a finite number of centers, and 100% of participants were Caucasian and predominantly female. In addition, due to extensive exclusionary criteria, there is limited generalizability of the results as the selected study population does not readily reflect “real world” practice. Furthermore, it is unclear whether the sham device can truly be considered “sham,” as there is the literature to suggest that the sham device used in this study may actually stimulate the vagus nerve as well.11 This may have resulted in confounding, with decreased differences between the 2 study groups, and could potentially explain why the study did not meet its primary endpoint. Among the secondary endpoints, there was the plan to look at differences in associated symptoms (such as nausea, vomiting, photophobia, and phonophobia), however, a low incidence of associated symptoms in the study population made statistical analysis difficult and underpowered to detect differences between groups, possibly due to early treatment design of the study and with the use of the devices within 20 minutes of migraine attack onset. Although the study does mention some of the preventative medications that were used by participants (such as topiramate, vitamin B2, magnesium, and propranolol), there was no information regarding the numbers of participants on each preventative medication, which could have been useful for subgroup analysis. Finally, it is important to disclose that the PRESTO study was in fact funded by electroCore, Inc., which produces and markets the gammaCore device.
Two other articles were reviewed in the critical appraisal process, both of which were published to provide additional post hoc findings on the PRESTO study cohort that were not proposed in the original prespecified study analysis. Grazzi et al12 specifically looked at the following endpoints: percentage of participants with ≥1 point reduction in pain intensity measured at 30, 60, and 120 minutes; rescue medication use between groups; pain freedom rates stratified by initial pain intensity (mild, moderate, or severe) at 30, 60, and 120 minutes after the first-treated attack during both the double-blind and open-label periods. They found statistically significant differences favoring nVNS when assessing ≥1-point reductions in headache intensity at 30, 60, and 120 minutes after the first treated attack, and at 60 and 120 minutes when looking at all attacks. More participants in the nVNS group went without rescue medication for the first attack (59.3% vs. 41.9%; P=0.013), and more participants in the nVNS group had attacks that did not require rescue medication (52.3% vs. 37.3%; P=0.008). When stratified by initial headache intensity, more participants in the nVNS group had pain freedom at 120 minutes after the first treated attack if they had mild pain at headache onset (50% vs. 25%; P=0.018); when looking at all attacks, they were also more likely to be pain-free if they had a mild headache at 60 (37% vs. 21.2%, P=0.025) and 120 minutes (46.7% vs. 30.1%, P=0.037). Martelletti et al13 found that when looking at all attacks with linear regression modeling, nVNS was superior to sham for pain freedom at 60 (16.3% vs. 8.6; P=0.005) and 120 minutes (22.9% vs. 14.8%; P=0.026). When looking at pain relief, nVNS was superior to sham at 60 (29.4% vs. 20.3%; P=0.025) and 120 minutes (35.2% vs. 24.4%; P=0.018).
CLINICAL BOTTOM LINES
- nVNS did not show superiority when compared with sham in terms of pain freedom at 120 minutes, the primary PRESTO trial endpoint.
- However, nVNS did have statistically significant pain freedom rates when compared with sham at 30 and 60 minutes, which were secondary trial endpoints.
- It seems that the nVNS device is well tolerated, safe, and associated with only minimal adverse effects.
- On post hoc analysis of the PRESTO study cohort, it seems that nVNS was beneficial for decreasing rescue medication use; more participants in the nVNS group went without rescue medication for the first attack (59.3% vs. 41.9%; P=0.013), and more participants in the nVNS group had attacks that did not require rescue medication (52.3% vs. 37.3%; P=0.008).
- Post hoc analysis of the PRESTO study participants also demonstrated that when stratified by initial headache intensity, more participants in the nVNS group had pain freedom at 120 minutes after the first treated attack if they had mild pain at headache onset (50% vs. 25%; P=0.018); when looking at all attacks, they were also more likely to be pain-free if they had a mild headache at 60 (37% vs. 21.2%; P=0.025) and 120 minutes (46.7% vs. 30.1%; P=0.037).
Although the PRESTO trial did not show a statistically significant benefit with regards to its primary endpoint of pain freedom at 120 minutes after first treated attack between the nVNS and sham groups, it does seem that nVNS may be beneficial with regards to providing meaningful pain relief and decreasing rescue medication use, especially in patients who used the device if their headache was mild in severity at onset. At the same time, nVNS seems to be a safe alternative for acute migraine use, with minimal AEs. The proposed mechanisms of action for nVNS in migraine control include direct inhibitory modulation of pain pathways at the trigeminal nucleus caudalis, and reduction in cortical spreading depression.4,14
It is also important to mention the FDA approval process, and how it relates specifically to medical device research, development, and market release. For devices that are considered little to no risk to patients (Class I, such as surgical gloves and scalpels), there is no need for premarket submission. For other devices that are considered slightly higher risk (Class II), the device may require special controls, such as patient registries and postmarket surveillance. However, only Class III devices (such as implantable devices like hip replacement hardware) require Premarket Authorization. The gammaCore device is considered Class II, and was cleared for acute migraine using the 510(k) approval process, which the FDA allows for marketing a device similar to a device already released to market (gammaCore was previously approved for cluster headache), even though the device did not meet its primary endpoint inclinical trials.
Headache Neurology Commentary
Migraine is a genetic neurologic disease. To date, there are over 38 different loci that have been identified for migraine susceptibility.15,16 Because of this vast genetic heterogeneity, we need a variety of treatment options. Using a “one size fits all” approach to the treatment of migraine is not an effective approach. In addition, poor adherence to treatment is common and may be due to inefficacy, tolerability, and patient preference.17,18 Furthermore, other treatment barriers, specifically in the acute treatment of migraine include contraindications in the setting of cardiovascular and cerebrovascular disease, and the risk of medication overuse headache with too frequent dosing of oral preventives like triptans and nonsteroidal anti-inflammatory medications. Thus, there is a great need for treatment modalities that are effective, are safe with minimal side effects, have no risk of medication overuse headache, and have limited contraindications. Noninvasive neuromodulation, including nVNS, may be a viable treatment option to fill this treatment gap. Simultaneously, it is important to ensure that a vulnerable migraine patient population, who is desperate for any pain relief, do not fall prey to direct marketing of devices that have been cleared by the FDA without strong evidence or based on less rigorous studies than oral medications.
In the above critically appraised study, nVNS did not meet the primary endpoint of pain freedom at 120 minutes. This is the accepted primary endpoint for acute treatment trials as recommended by the IHS.10 However, the repeated measures analysis, secondary endpoints, and post hoc analyses all suggest a potential benefit of nVNS for the acute treatment of migraine with minimal side effects. This is a promising treatment option for patients with migraine, but given the cost of the device, regardless of cash pay or insurance coverage, a post market clinical trial with an informed study design and an appropriate a priori statistical plan to demonstrate efficacy would strengthen the level of evidence.
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