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Supplements Considerations in Non-Invasive Vagus Nerve Stimulation: Clinical Data and Expert Panel Recommendations
Mechanism of Action of Non-Invasive Cervical Vagus Nerve Stimulation for the Treatment of Primary Headaches
Bruce Simon, PhD, and Justyna Blake, MSE
Review of Non-Invasive Vagus Nerve Stimulation (gammaCore): Efficacy, Safety, Potential Impact on Comorbidities, and Economic Burden for Episodic and Chronic Cluster Headache
Mkaya Mwamburi, MD, PhD (HEOR), MA (Econ); Eric J. Liebler, BA; and Andrew T. Tenaglia, BA
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The Emerging Role of gammaCore in the Management of Cluster Headache: Expert Panel Recommendations
Stephen D. Silberstein, MD; Anne H. Calhoun, MD, FAHS; Christina Treppendahl, FNP-BC, AQH; David W. Dodick, MD; Alan M. Rapoport, MD; Avinash Mamidi, PharmD, BCPS; Peter Vargas, RPh; Thomas H. Ebert

The Emerging Role of gammaCore in the Management of Cluster Headache: Expert Panel Recommendations

Stephen D. Silberstein, MD; Anne H. Calhoun, MD, FAHS; Christina Treppendahl, FNP-BC, AQH; David W. Dodick, MD; Alan M. Rapoport, MD; Avinash Mamidi, PharmD, BCPS; Peter Vargas, RPh; Thomas H. Ebert
Although advances have been made to increase portability, oxygen therapy is inconvenient for patients to transport and may pose a fire hazard.13 The AHS treatment guidelines recommend high-flow oxygen therapy at a rate of 12 to 15 liters per minute, and this results in the need for large oxygen tanks for this patient group. Patients must carry the oxygen tank with them to ensure the treatment is available at the time of an acute attack. As mentioned previously, CH attacks follow circadian rhythms and onset often occurs after a patient falls asleep. Home oxygen therapy may be beneficial for patients who experience nocturnal attacks.

The fire hazard risk is especially dangerous for patients who smoke, which is particularly problematic in this patient population, as Bahra et al in 2002 found that as many as 67% of patients with CH are known smokers.28 During attacks, the restlessness experienced by patients may prevent them from keeping the nonrebreather mask in place. Nonrebreather masks also have portability issues, as these masks include a face mask as well as an attached oxygen reservoir bag and 1-way valve. Furthermore, many insurance companies restrict coverage of oxygen, as it is considered durable medical equipment, may only be a covered benefit for those with a respiratory diagnosis, and is not FDA-approved for the treatment of CH; this may present a barrier to accessing necessary treatment if patients are required to pay out-of-pocket to receive oxygen therapy.13 At this time, neither Medicare nor Medicaid cover oxygen for CH.

The administration of suboccipital steroid injections is associated with minor AEs, including transient injection-site pain and, infrequently, hair loss at injection site and headache. Long-term use of steroids, regardless of route of administration, can result in Cushing’s syndrome, blood glucose abnormalities, avascular necrosis of the femoral head, mood abnormalities, and other AEs.20 This invasive procedure must be performed by a trained medical provider in an appropriate medical setting, which may be a less convenient and potentially costlier option than home-based treatments.

The AHS guidelines were published in 2016 and do not reflect the recent FDA clearance of the first nVNS therapy.29 Therefore, these treatment guidelines will require updates to reflect the expansion of available CH treatments.

The Role of gammaCore in the Management of CH

On April 18, 2017, the FDA cleared gammaCore, the first nVNS stimulation therapy for the acute treatment of pain associated with eCH in adult patients.29 The hand-held medical device is applied at the neck and transmits electrical stimulation to the cervical branch of the vagus nerve through the skin.29 Prior to the release of gammaCore, invasive stimulation of the vagus nerve had demonstrated efficacy in the treatment of refractory epilepsy, and the FDA granted LiaNova, formerly Cyberonics, approval for a surgically implanted VNS (iVNS) therapy.30 iVNS devices were subsequently reported to have additional clinical benefits in reducing depression, thus resulting in FDA approval of these devices for the treatment of refractory depression.30 In a report of patients who experienced intractable epilepsy and received VNS, 4 also suffered from episodic migraine, all of whom reported reduced frequency, average intensity, and maximum severity of their migraine attacks.31,32

Furthermore, in a case series of 6 patients who underwent VNS implantation for intractable primary headaches, 2 were diagnosed with cCH.31,33 Both of the patients with cCH experienced improvements in their condition. One patient experienced marked improvements after 2 months, and the second patient responded to VNS as well.31,33 These positive responses to treatment in conditions other than refractory epilepsy and depression highlighted the potential role of VNS therapy in primary headache disorders, including migraine and CH.31-33

Although the precise cause of CH is unknown, these headaches occur upon activation of the trigeminal-autonomic reflex pathway in the brainstem, and activation of the trigeminal nerve results in the ocular pain associated with CH as well as stimulation of the parasympathetic autonomic system, causing the associated symptoms of lacrimation, conjunctival injection, nasal congestion, and rhinorrhea.34 In a preclinical animal model, nVNS suppressed acute nociceptive activation of trigeminocervical neurons, which is thought to be one of the mechanisms by which nVNS relieves the pain of eCH.3,15,35

GammaCore has regulatory approval for the acute and/or preventive treatment of CH, migraine, and medication overuse headache in the United Kingdom and European Union and in Canada for CH and treatment of migraine.36 In the United States, gammaCore is approved only for the acute treatment of eCH. The safety and efficacy of gammaCore in the adjunctive preventive treatment of cCH was studied in the non-invasive vagus nerve stimulation for the PREVention and Acute Treatment of Chronic Cluster Headache (PREVA) trial, which is part of one of the largest clinical trial programs ever carried out in CH.37 The PREVA trial was a prospective, open-label, randomized study that compared adjunctive preventive nVNS (N = 48) with standard of care (SOC) alone (ie, the control group) (N = 49). SOC preventive medications included, but were not limited to, verapamil, lithium, topiramate, and corticosteroids.37 The results of the study demonstrated that patients in the intent-to-treat population who received standard of care plus nVNS (N = 45) had a significantly greater reduction in the number of attacks per week compared with patients in the control group (N = 48) (–5.9 vs –2.1, respectively); (95% CI, 0.5-7.2; P = .02).37 In the standard of care plus nVNS group, 40% (18/45) of patients had response rates of 50% or greater for reductions in the number of attacks per week compared with 8.3% of patients (4/48) in the control group (P <.01).37 Additionally, treatment with nVNS was more effective the longer patients used the therapy.37,38 Due to the lack of a control arm in this study, the FDA did not grant gammaCore approval for use in cCH prevention.

Patients in the nVNS treatment arm also demonstrated significant improvements in the quality-of-life measurement EQ-5D-3L VAS2 compared with baseline.37,38 Furthermore, patients in the nVNS group in the randomized phase reduced their use of subcutaneous sumatriptan by 61% (P = .007) and oxygen by 62% (P = .02); patients in the control group did not experience a substantial reduction in acute medication use (10.2% increase and 14% decrease, respectively).37,38 Upon study completion, 65% of patients stated that they would recommend nVNS to others and 75% of patients rated nVNS as easy to use.37,38 The authors of the study concluded that adjunctive preventive nVNS is a safe and well-tolerated novel treatment for cCH that offers improved benefits compared with standard of care, with no serious device AEs.37

Compared with implantable VNS, occipital nerve stimulation, and sphenopalatine ganglion stimulation, gammaCore is a portable, easy-to-use device that can be self-administered by patients as needed to provide relief from eCH-related pain. In contrast, VNS is an invasive procedure requiring surgical implantation of electrodes around the cervical vagus nerve, electrodes which are then connected to a stimulating device that is implanted under the anterior chest wall.29,39-41 Both iVNS and nVNS with gammaCore are safe and well tolerated; however, the implantable device and portable device differ in their AE profiles and treatment costs.39,40,42 Implantable VNS has been associated with postoperative infections, and common AEs include transient cough, hoarseness, voice alteration, and paresthesias.42 Potential AEs of gammaCore, all of which are transient, include hoarseness, shortness of breath, or voice alteration during treatment, and a tingling/pricking feeling where the device is applied.43

The FDA release of gammaCore was based on predefined subgroup analyses from 2 trials in the non-invasive vagus nerve stimulation for the ACute Treatment of Cluster Headache (ACT) clinical trial program, ACT1 and ACT2, which were designed to evaluate the safety and efficacy of gammaCore for the acute treatment of CH.29 These trials were prospective, double-blind, placebo-controlled, randomized studies that evaluated the use of gammaCore versus a sham device.29,44

The primary efficacy end point for ACT1 was the percentage of patients who reported mild or no pain 15 minutes after treatment initiation with gammaCore for the first treated CH attack in the study.44 In the total population, 26.7% of patients in the nVNS group had mild or no pain at 15 minutes after treatment initiation compared with 15.1% of patients in the sham group, but the results were not statistically significant (P = .1).44 The results of the ACT1 subgroup analysis, which evaluated 85 patients with eCH, demonstrated that 34.2% of patients in the active treatment group experienced a reduction in pain compared with 10.6% of patients who received sham treatment (P = .008).29,45 In the cCH cohort, however, patients did not achieve higher response rates in the nVNS treatment arm compared with the sham group (13.6% vs 23.1%, respectively; P = .48)

The primary outcome for ACT2 was the percentage of total attacks that were pain free at 15 minutes after the onset of pain, with no use of rescue medication through the treatment period (30 minutes).44 In the total population, 13.5% of patients in the nVNS group achieved pain-free status 15 minutes after the onset of pain compared with 11.5% in the sham group, but the results were not statistically significant (P = .713).44 The results of the ACT2 subgroup analysis, which evaluated 182 attacks in 27 patients with eCH, demonstrated that a significantly higher percentage of attacks were pain-free in eCH patients treated with gammaCore compared with placebo (47.5% vs 6.2%, respectively; P = .003).29,44 In the cCH cohort, however, patients did not perform better in the nVNS treatment arm compared with the sham group (4.8% vs 12.9%, respectively; P = .13).44

Similar to the PREVA trial, treatment with gammaCore was found to be safe and well tolerated in both ACT1 and ACT2. The majority of AEs were considered mild and transient, and they occurred during active treatment.29,44 AEs reported in ACT1 included application-site reactions (burning/tingling/soreness/stinging and skin irritation/redness/erythema), musculoskeletal disorders (lip or facial drooping/pulling/twitching), and nervous system disorders (dysgeusia/metallic taste).44 In ACT2, 1 subject who received nVNS reported severe lower abdominal and lower back pain which was not considered related to treatment and resolved without intervention.44 The results of ACT2 have been presented through oral and poster presentations and submitted to the FDA; the results also have been submitted for publication.

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