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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; Stewart J. Tepper, MD

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; Stewart J. Tepper, MD
A panel of 9 experts, including neurologists, other headache specialists, and medical and pharmacy directors, from 4 health plans (1 integrated delivery network and 3 plans with commercial, Medicare, and Medicaid lines of business), convened to discuss cluster headache (CH). Topics covered included the current treatment landscape, treatment challenges, economic impact of disease, and gaps in care for patients with CH. One major challenge in the management of CH is that it is underrecognized and frequently misdiagnosed, leading to delays in and suboptimal treatment for patients who suffer from this painful and disabling condition. The management of CH is challenging due to the lack of a robust evidence base for preventive treatment, the adverse events (AEs) associated with conventional preventive treatments, the variability of response to acute treatments, and the challenging reimbursement landscape for well-accepted treatments (eg, oxygen). The lack of effective prevention for many patients may lead to the excessive use of acute therapies, often multiple times each day, which drives the cost of illness up significantly.

The goal of the panel discussion was to discuss the role of gammaCore, the recently released first non-invasive vagus nerve stimulation (nVNS) therapy in the acute treatment of patients with episodic CH (eCH), in the management of CH. The panel reviewed current practices and formulated recommendations on incorporating a newly released therapy into CH management. The panel explored the role of traditional management strategies as well as that of gammaCore in the acute treatment of patients with eCH. Resources that may be useful in the treatment of patients with CH were also discussed.
Clinical Background and Socioeconomic and Humanistic Burden of CH

CH is a neurological disorder characterized by frequent short-duration and severe attacks of head and orbital pain, with accompanying motor agitation and cranial autonomic signs and symptoms. Attacks usually begin between the ages of 20 and 40 years, but may start earlier or later.1 CH can be subclassified into eCH and chronic CH (cCH).2,3 In eCH, patients experience at least 2 cluster periods of 7 days to 1 year in duration, which are separated by a headache-free interval of at least 1 month.2 Attacks typically occur over a period of 4 to 12 weeks (ie, cluster periods). cCH differs from eCH in that patients experience daily or near-daily headaches, often multiple times per day, for more than 1 year without remission, or experience a headache-free interval of less than 1 month.2

Characteristic signs and symptoms of CH include, but are not limited to, sudden-onset excruciating pain in a periorbital or temporal location lasting between 15 and 180 minutes associated with agitation and autonomic signs, such as ipsilateral lacrimation, rhinorrhea, nasal congestion, facial flushing or pallor, ptosis, and/or miosis.2,3 The affected side of the head typically does not change between attacks during a cycle or period. Headache specialist panel participants noted that CH attacks follow circadian rhythms and onset often occurs after a patient falls asleep. Attempts to mitigate attacks by changing sleep patterns generally are unsuccessful for these patients. Panel participants noted that patients usually have 1 to 3 attacks most days of the week during the cluster period; they cannot lie still, rock back and forth, and are quite irritable and agitated until the attack subsides.

The pathophysiology of CH is not entirely known; however, data suggest that there is trigeminal, hypothalamic, and brainstem involvement. Brain imaging revealed that the disorder involves abnormal activation patterns of the ipsilateral posterior hypothalamus and an autosomal dominant or autosomal recessive pattern of inheritance may be involved in some patients.2,4 The estimated prevalence of CH in the United States ranges from 0.1% to 0.4%, with approximately 80% of patients affected by eCH and 20% of patients affected by cCH.5,6 Patients with eCH may evolve to cCH and cCH may revert to eCH; between 4% and 13% of patients with eCH will evolve to cCH.2,7 CH affects males 4.3 times more often than females; eCH affects males 2 to 9 times more often than females.1,5,8

CH is one of the most painful conditions an individual may experience, and it impacts patients’ ability to perform daily activities, with 80% of patients reporting restricted daily activities as a result.9-11 In addition, CH is associated with a large socioeconomic burden for affected patients, but there is a lack of published literature surrounding the economic consequences of CH, and due to its low prevalence, the actual magnitude of its burden is unknown.9,10,12 CH is sometimes referred to as “suicide headache” because of the elevated risk for suicidality among patients with the condition.13 Research found that nearly 20% of patients with CH reported loss of employment and approximately 8% are unemployed or receiving disability services due to the disorder.13,14

Gaps in Care and Current Approaches to Diagnosis and Treatment

A diagnosis of CH is based on a careful patient history, with further evaluation and workup, including general physical and neurological examination and, when indicated, imaging tests to exclude secondary causes. Because CH is a primary headache disorder, conventional diagnostics may be of little use; however, neuroimaging is mandatory when indicated because CH is rare and secondary causes are always a concern.2,6,9,13,15 Diagnostic criteria for CH are published by the International Headache Society in the third edition of the International Classification of Headache Disorders (ICHD-3), which is in beta version and, when finalized, is intended to be synchronized with the upcoming 11th edition of the World Health Organization’s International Classification of Diseases.1 In ICHD-3 beta, the diagnostic criteria for CH require at least 5 attacks, each lasting 15 to 180 minutes, with a frequency between 1 every other day and up to 8 per day for more than half of the time when the disorder is active and with attacks accompanied by at least 1 of the following symptoms or signs, ipsilateral to the headache1:

Conjunctival injection and/or lacrimation

Eyelid edema

Forehead and facial flushing and/or facial sweating

Miosis and/or ptosis

Nasal congestion and/or rhinorrhea

Sensation of fullness in the ear

A sense of restlessness or agitation

CH is underrecognized and frequently misdiagnosed.13 Only 21% of patients receive a correct diagnosis upon initial presentation, and the average diagnostic delay for patients with CH is 5 years or longer, with an average of 3 healthcare providers seen before a patient receives a correct diagnosis.13,14,16 The expert panel stated that the underdiagnosis of CH may be a result of the limited number of headache specialists in the United States and/or the lack of knowledge/recognition of the specific symptoms associated with the disorder by general neurologists and primary care providers. In the United States, there are just over 500 headache specialists who are currently board-certified.17,18 Headache specialists include physicians who are board-certified through the United Council for Neurologic Subspecialties (UCNS). There is also a Certificate of Added Qualification in Headache Medicine (CAQ) for physicians, physician assistants, advanced practice nurses, dentists, and psychologists.17 As of September 2017, there are approximately 523 physicians nationwide with UCNS board-certification in headache medicine and fewer than 50 providers who have CAQ designation.17,18

Although there is a low prevalence of CH in the United States compared with migraine, the number of patients with CH far surpasses the number of available headache specialists, leaving many patients to seek care from their primary care provider, a provider in the emergency department setting, a provider who is not board-certified in headache medicine, or a neurologist without headache board-certification, certificate, or CAQ designation. If the patient does not have access to a provider, he or she may attempt to manage the condition with self-care, which is usually inadequate.17,18 The headache specialist panel participants noted that patients often seek help from dentists, ophthalmologists, or ear, nose, and throat specialists due to the location of the pain in trigeminal nerve divisions V1 and V2 and the autonomic symptoms. Headache specialists are able to distinguish the unique presentation of CH from other headache disorders; however, providers who are not trained in this specialty may not be able to definitively diagnose CH if the patient presents with overlapping or similar features of other headache disorders.10 In these instances, the presenting signs and symptoms may be mistaken for migraine, paroxysmal hemicrania, short-lasting unilateral neuralgiform headaches with conjunctival injection and tearing, tension headache, so-called sinus headaches, or trigeminal neuralgia.10,19 In addition, a variety of secondary causes, including vascular dissection and intracranial tumors/lesions, may mimic the symptoms and signs of CH, and appropriate investigations may be necessary to distinguish primary CH from secondary causes. The underrecognition, diagnostic delays, limited number of available specialists, and high suicide and disability rates highlight the need for improved identification of patients with CH.

Once a diagnosis is made, evidence-based treatment guidelines based on the literature for the management of CH are available from the American Headache Society (AHS) to help guide treatment.20 The AHS guideline provides recommendations for the treatment of CH according to the American Academy of Neurology grades for treatment evidence present in the 2010 systematic review.20 The Table provides descriptions of levels of recommendations.

For the acute treatment of CH, there is a level A recommendation for subcutaneous sumatriptan, zolmitriptan nasal spray, and high-flow oxygen (12-15 L/minute) administered only through a nonrebreather face mask over the nose and mouth.20 Parenteral dihydroergotamine (DHE) and subcutaneous sumatriptan both have FDA-approved indications for the acute treatment of CH. For transitional, short-term, or bridge prevention, there is a level A recommendation for suboccipital steroid injections, but the most commonly used preventive treatment worldwide is verapamil, a calcium channel antagonist, which has a level C recommendation.20 The AHS issued level B recommendations for the following treatments in the acute setting: sumatriptan nasal spray, oral zolmitriptan, and sphenopalatine ganglion stimulation, which is not approved for any indication in the United States at the current time, but is presently being evaluated in a randomized controlled trial.20 Level B recommendations were also issued for civamide nasal spray in the prophylactic setting; however, work on its development stopped many years ago.20

While often effective, subcutaneous sumatriptan, zolmitriptan nasal spray, oxygen therapy, and suboccipital steroid injections have drawbacks and practical limitations. Subcutaneous sumatriptan and zolmitriptan nasal spray are expensive treatments with wholesale acquisition costs (WACs) exceeding $60/dose.21 AEs associated with subcutaneous sumatriptan include injection-site reactions, nausea, vomiting, dizziness, fatigue, paresthesias, and chest tightness.11,21 A common AE of intranasal sumatriptan is a bad taste in the mouth.22 Triptans are contraindicated in patients with ischemic, cardiac, cerebrovascular, or peripheral vascular disease, and the maximum FDA-approved doses of subcutaneous sumatriptan and intranasal zolmitriptan are 12 mg and 10 mg daily, respectively.23-25 For patients who experience more than 2 attacks per day, particularly those who experience up to 8 attacks per day, the FDA-recommended maximum doses of these medications are insufficient to provide relief from their multiple attacks, and these patients will exceed the maximum daily doses of these treatments if they can access them because of the excruciating pain they experience.

Triptan overuse results in elevated treatment costs and medication waste.26 One study revealed that nearly 70% of patients who experienced an average of 1 to 6 CH attacks per day were found to be using more than the recommended 12 mg of sumatriptan per 24-hour period, with some patients using as much as 36 mg during this time frame.27

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