P e r i p h e r a l N e u ro m o d u l a t i o n f o r Trea t m e n t o f C h ro n i c Migraine Headache

Daryoush Tavanaiepour, MD, Robert M. Levy, MD, PhD*

KEYWORDS
 Migraine  Neuromodulation  Occipital nerve stimulation  Headache

KEY POINTS
 Chronic migraine affects a large proportion of the population and is a significant source of disability and lost productivity.  Traditional neurosurgical procedures that favor lesioning or decompressing the greater occipital nerve have not gained favor.  Occipital nerve stimulation provides an attractive nondestructive alternative, but its degree of efficacy remains to be fully elucidated in randomized controlled trials.  Mechanism of action is unknown but it has been attributed to the gate theory of pain or modulation of the trigeminocervical complex in the rostral spinal cord.

Department of Neurological Surgery, University of Florida College of Medicine, Jacksonville, FL, USA * Corresponding author. E-mail address: rlevy@neuromodulation.com Neurosurg Clin N Am 25 (2014) 1114 http://dx.doi.org/10.1016/j.nec.2013.08.010 1042-3680/14/$ see front matter 2014 Elsevier Inc. All rights reserved.

neurosurgery.theclinics.com

Between 25 and 45 million Americans experience migraine headaches; approximately 2.0% have chronic migraine (CM) headaches.1,2 CM is characterized by a minimum of 15 headache days per month, and approximately half of the headache days meet the diagnostic criteria for migraine without aura or respond to a migraine-specific acute medication.3 Individuals with CM are 4 times more likely to have major depression with more frequent suicide attempts than in the general population.46 Furthermore, compared with episodic migraine, CM is associated with significantly greater disability, economic burden, and impairments in health-related quality of life.710 Pharmacotherapy for migraine headaches includes medications to relieve the acute pain (abortive agents) and medication to prevent the onset of headache (preventative agents). Abortive agents include nonsteroidal antiinflammatory agents, tryptans, opioids, ergot compounds, and sedatives. Preventative agents include anticonvulsants, antidepressants, b-adrenergic blockers, and serotonin

antagonists. In addition, recognition and prevention of exposure to precipitating agents such as caffeine, many foods including cheeses and red wines, and stress can provide significant relief and reduce medication intake. Historically, neurosurgical therapies for headache have included destructive procedures including dorsal root entry zone (DREZ) lesioning, dorsal root ganglionectomy, peripheral neurolysis, and neurectomy. These therapies, however, have not been effective for migraine headaches and such techniques may result in secondary neuropathic pain in the distribution of the surgically treated nerve(s). For example, ganglionectomy at the second cervical level has been reported to be 80% effective at 3 year follow-up in posttraumatic second cervical pain syndromes.11 Nontraumatic pain in this region, however, was not significantly relieved by ganglionectomy. Ventrolateral DREZ lesioning at the first, second, or third cervical level has been variably effective for occipital neuralgia but is highly invasive and has

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significant risks.12 Greater occipital nerve neurolysis has demonstrated short-term efficacy, however, there was a significant recurrence rate within 2 years.13 In addition to neurolysis and neurectomy, fusion of the first and second cervical vertebrae has relieved pain in some patients with occipital neuralgia.14 Initially, peripheral nerve stimulation using a cuff electrode or direct stimulation of the greater occipital nerve was found to be effective for treating occipital neuralgia.15,16 More recently, peripheral neuromodulation in the occipital region has emerged as a promising treatment modality for a variety of chronic headache disorders, including CM.1725 Weiner and Reed26 first reported the use of occipital nerve stimulation (ONS) for the treatment of occipital neuralgia. However, positron emission tomography (PET) imaging of these patients demonstrated activation patterns more consistent with CM than with occipital neuralgia, leading Matharu and colleagues17 to suggest that Weiner and Reeds patients suffered from CM. Since then, ONS has been reported to be efficacious for the treatment of several headache disorders including migraine headaches,4,5 cluster headache,6 hemicrania continua,25 and true occipital neuralgia.24 An extensive literature search was performed with a specific focus on high-quality clinical trials of peripheral neuromodulation for the treatment of intractable CM. This search revealed 6 independent and 3 industry-sponsored clinical trials, the results of which are listed here.  Slavin and colleagues.28 This open-label trial included 10 patients with CM implanted with percutaneous occipital nerve stimulating leads. At the 22-month follow-up, 70% of patients had pain reduction ranging from 60% to 90% with a corresponding decrease in the use of analgesics.  Levy.29 This open-label prospective trial included 45 patients treated with peripheral nerve stimulation for CM. At the 2-year follow-up, 83% of patients reported good to excellent (>50% relief) results with an additional 9% of patients reporting fair (30%50%) results; 92% of the patients reported satisfaction with the therapy, a willingness to have the device implanted again based on their treatment experience, and their unwillingness to have the device removed even at no cost.  Silberstein and colleagues.30 This prospective, randomized, double-blind study included 157 patients with CM randomized 2:1 between active (n 5 105) and sham (n 5 52) ONS. At 12 weeks, there was no statistically significant difference between the groups in terms of responder rate, defined as greater than 50% pain reduction, which was their primary end point. There was, however, a statistically significant difference between groups at the level of 30% pain reduction. Furthermore, the active group had a statistically significant reduction in the number of headache days and in the degree of migraine-related disability.

INDEPENDENT CLINICAL TRIALS

 Weiner and Reed.26 This open-label trial included 13 patients implanted with percutaneous occipital leads for CM. Twelve patients reported a good to excellent response and required minimal oral analgesic medications at follow-up ranging from 18 months to 6 years.  Popeney and Alo.25 This open-label trial included 25 patients implanted with percutaneous occipital leads for CM. At the 18-month follow-up, 88% of patients showed a positive response, with an overall 50% reduction in the number of headache days per month.  Oh and colleagues.27 This open-label trial included 20 patients with transformed migraine headaches implanted with paddletype occipital nerve stimulating leads. At 6 months, 80% of patients reported greater than 75% pain relief and 95% reported improvement in their quality of life and their willingness to undergo the procedure again.

INDUSTRY-SPONSORED CLINICAL TRIALS

In 2013, peripheral neurostimulation for the treatment of CM has been approved for use in the European Union and in Australia. However, it has not yet been approved by the US Food and Drug Administration (FDA). ONS for CM is therefore used by physicians in the United States on an off-label basis. Industry is not allowed to market or promote the use of their products for off-label indications. Because of this limitation and the significant potential of this therapy for the treatment of migraine headache, the 3 major device manufacturers in this sector (Medtronic, Boston Scientific, St. Jude Medical) have sponsored research trials to investigate the safety and efficacy of their neurostimulation products for the treatment of migraine headaches.

Medtronic ONSTIM Trial

The Occipital Nerve Stimulation for the Treatment of Intractable Migraine (ONSTIM) trial, sponsored

Treatment of Chronic Migraine Headache

by Medtronic, was a multicenter, randomized, blind, controlled feasibility study. Patients with CM were included if they responded to occipital nerve block and were randomized to 3 groups: adjustable stimulation (AS), preset (sham) stimulation (PS), or medical management (MM). Seventyfive of the 110 enrolled participants were assigned to a treatment group and complete data were available for 66 of these patients. The response rate, defined as greater than 50% pain reduction, was 39%, 6%, and 0% for the AS, PS, and MM groups, respectively. Lead migration occurred in 24% of patients and infections developed in 14%.20 for 12 weeks. After 12 weeks, participants were unblinded but patients were followed for 1 year. Data collection from this study have been completed and publication is pending.

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MECHANISM OF ACTION
The exact mechanism of peripheral neuromodulation for CM is unknown; however, there are 2 prevailing theories. The first proposed mechanism is similar to the pain gait theory implicated in the mechanism of action of spinal cord or peripheral nerve stimulation for somatic neuropathic pain.31 The second theory, based on a PET imaging study, suggests that ONS results in retrograde modulation of the brainstem nuclei involved in the trigeminal-vascular system thus inhibiting or aborting migraine headaches.32

Boston Scientific PRISM Trial

The Precision Implantable Stimulator for Migraine (PRISM) trial, sponsored by Boston Scientific, was a prospective, randomized, double-blind, placebo-controlled trial of ONS for medically intractable migraine. All 139 patients had 6 days or more per month of migraine headaches and had failed therapy with a least 2 acute and 2 preventative medications. Before permanent implantation, all participants underwent percutaneous trial stimulation. There was a 12-week blind period when patients were randomized to receive bilateral active stimulation or sham stimulation; after 12 weeks, all patients were converted to active stimulation. The primary end point of the study at 12 weeks was change from baseline in migraine days per month; there was no significant difference between groups. Following permanent implantation, however, patients with a positive percutaneous trial demonstrated a reduction of 8.8 migraine days per month compared with a reduction of only 0.7 migraine days for those patients for whom the trial failed to provide relief (P<.001). The most frequent adverse events were device infection, nontarget area sensory phenomena, and pain at the implant site. These results were presented at the 14th Congress of the International Headache Society and the 51st Annual Scientific Meeting of the American Headache Society in September, 2009.

SUMMARY
Peripheral nerve stimulation, whether of the occipital nerve(s) alone or in combination with others, seems to be both safe and effective for the treatment of medically intractable migraine headaches. Further work is needed to optimize our knowledge regarding patient selection, stimulation targets and parameters, and device programing. At present, neurostimulation for migraine headache pain is performed in the United States on an offlabel basis, but based on our experience and the increasing evidence in the medical literature, we can look forward to its approval by the FDA in the near future so that patients with severe, medically intractable headache pain may gain access to these potentially important therapies.

REFERENCES
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St. Jude Medical Trial

St. Jude Medical Neuromodulation sponsored a randomized, controlled, pivotal trial of ONS for CM; 150 patients from 15 centers were enrolled, with success defined as a 50% reduction in pain and no increase in headache frequency or duration. Patients were randomized to either a stimulation trial followed by device implantation and active stimulation for 12 weeks or a stimulation trial followed by device implantation but sham stimulation

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