Peripheral Neuromodulationfor Treatment of ChronicMigraine 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 disabilityand lost productivity.

� Traditional neurosurgical procedures that favor lesioning or decompressing the greater occipitalnerve have not gained favor.

� Occipital nerve stimulation provides an attractive nondestructive alternative, but its degree of effi-cacy 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 modulationof the trigeminocervical complex in the rostral spinal cord.

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Between 25 and 45 million Americans experiencemigraine headaches; approximately 2.0% havechronic migraine (CM) headaches.1,2 CM is char-acterized by a minimum of 15 headache days permonth, and approximately half of the headachedays meet the diagnostic criteria for migrainewithout aura or respond to a migraine-specificacute medication.3 Individuals with CM are 4 timesmore likely to have major depression with morefrequent suicide attempts than in the general pop-ulation.4–6 Furthermore, compared with episodicmigraine, CM is associated with significantlygreater disability, economic burden, and impair-ments in health-related quality of life.7–10

Pharmacotherapy for migraine headaches in-cludes medications to relieve the acute pain (abor-tive agents) and medication to prevent the onset ofheadache (preventative agents). Abortive agentsinclude nonsteroidal antiinflammatory agents, tryp-tans, opioids, ergot compounds, and sedatives.Preventative agents include anticonvulsants, anti-depressants, b-adrenergic blockers, and serotonin

Department of Neurological Surgery, University of Florid* Corresponding author.E-mail address: rlevy@neuromodulation.com

Neurosurg Clin N Am 25 (2014) 11–14http://dx.doi.org/10.1016/j.nec.2013.08.0101042-3680/14/$ – see front matter � 2014 Elsevier Inc. All

antagonists. In addition, recognition and preven-tion of exposure to precipitating agents such ascaffeine, many foods including cheeses and redwines, and stress can provide significant reliefand reduce medication intake.

Historically, neurosurgical therapies for head-ache have included destructive proceduresincluding dorsal root entry zone (DREZ) lesioning,dorsal root ganglionectomy, peripheral neurolysis,and neurectomy. These therapies, however, havenot been effective for migraine headaches andsuch techniques may result in secondary neuro-pathic pain in the distribution of the surgicallytreated nerve(s). For example, ganglionectomy atthe second cervical level has been reported tobe 80% effective at 3 year follow-up in posttrau-matic second cervical pain syndromes.11 Nontrau-matic pain in this region, however, was notsignificantly relieved by ganglionectomy. Ventro-lateral DREZ lesioning at the first, second, orthird cervical level has been variably effective foroccipital neuralgia but is highly invasive and has

a College of Medicine, Jacksonville, FL, USA

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Tavanaiepour & Levy12

significant risks.12 Greater occipital nerve neuroly-sis has demonstrated short-term efficacy, how-ever, there was a significant recurrence ratewithin 2 years.13 In addition to neurolysis and neu-rectomy, fusion of the first and second cervicalvertebrae has relieved pain in some patients withoccipital neuralgia.14

Initially, peripheral nerve stimulation using a cuffelectrode or direct stimulation of the greater occip-ital nerve was found to be effective for treatingoccipital neuralgia.15,16 More recently, peripheralneuromodulation in the occipital region hasemerged as a promising treatment modality for avariety of chronic headache disorders, includingCM.17–25 Weiner and Reed26 first reported theuse of occipital nerve stimulation (ONS) for thetreatment of occipital neuralgia. However, positronemission tomography (PET) imaging of these pa-tients demonstrated activation patterns moreconsistent with CM than with occipital neuralgia,leading Matharu and colleagues17 to suggest thatWeiner and Reed’s patients suffered from CM.Since then, ONS has been reported to be effica-cious for the treatment of several headache disor-ders including migraine headaches,4,5 clusterheadache,6 hemicrania continua,25 and true oc-cipital neuralgia.24

An extensive literature search was performedwith a specific focus on high-quality clinical trialsof peripheral neuromodulation for the treatmentof intractable CM. This search revealed 6 indepen-dent and 3 industry-sponsored clinical trials, theresults of which are listed here.

INDEPENDENT CLINICAL TRIALS

� Weiner and Reed.26 This open-label trialincluded 13 patients implanted with percuta-neous occipital leads for CM. Twelve patientsreported a good to excellent response andrequired minimal oral analgesic medicationsat follow-up ranging from 18 months to6 years.

� Popeney and Alo.25 This open-label trialincluded 25 patients implanted with percuta-neous occipital leads for CM. At the 18-monthfollow-up, 88% of patients showed a positiveresponse, with an overall 50% reduction in thenumber of headache days per month.

� Oh and colleagues.27 This open-label trialincluded 20 patients with transformedmigraine headaches implanted with paddle-type occipital nerve stimulating leads. At6 months, 80% of patients reported greaterthan 75% pain relief and 95% reportedimprovement in their quality of life and theirwillingness to undergo the procedure again.

� Slavin and colleagues.28 This open-label trialincluded 10 patients with CM implanted withpercutaneous occipital nerve stimulatingleads. At the 22-month follow-up, 70% ofpatients had pain reduction ranging from60% to 90% with a corresponding decreasein the use of analgesics.

� Levy.29 This open-label prospective trialincluded 45 patients treated with peripheralnerve stimulation for CM. At the 2-yearfollow-up, 83% of patients reported goodto excellent (>50% relief) results with anadditional 9% of patients reporting fair(30%–50%) results; 92% of the patients re-ported satisfaction with the therapy, a willing-ness to have the device implanted againbased on their treatment experience, andtheir unwillingness to have the deviceremoved even at no cost.

� Silberstein and colleagues.30 This prospec-tive, randomized, double-blind study included157 patients with CM randomized 2:1 be-tween active (n 5 105) and sham (n 5 52)ONS. At 12 weeks, there was no statisticallysignificant difference between the groups interms of responder rate, defined as greaterthan 50% pain reduction, which was their pri-mary end point. There was, however, a statis-tically significant difference between groupsat the level of 30% pain reduction. Further-more, the active group had a statistically sig-nificant reduction in the number of headachedays and in the degree of migraine-relateddisability.

INDUSTRY-SPONSORED CLINICAL TRIALS

In 2013, peripheral neurostimulation for the treat-ment of CM has been approved for use in theEuropean Union and in Australia. However, it hasnot yet been approved by the US Food and DrugAdministration (FDA). ONS for CM is thereforeused by physicians in the United States on anoff-label basis. Industry is not allowed to marketor promote the use of their products for off-labelindications. Because of this limitation and thesignificant potential of this therapy for the treat-ment of migraine headache, the 3 major devicemanufacturers in this sector (Medtronic, BostonScientific, St. Jude Medical) have sponsoredresearch trials to investigate the safety and effi-cacy of their neurostimulation products for thetreatment of migraine headaches.

Medtronic ONSTIM Trial

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

Treatment of Chronic Migraine Headache 13

by Medtronic, was a multicenter, randomized,blind, controlled feasibility study. Patients withCM were included if they responded to occipitalnerve block and were randomized to 3 groups:adjustable stimulation (AS), preset (sham) stimula-tion (PS), or medical management (MM). Seventy-five of the 110 enrolled participants were assignedto a treatment group and complete data wereavailable for 66 of these patients. The responserate, defined as greater than 50% pain reduction,was 39%, 6%, and 0% for the AS, PS, andMM groups, respectively. Leadmigration occurredin 24% of patients and infections developedin 14%.20

Boston Scientific PRISM Trial

The Precision Implantable Stimulator for Migraine(PRISM) trial, sponsored by Boston Scientific,was a prospective, randomized, double-blind, pla-cebo-controlled trial of ONS for medically intrac-table migraine. All 139 patients had 6 days ormore per month of migraine headaches and hadfailed therapy with a least 2 acute and 2 preven-tative medications. Before permanent implanta-tion, all participants underwent percutaneous trialstimulation. There was a 12-week blind periodwhen patients were randomized to receive bilat-eral active stimulation or sham stimulation; after12 weeks, all patients were converted to activestimulation. The primary end point of the study at12 weeks was change from baseline in migrainedays per month; there was no significant dif-ference between groups. Following permanent im-plantation, however, patients with a positivepercutaneous trial demonstrated a reduction of8.8 migraine days per month compared with areduction of only 0.7 migraine days for those pa-tients for whom the trial failed to provide relief(P<.001). The most frequent adverse events weredevice infection, non–target area sensory phe-nomena, and pain at the implant site. These resultswere presented at the 14th Congress of the Inter-national Headache Society and the 51st AnnualScientific Meeting of the American Headache So-ciety in September, 2009.

St. Jude Medical Trial

St. Jude Medical Neuromodulation sponsored arandomized, controlled, pivotal trial of ONS forCM; 150 patients from 15 centers were enrolled,with success defined as a 50% reduction in painand no increase in headache frequency or dura-tion. Patients were randomized to either a stimula-tion trial followed by device implantation and activestimulation for 12 weeks or a stimulation trial fol-lowed by device implantation but sham stimulation

for 12weeks. After 12weeks, participants were un-blinded but patients were followed for 1 year. Datacollection from this study have been completedand publication is pending.

MECHANISM OF ACTION

The exact mechanism of peripheral neuromodula-tion for CM is unknown; however, there are 2 pre-vailing theories. The first proposed mechanism issimilar to the pain gait theory implicated in themechanism of action of spinal cord or peripheralnerve stimulation for somatic neuropathic pain.31

The second theory, based on a PET imaging study,suggests that ONS results in retrograde modula-tion of the brainstem nuclei involved in thetrigeminal-vascular system thus inhibiting oraborting migraine headaches.32

SUMMARY

Peripheral nerve stimulation, whether of the occip-ital nerve(s) alone or in combination with others,seems to be both safe and effective for the treat-ment of medically intractable migraine headaches.Further work is needed to optimize our knowledgeregarding patient selection, stimulation targetsand parameters, and device programing. At pre-sent, neurostimulation for migraine headachepain is performed in the United States on an off-label basis, but based on our experience and theincreasing evidence in the medical literature, wecan look forward to its approval by the FDA inthe near future so that patients with severe, medi-cally intractable headache pain may gain accessto these potentially important therapies.

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