Migraine

Migraine is the most common type of vascular headache. Migraine headaches are usually characterized by severe pain on one or both sides of the head, an upset stomach, and, at times, disturbed vision. One year prevalence of migraine ranges from 6% to 15% in adult men and from 14% to 35% in adult women. Migraine headaches may last a day or more, and can strike as often as several times a week or as rarely as once every few years.

Treatment of Migraine

Drug therapy for migraine is often combined with biofeedback and relaxation training. Sumatriptan and other triptans are commonly used for relief of symptoms. Drugs used to prevent migraine include amitriptyline, propranolol and other β-blockers, topiramate and other antiepileptic drugs, and verapamil.

Hemicrania Continua

Hemicrania continua causes moderate and occasionally severe pain on only one side of the head. At least one of the following symptoms must also occur: conjunctival injection and/or lacrimation, nasal congestion and/or rhinorrhea, or ptosis, and/or miosis. Headache occurs daily and is continuous with no pain-free periods. Hemicrania continua occurs mainly in women, and its true prevalence is not known.

Treatment of Hemicrania Continua

Indomethacin usually provides rapid relief of symptoms. Other nonsteroidal anti-inflammatory drugs, including ibuprofen, celecoxib, and naproxen, can provide some relief of symptoms. Amitriptyline and other tricyclic antidepressants are effective in some patients.

Cluster Headache

Cluster headache occurs in cyclical patterns or clusters of severe or very severe unilateral orbital or supraorbital and/or temporal pain. The headache is accompanied by at least one of the following autonomic symptoms: ptosis, conjunctival injection, lacrimation, rhinorrhea, and, less commonly, facial blushing, swelling, or sweating. Bouts of 1 headache every other day up to 8 attacks per day may last from weeks to months, usually followed by remission periods when the headache attacks stop completely. The pattern varies by person, but most people have 1 or 2 cluster periods a year. During remission, no headaches occur for months, and sometimes even years. The intense pain is caused by the dilation of blood vessels, which creates pressure on the trigeminal nerve. While this process is the immediate cause of the pain, the etiology is not fully understood. It is more common in men than in woman. One-year prevalence is estimated to be 0. to 1. in 1000.

Treatment of Cluster Headache

Management of cluster headache consists of abortive and preventive treatment. Abortive treatments include subcutaneous injection of sumatriptan, topical anesthetics sprayed into the nasal cavity, and strong coffee. Some patients respond to rapidly inhaled pure oxygen. A variety of other pharmacologic and behavioral methods of aborting and preventing attacks have been reported with wide variation in patient response.

Peripheral Nerve Stimulators

Implanted peripheral nerve stimulators have been used to treat refractory pain for many years, but have only recently been proposed to manage craniofacial pain. Occipital, supraorbital, and infraorbital stimulation have been reported in the literature.

Regulatory Status

The U.S. Food and Drug Administration (FDA) has not cleared or approved any occipital nerve stimulation device for treatment of headache. In 1999, the Synergy™ IPG device (Medtronic), an implantable pulse generator, was approved by the FDA through the premarket approval process for management of chronic, intractable pain of the trunk or limbs, and off-label use for headache is described in the literature. The Genesis™ Neuromodulation System (St. Jude Medical) was approved by the FDA for spinal cord stimulation, and the Eon™ stimulator has received CE mark approval in Europe for the treatment of chronic migraines.

RELATED POLICIES

• Spinal Cord and Implantable Peripheral Nerve Stimulators (Policy #067 in the Surgery Section)
• Electrotherapies in Pain Management (Policy #025 in the Treatment Section)

Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function, including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Migraine Headache
Clinical Context and Therapy Purpose

Migraine is the most common type of vascular headache. Migraine headaches are usually characterized by severe pain on one or both sides of the head, an upset stomach, and, at times, disturbed vision. One-year prevalence of migraine ranges from 6% to 15% in adult men and from 14% to 35% in adult women. Migraine headaches may last a day or more, and can strike as often as several times a week or as rarely as once every few years.

The purpose of occipital nerve stimulation in patients who have migraines is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this policy is: Does occipital nerve stimulation improve the net health outcome in patients who have migraines?

The following PICO was used to select literature to inform this policy.

Patients
The relevant population of interest is patients with migraine headache.

Intervention

The therapy being considered is occipital nerve stimulation.

Occipital nerve stimulation delivers a small electrical charge to the occipital nerve intended to prevent migraines and other headaches in patients who have not responded to medications. The device consists of a subcutaneously implanted pulse generator (in the chest wall or abdomen) attached to extension leads that are tunneled to join electrodes placed across one or both occipital nerves at the base of the skull. Continuous or intermittent stimulation may be used.

The occipital nerve stimulation device is implanted by a physician trained in the procedure, such as a neurologist, in an outpatient clinical setting.

Comparators

Comparators of interest include medication and self-management (eg, relaxation, exercise), which are prescribed by general practitioner physicians or neurologists in an outpatient clinical setting.

Outcomes
The general outcomes of interest are symptoms, functional outcomes, quality of life, and treatment-related morbidity. Based on the available literature, follow-up of 12 weeks to 1 year is recommended.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

1. To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for randomized controlled trials (RCTs).
2. In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
3. To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
4. Studies with duplicative or overlapping populations were excluded.

Yang et al (2016)^2, identified the same 5 RCTs as Chen in their systematic review. The Yang review only included studies conducted with patients who had migraines for at least 6 months in duration who did not respond to oral medications. In addition to the RCTs, 5 case series met the inclusion criteria. Yang did not pool study findings. The definition of response rate varied across studies and could include frequency and/or severity of headaches. Response rates in 3 case series with self-reported efficacy were 100% in each, and response rates in the other 2 series were 50% and 89%, respectively. Complication rates in the series ranged from 40% to 100%. Reviewers noted that the case series were subject to biases (eg, inability to control for the placebo effect), that RCT evidence was limited, and that complication rates were high. The most common complications were lead migration (21% of patients) and infection (7% of patients).

The 2 parallel-group RCTs published as full-text journal articles are detailed next. Saper et al (2011) reported on the Occipital Nerve Stimulation for the Treatment of Intractable Chronic Migraine Headache trial, which was a multicenter, randomized feasibility study of occipital nerve stimulation for treatment of intractable chronic migraine headache refractory to preventive medical management.^3, The trial evaluated study design and had no primary endpoint. One hundred ten patients were enrolled, and patients who had a positive response to a short-acting occipital nerve block were randomized as follows: 33 to adjustable stimulation, 17 to preset stimulation of 1 min/d, and 17 to medical management. At the 3-month evaluation, the response rate (percentage of patients who achieved ≥50% reduction in number of headache days per month or a ≥3-point reduction in average overall pain intensity vs. baseline) was 39% in the adjustable stimulation group, 6% in the preset stimulation group, and 0% in the medical management group. Twelve (24%) of 51 subjects who had successful occipital nerve stimulation device implantation experienced lead migration and 3 (6%) of the 51 subjects were hospitalized for adverse events (infection, lead migration, nausea). Trial limitations included a short observation period and ineffective blinding of subjects and investigators to treatment groups.

Silberstein et al (2012) reported on an industry-sponsored, double-blind trial, regulated by U.S. Food and Drug Administration (FDA) that randomized 157 patients with chronic migraine refractory to preventive medical management in a 2:1 ratio to active or sham stimulation.^4, Intention-to-treat (ITT) analysis revealed no significant differences between groups in the percentage of patients who achieved 50% or greater reduction in visual analog scale scores for pain at 12 weeks (active, 17.1%; control, 13.5%). More patients in the occipital nerve stimulation group had fewer days with headache, less migraine-related disability, and greater pain relief, although benefits were modest. The most common adverse event was persistent implant site pain. Dodick et al (2015) published results from the 52-week open-label extension of this trial.^5, Results were reported for the intention to treat (ITT) population and for the 125 patients who met selection criteria for intractable chronic migraine. Twenty-four patients were excluded from analysis due to explantation of the occipital nerve stimulation system (n=18) or loss to follow-up. Mean headache days at baseline were 21.6 for the intention to treat (ITT) population and 24.2 for the intractable chronic migraine group. In the ITT population, headache days were reduced by 6.7 days, and a reduction of 50% or more in the number of headache days and/or pain intensity was observed in 47.8% of this group. Seventy percent of patients experienced at least 1 of 183 device-related adverse events, of which 8.6% of events required hospitalization and 40.7% of events required surgical intervention. Eighteen percent of patients had persistent pain and/or numbness with the device.

Section Summary: Migraine Headache

Two systematic reviews (2015, 2016) each identified 5 sham-controlled randomized trials. One of the systematic reviews also identified 5 case series. Findings from pooled analyses of RCTs were mixed. For example, compared with sham stimulation, response rates (ie, ≥50% reduction in visual analog scale score for occipital nerve stimulation did not differ significantly, but the number of days with prolonged moderate-to-severe headache was reduced. Occipital nerve stimulation was also associated with a substantial number of minor and serious adverse events.

Non-Migraine Headaches
Clinical Context and Therapy Purpose

The non-migraine headaches included in this policy are hemicrania continua and cluster headache. Hemicrania continua causes moderate and occasionally severe pain on only one side of the head. At least one of the following symptoms must also occur: conjunctival injection and/or lacrimation, nasal congestion and/or rhinorrhea, or ptosis, and/or miosis. Headache occurs daily and is continuous with no pain-free periods. Hemicrania continua occurs mainly in women, and its true prevalence is not known.

Cluster headache occurs in cyclical patterns or clusters of severe or very severe unilateral orbital or supraorbital and/or temporal pain. The headache is accompanied by at least one of the following autonomic symptoms: ptosis, conjunctival injection, lacrimation, rhinorrhea, and, less commonly, facial blushing, swelling, or sweating. Bouts of one headache every other day up to 8 attacks per day may last from weeks to months, usually followed by remission periods when the headache attacks stop completely. The pattern varies by person, but most people have 1 or 2 cluster periods a year. During remission, no headaches occur for months, and sometimes even years. The intense pain is caused by the dilation of blood vessels, which creates pressure on the trigeminal nerve. While this process is the immediate cause of the pain, the etiology is not fully understood. It is more common in men than in women. One-year prevalence is estimated to be 0 to 1 in 1000.

The purpose of occipital nerve stimulation in patients who have non-migraine headache is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this policy is: Does occipital nerve stimulation improve the net health outcome in patients who have non-migraine headache?

The following PICO was used to select literature to inform this policy.

Patients

The relevant population of interest is patients with non-migraine headache.

Intervention

The therapy being considered is occipital nerve stimulation.

Occipital nerve stimulation delivers a small electrical charge to the occipital nerve intended to prevent migraines and other headaches in patients who have not responded to medications. The device consists of a subcutaneously implanted pulse generator (in the chest wall or abdomen) attached to extension leads that are tunneled to join electrodes placed across one or both occipital nerves at the base of the skull. Continuous or intermittent stimulation may be used.

The occipital nerve stimulation device is implanted by a physician trained in the procedure, such as a neurologist, in an outpatient clinical setting.

Comparators

Comparators of interest include medication and self-management (eg, relaxation, exercise), which are prescribed by general practitioner physicians or neurologists in an outpatient clinical setting.

Outcomes

The general outcomes of interest are symptoms, functional outcomes, quality of life, and treatment-related morbidity. Based on the available literature, follow-up of 12 weeks to 1 year is recommended.

Study Selection Criteria

Methodologically credible studies were selected using the principles described in the first indication.

Hemicrania Continua

The evidence evaluating the use of occipital nerve stimulation for hemicrania continua consists of a small crossover study. Burns et al (2008) reported on the efficacy of continuous unilateral occipital nerve stimulation in 6 patients.^6, Pain on a 10-point scale was recorded hourly in patient diaries, and the Migraine Disability Assessment was administered at each follow-up visit. Four of 6 patients reported substantially less pain (range, 80%-95% less), one reported 30% less pain, and one reported 20% worse pain. Adverse events were mild and associated with transient overstimulation.

Cluster Headache

Several case series assessing cluster headache were identified, with sample sizes ranging from 10 to 67 patients.^{7,8,9,10,11,12,} Fontaine et al (2017) published a prospective case series of 67 patients with chronic cluster headache.^10, Data were taken from a French occipital nerve stimulation database on treatment of refractory headache disorders. Sixty-seven patients with chronic cluster headache were included in the database; data were available for 52 (78%) patients at 3 months and 44 (66%) patients at 12 months. The primary outcome was a composite score that incorporated patient’s global impression of change, reduction in the frequency of headache attacks, and changes in prophylactic medications. For patients with available data, at 3 months, 34 (65.4%) of 52 were considered to be excellent responders, 9 (17.3%) of 52 were mild responders, and 9 (17.3%) of 52 were nonresponders. At 12 months, 22 (48%) of 44 were excellent responders, 10 (21.7%) of 44 were mild responders, and 15 (32.6%) of 44 were nonresponders. The series had a large amount of missing data at follow-up.

Leone et al (2017) published a case series on use of occipital nerve stimulation in 35 patients with chronic cluster headache.^11, This series had the longest follow-up (median, 6.1 years; range, 1.6-10.7 years). Selection criteria included daily or almost daily cluster headache attacks in the past year and resistance of prophylactic drugs. Twenty (66.7%) of the 30 patients in the per protocol analysis had 50% or more reduction in number of headaches per day and were considered responders. In 12 (40%) patients, improvement was considered stable (ie, ≤3 headache attacks per month).

Limitations of the series reporting on cluster headaches included lack of blinding and comparison groups.

Headache Associated With Chiari Malformation

Vadivelu et al (2012) reported on a series of 22 patients with Chiari malformation and persistent occipital headaches.^13, Of the 22, 15 (68%) had a successful occipital neurostimulator trial and underwent permanent implantation. At a mean follow-up of 18.9 months (range, 6-51 months), 13 (87%) of the 15 patients reported pain relief greater than 50%. Forty percent of patients reported device-related complications requiring additional surgery (lead migration, uncomfortable position of generator, wound infection) during follow-up.

Occipital Neuralgia

A systematic review by Sweet et al (2015) identified 9 small case series (<15 patients each) assessing the efficacy of occipital nerve stimulation for treating medically refractory occipital neuralgia.^14, Reviewers did not pool study findings. Conclusions cannot be drawn on the impact of occipital nerve stimulation on occipital neuralgia due to the lack of RCTs or other controlled studies.

Section Summary: Non-Migraine Headaches

The evidence on occipital nerve stimulation for treatment of non-migraine headaches consists of case series; no RCTs or nonrandomized comparative studies were identified. Many of the case series were small; series with over 25 patients were available only for treatment of cluster headache. Although case series tended to find that a substantial number of patients improved after occipital nerve stimulation, the studies lacked blinding and comparison groups. RCTs are needed to assess outcomes between occipital nerve stimulation and comparators (eg, to control for a potential placebo effect).

Summary of Evidence

For individuals who have migraine headaches refractory to preventive medical management who receive occipital nerve stimulation, the evidence includes randomized controlled trials (RCTs), systematic reviews of RCTs, and observational studies. Relevant outcomes are symptoms, functional outcomes, quality of life, and treatment-related morbidity. Systematic reviews identified 5 sham-controlled randomized trials. Findings from pooled analyses of these RCTs were mixed. For example, compared with placebo, response rates to occipital nerve stimulation did not differ significantly but did reduce the number of days with prolonged moderate-to-severe headache. Occipital nerve stimulation was also associated with a substantial number of minor and serious adverse events. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have non-migraine headaches (eg, hemicrania continua, cluster headaches) who receive occipital nerve stimulation, the evidence includes case series. Relevant outcomes are symptoms, functional outcomes, quality of life, and treatment-related morbidity. Many of the case series had small sample sizes; series with over 25 patients were available only for treatment of cluster headache. Although the case series tended to find that a substantial number of patients improved after occipital nerve stimulation, these studies lacked blinding and comparison groups. RCTs are needed to compare outcomes between occipital nerve stimulation and comparators (eg, to control for a potential placebo effect). The evidence is insufficient to determine the effects of the technology on health outcomes.

SUPPLEMENTAL INFORMATION
Practice Guidelines and Position Statements
Congress of Neurological Surgeons

In 2015, the Congress of Neurological Surgeons released an evidence-based guideline that stated, “the use of occipital nerve stimulators is a treatment option for patients with medically refractory occipital neuralgia.”^14, The statement had a level III recommendation based on a systematic review of literature (see Rationale section) that only identified case series.

National Institute for Health and Care Excellence

In 2013, the National Institute for Health and Care Excellence issued a guidance noting that the evidence on occipital nerve stimulation for intractable chronic migraine showed “some efficacy in the short term but very little evidence about long‑term outcomes. With regard to safety, there is a risk of complications, needing further surgery.”^15,

U.S. Preventive Services Task Force Recommendations

Not applicable.

Medicare National Coverage

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this policy are listed in Table 1.

Table 1. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT01151631	Occipital Nerve Stimulation in Medically Intractable Chronic Cluster Headache (ICON).	144	March 2019
NCT03475797	Evaluation of Occipital Nerve Stimulation in Intractable Occipital Neuralgia: A Multicentric, Controlled, Randomized Study	70	December 2022
Unpublished
NCT03398668	Combined Occipital and Supraorbital Transcutaneous Nerve Stimulation for Treatment of Migraine	58

NCT: national clinical trial.]
________________________________________________________________________________________

Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

___________________________________________________________________________________________________________________________

Index:
Occipital Nerve Stimulation
Synergy
Precision

References:
1. Chen YF, Bramley G, Unwin G, et al. Occipital nerve stimulation for chronic migraine--a systematic review and meta-analysis. PLoS One. Mar 2015;10(3):e0116786. PMID 25793740

2. Yang Y, Song M, Fan Y, et al. Occipital nerve stimulation for migraine: a systematic review. Pain Pract. Apr 2016;16(4):509-517. PMID 25865962

3. Saper JR, Dodick DW, Silberstein SD, et al. Occipital nerve stimulation for the treatment of intractable chronic migraine headache: ONSTIM feasibility study. Cephalalgia. Feb 2011;31(3):271-285. PMID 20861241

4. Silberstein SD, Dodick DW, Saper J, et al. Safety and efficacy of peripheral nerve stimulation of the occipital nerves for the management of chronic migraine: results from a randomized, multicenter, double-blinded, controlled study. Cephalalgia. Dec 2012;32(16):1165-1179. PMID 23034698

5. Dodick DW, Silberstein SD, Reed KL, et al. Safety and efficacy of peripheral nerve stimulation of the occipital nerves for the management of chronic migraine: long-term results from a randomized, multicenter, double- blinded, controlled study. Cephalalgia. Apr 2015;35(4):344-358. PMID 25078718

6. Burns B, Watkins L, Goadsby PJ. Treatment of hemicrania continua by occipital nerve stimulation with a bion device: long-term follow-up of a crossover study. Lancet Neurol. Nov 2008;7(11):1001-1012. PMID 18845482

7. Burns B, Watkins L, Goadsby PJ. Treatment of intractable chronic cluster headache by occipital nerve stimulation in 14 patients. Neurology. Jan 27 2009;72(4):341-345. PMID 19171831

8. Magis D, Gerardy PY, Remacle JM, et al. Sustained effectiveness of occipital nerve stimulation in drug-resistant chronic cluster headache. Headache. Sep 2011;51(8):1191-1201. PMID 21848953

9. Mueller OM, Gaul C, Katsarava Z, et al. Occipital nerve stimulation for the treatment of chronic cluster headache - lessons learned from 18 months experience. Cen Eur Neurosurg. May 2011;72(2):84-89. PMID 21448856

10. Fontaine D, Blond S, Lucas C, et al. Occipital nerve stimulation improves the quality of life in medically- intractable chronic cluster headache: Results of an observational prospective study. Cephalalgia. Oct 2017;37(12):1173-1179. PMID 27697849

11. Leone M, Proietti Cecchini A, Messina G, et al. Long-term occipital nerve stimulation for drug-resistant chronic cluster headache. Cephalalgia. Jul 2017;37(8):756-763. PMID 27250232

12. Miller S, Watkins L, Matharu M. Treatment of intractable chronic cluster headache by occipital nerve stimulation: a cohort of 51 patients. Eur J Neurol. Feb 2017;24(2):381-390. PMID 27995704

13. Vadivelu S, Bolognese P, Milhorat TH, et al. Occipital nerve stimulation for refractory headache in the Chiari malformation population. Neurosurgery. Jun 2012;70(6):1430-1436; discussion 1436-1437. PMID 22418582

14. Sweet JA, Mitchell LS, Narouze S, et al. Occipital nerve stimulation for the treatment of patients with medically refractory occipital neuralgia: Congress of Neurological Surgeons Systematic Review and Evidence-Based Guideline. Neurosurgery. Sep 2015;77(3):332-341. PMID 26125672

15. National Institute for Health and Care Excellence. Occipital nerve stimulation for intractable chronic migraine [IPG452]. 2013; https://www.nice.org.uk/guidance/ipg452. Accessed March 4, 2020.

64555
64575
64585
64590
64595

L8679
L8680
L8681
L8685
L8686
L8687
L8688
L8689