Efficacy of Electrical Stimulation of the Occipital Nerve in Intractable Primary Headache Disorders: A Systematic Review with Meta-Analyses

Aims: To determine the efficacy of occipital nerve stimulation (ONS) in reducing the intensity, duration, and frequency of medically intractable primary headaches. Methods: A systematic review was carried out by searching three electronic databases: the Cochrane Library, MEDLINE via PubMed, and Web of Science. Randomized controlled trials (RCTs) and case series were eligible for inclusion. RCTs were assessed for quality of evidence by using the Cochrane Risk of Bias and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) tools. Descriptive statistics of reported outcomes in eligible studies are presented in tabular form. Meta-analyses of RCTs comparing ONS therapy to sham therapy in chronic migraine patients were conducted for the outcomes responder rate, headache frequency, and headache intensity. Results: Four RCTs, 1 follow-up study, and 19 case series met the inclusion criteria. The quality of the evidence was low, with all four RCTs assessed as having a high risk of bias and small sample size. Meta-analyses of three RCTs showed patients receiving ONS therapy had a significant reduction of 3 headache days per month (difference in means = –3.061; 95% confidence interval [CI] = –5.162 to –0.961; P = .004) and a significant reduction in Migraine Disability Assessment score (standardized difference in means [SDM] = –0.634; 95% CI = –0.933 to –0.335; P < .001) compared to sham (subthreshold) therapy. There were no statistically significant differences in reduction in pain intensity (SDM = –1.220; 95% CI = –2.489 to –0.049; P = .060) or in the number of responders (risk ratio [RR] = 1.581; 95% CI = 0.749 to 3.355; P = .229). Conclusion: ONS may be effective when compared to sham therapy, but the small number of RCTs and the heterogeneity of outcomes suggest further research in this field is needed.

chronic migraine;cluster headache;meta-analyses;occipital nerve stimulation;primary headache disorders

1. Silberstein SD. Preventive treatment of headaches. Curr Opin Neurol 2005;18:289–292.

2. Marmura MJ, Silberstein SD, Schwedt TJ. The acute treat- ment of migraine in adults: The American Headache Society Evidence Assessment of Migraine Pharmacotherapies. Headache 2015;55:3–20.

3. Pringsheim T, Davenport WJ, Marmura MJ, Schwedt TJ, Silberstein S. How to apply the AHS Evidence Assessment of the Acute Treatment of Migraine in Adults to your patient with migraine. Headache 2016;56:1194–1200.

4. Jackson JL, Shimeall W, Sessums L, et al. Tricyclic antidepres- sants and headaches: Systematic review and meta-analysis. BMJ 2010;341:c5222.

5. Wall PD, Sweet WH. Temporary abolition of pain in man. Science 1967;155:108–109.

6. Weiner RL, Reed KL. Peripheral neurostimulation for control of intractable occipital neuralgia. Neuromodulation 1999;2: 217–221.

7. Tepper D. Stimulators for the treatment of headache. Headache 2014;54:593–594.

8. Popeney CA, Aló KM. Peripheral neurostimulation for the treat- ment of chronic, disabling transformed migraine. Headache 2003;43:369–375.

9. Saper JR, Dodick DW, Silberstein SD, et al. Occipital nerve stimulation for the treatment of intractable chronic migraine headache: ONSTIM feasibility study. Cephalalgia 2011;31: 271–285.

10. Serra G, Marchioretto F. Occipital nerve stimulation for chronic migraine: A randomized trial. Pain Physician 2012;15:245–253.

11. Silberstein SD, Dodick DW, Saper J, et al. Safety and efficacy of peripheral nerve stimulation of the occipital nerves for the man- agement of chronic migraine: Results from a randomized, mul-ticenter, double blinded, controlled study. Cephalalgia 2012; 32:1165–1179.

12. Slotty PJ, Bara G, Kowatz L, et al. Occipital nerve stimulation for chronic migraine: A randomized trial on subthreshold stimula- tion. Cephalalgia 2015;35:73–78.

13. Bartsch T, Goadsby PJ. Increased responses in trigeminocervi- cal nociceptive neurons to cervical input after stimulation of the dura mater. Brain 2003;126:1801–1813.

14. Bartsch T, Goadsby PJ. Stimulation of the greater occipital nerve induces increased central excitability of dural afferent in- put. Brain 2002;125:1496–1509.

15. Goadsby PJ, Knight YE, Hoskin KL. Stimulation of the great- er occipital nerve increases metabolic activity in the trigemi- nal nucleus caudalis and cervical dorsal horn of the cat. Pain 1997;73:23–28.

16. Sharan A, Huh B, Narouze S, et al. Analysis of adverse events in the management of chronic migraine by peripheral nerve stimu- lation. Neuromodulation 2015;18:305–312.

17. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med 2009;6:e1000097.

18. Dodick DW, Silberstein SD, Reed KL, et al. Safety and effi- cacy 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 2015;35:344–358.

19. Higgins J, Green S (eds). Cochrane Handbook for Systematic Reviews of Interventions, version 5.1.0. Cochrane Collaboration, 2011.

20. Cochran WG. The combination of estimates from different ex-periments. Biometrics 1954;10:101–129.

21. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002;21:1539–1558.

22. Weiner RL, Reed KL. Peripheral neurostimulation for con- trol of intractable occipital neuralgia. Neuromodulation 1999;2:217–221.

23. Oh MY, Ortega J, Bellotte JB, Whiting DM, Aló K. Peripheral nerve stimulation for the treatment of occipital neuralgia and transformed migraine using a C1-2-3 subcutaneous paddle style electrode: A technical report. Neuromodulation 2004;7: 103–112.

24. Kapural L, Mekhail N, Hayek SM, Stanton-Hicks M, Malak O. Occipital nerve electrical stimulation via the midline approach and subcutaneous surgical leads for treatment of severe occip- ital neuralgia: A pilot study. Anesth Analg 2005;101:171–174.

25. Mueller O, Diener HC, Dammann P, et al. Occipital nerve stim- ulation for intractable chronic cluster headache or migraine: A critical analysis of direct treatment costs and complications. Cephalalgia 2013;33:1283–1291.

26. Mueller OM, Gaul C, Katsarava Z, Diener HC, Sure U, Gasser T. Occipital nerve stimulation for the treatment of chronic clus- ter headache—Lessons learned from 18 months experience. Cent Eur Neurosurg 2011;72:84–89.

27. Schwedt TJ, Dodick DW, Hentz J, Trentman TL, Zimmerman RS. Occipital nerve stimulation for chronic headache—Long- term safety and efficacy. Cephalalgia 2007;27:153–157.

28. Strand NH, Trentman TL, Vargas BB, Dodick DW. Occipital nerve stimulation with the Bion microstimulator for the treat- ment of medically refractory chronic cluster headache. Pain Physician 2011;14:435–440.

29. Magis D, Allena M, Bolla M, De Pasqua V, Remacle JM, Schoenen J. Occipital nerve stimulation for drug-resistant chronic cluster headache: A prospective pilot study. Lancet Neurol 2007;6:314–321.

30. Magis D, Gerardy PY, Remacle JM, Schoenen J. Sustained effectiveness of occipital nerve stimulation in drug-resistant chronic cluster headache. Headache 2011;51:1191–1201.

31. Burns B, Watkins L, Goadsby PJ. Treatment of medically in- tractable cluster headache by occipital nerve stimulation: Long- term follow-up of eight patients. Lancet 2007;369:1099–1106.

32. Burns B, Watkins L, Goadsby PJ. Treatment of intractable chronic cluster headache by occipital nerve stimulation in 14 patients. Neurology 2009;72:341–345.

33. 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 2008;7:1001–1012.

34. Matharu MS, Bartsch T, Ward N, Frackowiak RS, Weiner R, Goadsby PJ. Central neuromodulation in chronic migraine pa- tients with suboccipital stimulators: A PET study. Brain 2004; 127:220–230.

35. Melvin EA Jr, Jordan FR, Weiner RL, Primm D. Using peripheral stimulation to reduce the pain of C2-mediated occipital head- aches: A preliminary report. Pain Physician 2007;10:453–460.

36. Fontaine D, Christophe Sol J, Raoul S, et al. Treatment of re- fractory chronic cluster headache by chronic occipital nerve stimulation. Cephalalgia 2011;31:1101–1105.

37. Mueller O, Diener HC, Dammann P, et al. Occipital nerve stim- ulation for intractable chronic cluster headache or migraine: A critical analysis of direct treatment costs and complications. Cephalalgia 2013;33:1283–1291.

38. Chen YF, Bramley G, Unwin G, et al. Occipital nerve stimulation for chronic migraine—A systematic review and meta-analysis. PLoS One 2015;10:e0116786.

39. Lambru G, Matharu MS. Peripheral neurostimulation in primary headaches. Neurol Sci 2014;35(suppl):s77–s81.

40. Johnstone CS, Sundaraj R. Occipital nerve stimulation for the treatment of occipital neuralgia—eight case studies. Neuromodulation 2006;9:41–47.

41. Slavin KV, Nersesyan H, Wess C. Peripheral neurostimulation for treatment of intractable occipital neuralgia. Neurosurgery 2006;58:112–119.

42. Trentman TL, Zimmerman RS, Dodick DW. Occipital nerve stimulation: Technical and surgical aspects of implantation. Prog Neurol Surg 2011;24:96–108.

43. Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders: 2nd edition. Cephalalgia 2004;24(suppl 1):s9–s160.