Emerging Therapies for Chronic Migraine

  • Alberto Proietti CecchiniEmail author
  • Licia Grazzi
Chronic Daily Headache (SJ Wang, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Chronic Daily Headache


Not all chronic migraines are medication-overuse headaches and so the challenge is how to treat them. Currently available pharmacological therapies may be ineffective or they are abandoned because of intolerable side effects. There is still much room for novel therapeutic approaches in those with drug refractory migraine (RM). Occipital nerve stimulation (ONS) and botulinum toxin type A have finally gained a level of evidence based on the results of RCTs and pooled analysis, which by and large have shown at least a modest but valuable therapeutic effect. For a long time, these two approaches were only supported by clinical experience and open-label studies. Considering the disabling nature of migraine disorder, the large prevalence and serious impact on health-related quality of life and health care costs, any degree of response to treatment is acceptable and welcomed by the patient. An important issues for future studies would be better patient selection when finding candidates for each procedure.


Neurostimulation Occipital nerve stimulation Chronic migraine Refractory migraine Chronic pain Botulinum toxin type A 


Compliance with Ethics Guidelines

Conflict of Interest

Dr. Alberto Proietti Cecchini and Dr. Licia Grazzi each declare no potential conflicts of interest relevant to this article.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    Aubrey N, Manack AN, Buse DC, Lipton RB. Chronic migraine: epidemiology and disease burden. Curr Pain Headache Rep. 2011;15(1):70–8.CrossRefGoogle Scholar
  2. 2.
    Schulman E. Refractory migraine - a review. Headache. 2013;53(4):599–613.PubMedCrossRefGoogle Scholar
  3. 3.
    Silberstein SD, Dodick DW, Pearlman S. Defining the pharmacologically intractable headache for clinical trials and clinical practice. Headache. 2010;50(9):1499–506.PubMedCrossRefGoogle Scholar
  4. 4.
    Coppola G, Schoenen J. Cortical excitability in chronic migraine. Curr Pain Headache Rep. 2012;16:93–100.PubMedCrossRefGoogle Scholar
  5. 5.
    Magis D, Vigano A, Sava S, D'Elia TS, Schoenen J, Coppola G. Pearls and pitfalls: electrophysiology for primary headaches. Cephalalgia. 2013;33(8):526–39.PubMedCrossRefGoogle Scholar
  6. 6.
    Lakhan SE, Avramut M, Tepper SJ. Structural and functional neuroimaging in migraine: insights from 3 decades of research. Headache. 2013;53:46–66.PubMedCrossRefGoogle Scholar
  7. 7.
    Picaza JA, Cannon BW, Hunter SE, et al. Pain suppression by peripheral nerve stimulation. Part II. Observations with implanted devices. Surg Neurol. 1975;4:115–26.PubMedGoogle Scholar
  8. 8.
    Waisbrod H, Panhans C, Hansen D, Gerbershagen HU. Direct nerve stimulation forpainful peripheral neuropathies. J Bone Joint Surg Br. 1985;67(3):470–2.PubMedGoogle Scholar
  9. 9.
    Weiner RL, Reed KL. Peripheral neurostimulation for control of intractable occipital neuralgia. Neuromodulation. 1999;2(3):217–21.PubMedCrossRefGoogle Scholar
  10. 10.
    Akerman S, Holland PR, Goadsby PJ. Diencephalic and brainstem mechanisms in migraine. Nat Rev Neurosci. 2011;12:570–84.PubMedCrossRefGoogle Scholar
  11. 11.•
    Magis D, Schoenen J. Advances and challenges in neurostimulation for headaches. Lancet Neurol. 2012;11(8), 708–19. This paper provides an exhaustive and updated review of various central and peripheral neuromodulation modalities for treatment of severe intractable primary headache. Google Scholar
  12. 12.
    Lipton R, Goadsby PJ, Cady R, et al. PRISM study: occipital nerve stimulation for treatment refractory migraine. Cephalalgia. 2009;29 suppl 1:30 (abstract).Google Scholar
  13. 13.
    Saper JR, Dodick DW, Silberstein SD, McCarville S, Sun M, Goadsby PJ, et al. Occipital nerve stimulation for the treatment of intractable chronic migraine headache: ONSTIM feasibility study. Cephalalgia. 2011;31(3):271–85.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    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. 2012;32(16):1165–79.PubMedCrossRefGoogle Scholar
  15. 15.
    Pedersen JL, Barloese M, Jensen RH. Neurostimulation in cluster headache: a review of current progress. Cephalalgia. 2013;33(14):1179–93.PubMedCrossRefGoogle Scholar
  16. 16.
    Matharu MS, Bartsch T, Ward N, et al. Central neuromodulation in chronic migraine patients with suboccipital stimulators: a PET study. Brain. 2004;127(Pt 1):220–30.PubMedCrossRefGoogle Scholar
  17. 17.
    Levy RM. The conflict of safety versus access to new therapies: the FDA, clinical trial design and neuromodulation. Neuromodulation. 2012;15:1–4.PubMedCrossRefGoogle Scholar
  18. 18.
    Ranoux D, Attal N, Morain F, Bouhasira D. Botulinum toxin type A induces direct analgesic effects in chronic neuropathic pain. Ann Neurol. 2008;2008(64):274–83.CrossRefGoogle Scholar
  19. 19.
    Mathew N, Frishberg BM, Gawel M, Dimitrova R, Gibson J, Turkel C. Botulinum toxin type A (BOTOX) for the prophylactic treatment of chronic daily headache. A randomized, double blind, placebo controlled trial. Headache. 2005;45:293–307.PubMedCrossRefGoogle Scholar
  20. 20.
    Sandrini G, Perrotta A, Tassorelli C, Torelli P, Brighina F, Sances G, et al. Botulinum toxin type-A in the prophylaxis treatment of medication-overuse headache: a multi center, double blind, randomized, placebo-controlled, parallel group study. J Head Pain. 2011;12:427–33.CrossRefGoogle Scholar
  21. 21.
    BOTOX 100 units: UK summary of product characteristics. Available at: [Accessed 2011 Nov 1].
  22. 22.
    Vistabel: UK summary of product characteristics [online]. Available at: [Accessed 2011 Nov 16].
  23. 23.
    BOTOX (onabotulinumtoxinA) for injection, for intramuscular, intradetrusor, or intradermal use: US prescribing information. Available at: [Accessed 2011 Nov 2].
  24. 24.
    BOTOX® Cosmetic (onabotulinumtoxinA) for injection: US prescribing information. Available at: [Accessed 2011 Nov 16].
  25. 25.
    BOTOX 200 units: UK summary of product characteristics. Available at:[Accessed 2011 Nov 1].
  26. 26.
    Blumenfeld A, Silberstein S, Dodick D, Aurora S, Turkel C, Binder W. Method of injection of Onabotulinum toxin A for Chronic Migraine: a safe, well-tolerated and effective treatment paradigm based on the PREEMPT clinical program. Headache. 2010;50:1406–18.PubMedCrossRefGoogle Scholar
  27. 27.
    Turton K, Chaddock JA, Acharya KR. Botulinum and tetanus neurotoxins: structure, function and therapeutic utility. Trends Biochem Sci. 2002;27(11):552–8.PubMedCrossRefGoogle Scholar
  28. 28.
    Wollina U. Botulinum toxin: non-cosmetic indications and possible mechanisms of action. J Cutan Aesthet Surg. 2008;1(1):3–6.PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Aoki KR. Review of a proposed mechanism for the anti-nociceptive action of botulinum toxin type A. Neurotoxicol. 2005;26(5):785–93.CrossRefGoogle Scholar
  30. 30.
    Durham PL, Cady R. Insights into the mechanism of ona-botulinumtoxinA in chronic migraine. Headache. 2011;51(10):1573–7.PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Aoki KR. Review of a proposed mechanisms for the antinociceptive action of botulinum toxin type A. Neurotoxicology. 2005;26:785–93.PubMedCrossRefGoogle Scholar
  32. 32.
    Aoki KR. Evidence for antinociceptive activity of botulinum toxin type A in pain management. Headache. 2003;43(Suppl):S9–S15.PubMedCrossRefGoogle Scholar
  33. 33.
    Gazerani P, Pedersen NS, Staahl C, Drewes AM, Arendt-Nielsen L. Subcutaneous botulinum toxin type A reduces capsaicin-induced trigeminal pain and vasomotor reactions in human skin. Pain. 2009;141:60–9.PubMedCrossRefGoogle Scholar
  34. 34.
    Frampton J. Onabotulinumtoxin A (BOTOX). A review of its use in the prophlylaxis of Headaches in adults with Chronic Migraine. DRUGS. 2012;72(6):625–45.CrossRefGoogle Scholar
  35. 35.
    Allergan. A study using botulinum toxin type A as headache prophylaxis for migraine patients with frequent headaches [ identifier NCT00156910]. US National Institutes of Health, Available at: [Accessed 2011 Nov 2].
  36. 36.
    Allergan. A study using botulinum toxin type A as headache prophylaxis for migraine patients with frequent headaches [ identifier NCT00168428]. US National Institutes of Health, Available at: [Accessed 2011 Nov 2].
  37. 37.
    Mathew NT, Frishberg BM, Gawel M, et al. Botulinum toxin type A (BOTOX) for the prophylactic treatment of chronic daily headache: a randomized, double-blind, placebo-controlled trial. Headache. 2005;45(4):293–307.PubMedCrossRefGoogle Scholar
  38. 38.
    Silberstein SD, Stark SR, Lucas SM. Botulinum toxin type A for the prophylactic treatment of chronic daily headache: a randomized, double-blind, placebo-controlled trial. Mayo Clin Proc. 2008;80(9):1126–37.CrossRefGoogle Scholar
  39. 39.
    Mathew NT, Jaffri SFA. A double-blind comparison of onabotulinumtoxinA (BOTOX) and topiramate (TOPA-MAX) for the prophylactic treatment of chronic migraine: a pilot study. Headache. 2009;49(10):1466–78.PubMedCrossRefGoogle Scholar
  40. 40.
    Cady RK, Schreiber CP, Porter JAH, et al. A multi-center double-blind pilot comparison of onabotulinumtoxinA and topiramate for the prophylactic treatment of chronic migraine. Headache. 2011;51(1):21–32.PubMedCrossRefGoogle Scholar
  41. 41.
    Aurora SK, Winner P, Freeman MC, et al. OnabotulinumtoxinA for treatment of chronic migraine: pooled analyses of the 56-week PREEMPT clinical program. Headache. 2011;51:1358–73.PubMedCrossRefGoogle Scholar
  42. 42.
    Yang CP, Chang MH, Liu PE, et al. Acupuncture versus topiramate in chronic migraine prophylaxis: a randomized clinical trial. Cephalalgia. 2011;31(15):1510–21.PubMedCrossRefGoogle Scholar
  43. 43.•
    Colloca L, Klinger R, Flor H, Bingel U. Placebo analgesia: psychological and neurobiological mechanisms. Pain. 2013 Apr;154(4):511–4. Placebo effect is not that demon and we should learn how to maximize it in clinical use in the meantime that scientists will work out its role in RCTs. Google Scholar
  44. 44.
    Botulinum toxin type A for the prevention of headaches in adults with chronic migraine. Available at: Accessed June 2012.

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Headache Centre - Neuromodulation UnitNational Neurological Institute IRCCS “C.Besta” FoundationMilanoItaly

Personalised recommendations