Prophylactic Drugs

  • Andrea NegroEmail author
  • Paolo Martelletti
Part of the Headache book series (HEAD)


Prophylactic treatment is the mainstay in the management for both episodic and chronic cluster headache (CH).

The primary goal of prophylactic treatment is to shorten cluster episodes and reduce the number of attacks during the bouts and maintain the patient attack-free for all the expected duration of the cluster period.

Prophylactic therapy often becomes effective quite rapidly, but unfortunately total attack suppression is not always achievable, and patients need to wait the natural ending of the bouts.

There are fundamental principles in the pharmacological prevention of CH: medications should be selected on the basis of CH course (episodic or chronic), attack frequency and duration, pain intensity, contraindications, and patients comorbidities; prophylaxis should begin at the first signals of the start of a new cluster bout, maintained during the cluster period and then discontinued by slowly tapering the doses after full remission; treatments for chronic CH may need to be continued for very long periods. Combinations of prophylactic medications are often required, particularly for chronic CH patients.

Only few randomized clinical trials have evaluated preventive drugs in CH; hence decisions on treatments often rely on insufficient body of evidence.

In 2006 a Task Force of the European Federation of Neurological Societies (EFNS) published comprehensive guidelines on the treatment of cluster headache.


Cluster headache Cluster headache prophylaxis Prophylactic drugs Prophylactic treatments 


  1. 1.
    Mitsikostas DD, Edvinsson L, Jensen RH, Katsarava Z, Lampl C, Negro A, Osipova V, Paemeleire K, Siva A, Valade D, Martelletti P. Refractory chronic cluster headache: a consensus statement on clinical definition from the European Headache Federation. J Headache Pain. 2014;15:79.CrossRefGoogle Scholar
  2. 2.
    Tfelt-Hansen PC, Jensen RH. Management of cluster headache. CNS Drugs. 2012;26:571–80.CrossRefGoogle Scholar
  3. 3.
    Martelletti P, Curto M. Headache: cluster headache treatment—RCTs versus real-world evidence. Nat Rev Neurol. 2016;12:557–8.CrossRefGoogle Scholar
  4. 4.
    May A, Leone M, Afra J, Linde M, Sándor PS, Evers S, Goadsby PJ, EFNS Task Force. EFNS guidelines on the treatment of cluster headache and other trigeminal-autonomic cephalalgias. Eur J Neurol. 2006;13:1066–77.CrossRefGoogle Scholar
  5. 5.
    May A. Headaches with (ipsilateral) autonomic symptoms. J Neurol. 2003;250:1273–8.CrossRefGoogle Scholar
  6. 6.
    Matharu MS, Boes CJ, Goadsby PJ. Management of trigeminal autonomic cephalgias and hemicrania continua. Drugs. 2003;63:1637–77.CrossRefGoogle Scholar
  7. 7.
    Gabai IJ, Spierings EL. Prophylactic treatment of cluster headache with verapamil. Headache. 1989;29:167–8.CrossRefGoogle Scholar
  8. 8.
    Leone M, D’Amico D, Frediani F, Moschiano F, Grazzi L, Attanasio A, Bussone G. Verapamil in the prophylaxis of episodic cluster headache: a double-blind study versus placebo. Neurology. 2000;54:1382–5.CrossRefGoogle Scholar
  9. 9.
    Bussone G, Leone M, Peccarisi C, Micieli G, Granella F, Magri M, Manzoni GC, Nappi G. Double blind comparison of lithium and verapamil in cluster headache prophylaxis. Headache. 1990;30(7):411–7.CrossRefGoogle Scholar
  10. 10.
    Weaver-Agostoni J. Cluster headache. Am Fam Physician. 2013;88:122–8.PubMedGoogle Scholar
  11. 11.
    Tfelt-Hansen P, Tfelt-Hansen J. Verapamil for cluster headache. Clinical pharmacology and possible mode of action. Headache. 2009;49:117–25.CrossRefGoogle Scholar
  12. 12.
    Blau JN, Engel HO. Individualizing treatment with verapamil for cluster headache patients. Headache. 2004;44:1013–8.CrossRefGoogle Scholar
  13. 13.
    Francis GJ, Becker WJ, Pringsheim TM. Acute and preventive pharmacologic treatment of cluster headache. Neurology. 2010;75:463–73.CrossRefGoogle Scholar
  14. 14.
    Kivistö KT, Neuvonen PJ, Tarssanen L. Pharmacokinetics of verapamil in overdose. Hum Exp Toxicol. 1997;16:35–7.CrossRefGoogle Scholar
  15. 15.
    Busse D, Templin S, Mikus G, Schwab M, Hofmann U, Eichelbaum M, Kivistö KT. Cardiovascular effects of (R)- and (S)-verapamil and racemic verapamil in humans: a placebo-controlled study. Eur J Clin Pharmacol. 2006;62:613–9.CrossRefGoogle Scholar
  16. 16.
    Cohen AS, Matharu MS, Goadsby PJ. Electrocardiographic abnormalities in patients with cluster headache on verapamil therapy. Neurology. 2007;69:668–75.CrossRefGoogle Scholar
  17. 17.
    Lanteri-Minet M, Silhol F, Piano V, Donnet A. Cardiac safety in cluster headache patients using the very high dose of verapamil (≥720 mg/day). J Headache Pain. 2011;12:173–6.CrossRefGoogle Scholar
  18. 18.
    Abernethy DR, Wainer IW, Anacleto AI. Verapamil metabolite exposure in older and younger men during steady-state oral verapamil administration. Drug Metab Dispos. 2000;28:760–5.PubMedGoogle Scholar
  19. 19.
    de Andrés F, Lionetto L, Curto M, Capi M, Cipolla F, Negro A, Martelletti P. Acute, transitional and long-term cluster headache treatment: pharmacokinetic issues. Expert Opin Drug Metab Toxicol. 2016;129:1011–20.CrossRefGoogle Scholar
  20. 20.
    Pillai U, Muzaffar J, Sen S, Yancey A. Grapefruit juice and verapamil: a toxic cocktail. South Med J. 2009;102:308–9.CrossRefGoogle Scholar
  21. 21.
    Bailey DG, Dresser G, Arnold JM. Grapefruit-medication interactions: Forbidden fruit or avoidable consequences? CMAJ. 2013;185:309–16.CrossRefGoogle Scholar
  22. 22.
    Wishart DS, Knox C, Guo AC, Shrivastava S, Hassanali M, Stothard P, Chang Z, Woolsey J. DrugBank: a comprehensive resource for in silico drug discovery and exploration. Nucleic Acids Res. 2006;34:D668–72.CrossRefGoogle Scholar
  23. 23.
    Dubovsky SL, Franks RD, Allen S. Verapamil: a new antimanic drug with potential interactions with lithium. J Clin Psychiatry. 1987;48:371–2.PubMedGoogle Scholar
  24. 24.
    Ekbom K. Lithium for cluster headache: review of the literature and preliminary results of long-term treatment. Headache. 1981;21:132–9.CrossRefGoogle Scholar
  25. 25.
    Kudrow L. Lithium prophylaxis for chronic cluster headache. Headache. 1977;17:15–8.CrossRefGoogle Scholar
  26. 26.
    Steiner TJ, Hering R, Couturier EGM, Davies PTG, Whitmarsh TE. Double-blind placebo-controlled trial of lithium in episodic cluster headache. Cephalalgia. 1997;17:673–5.CrossRefGoogle Scholar
  27. 27.
    Ashkenazi A, Schwedt T. Cluster headache-acute and prophylactic therapy. Headache. 2011;51:272–86.CrossRefGoogle Scholar
  28. 28.
    Becker WJ. Cluster headache: conventional pharmacological management. Headache. 2013;53:1191–6.CrossRefGoogle Scholar
  29. 29.
    Shine B, McKnight RF, Leaver L, Geddes JR. Long-term effects of lithium on renal, thyroid, and parathyroid function: a retrospective analysis of laboratory data. Lancet. 2015;386:461–8.CrossRefGoogle Scholar
  30. 30.
    Sternieri E, Coccia CP, Pinetti D, Guerzoni S, Ferrari A. Pharmacokinetics and interactions of headache medications, part II: prophylactic treatments. Expert Opin Drug Metab Toxicol. 2006;2:981–1007.CrossRefGoogle Scholar
  31. 31.
    Juurlink DN, Mamdani MM, Kopp A, Rochon PA, Shulman KI, Redelmeier DA. Drug-induced lithium toxicity in the elderly: a population-based study. J Am Geriatr Soc. 2004;52:794–8.CrossRefGoogle Scholar
  32. 32.
    Finley PR, Warner MD, Peabody CA. Clinical relevance of drug interactions with lithium. Clin Pharmacokinet. 1995;29:172–91.CrossRefGoogle Scholar
  33. 33.
    Krabbe AA. Cluster headache: a review. Acta Neurol Scand. 1986;74:1–9.CrossRefGoogle Scholar
  34. 34.
    Sicuteri F. Prophylactic and therapeutic properties of 1-methyl-lysergic acid butanolamide in migraine. Int Arch Allergy Appl Immunol. 1959;15:300–7.CrossRefGoogle Scholar
  35. 35.
    Graham JR, Suby HI, LeCompte PR, Sadowsky NL. Fibrotic disorders associated with methysergide therapy for headache. N Engl J Med. 1966;274:359–68.CrossRefGoogle Scholar
  36. 36.
    Müller R, Weller P, Chemaissani A. Pleural fibrosis as a side effect of years-long methysergide therapy. Dtsch Med Wochenschr. 1991;116(38):1433–6.CrossRefGoogle Scholar
  37. 37.
    Pascual J, Láinez MJ, Dodick D, Hering-Hanit R. Antiepileptic drugs for the treatment of chronic and episodic cluster headache: a review. Headache. 2007;47:81–9.PubMedGoogle Scholar
  38. 38.
    Leone M, Dodick D, Rigamonti A, D’Amico D, Grazzi L, Mea E, Bussone G. Topiramate in cluster headache prophylaxis: an open trial. Cephalalgia. 2003;23:1001–2.CrossRefGoogle Scholar
  39. 39.
    Perucca E, Bialer M. The clinical pharmacokinetics of the newer antiepileptic drugs. Focus on topiramate, zonisamide and tiagabine. Clin Pharmacokinet. 1996;31:29–46.CrossRefGoogle Scholar
  40. 40.
    Rosenfeld WE, Doose DR, Walker SA, Nayak RK. Effect of topiramate on the pharmacokinetics of an oral contraceptive containing norethindrone and ethinyl estradiol in patients with epilepsy. Epilepsia. 1997;38:317–23.CrossRefGoogle Scholar
  41. 41.
    Benedetti MS. Enzyme induction and inhibition by new antiepileptic drugs: a review of human studies. Fundam Clin Pharmacol. 2000;14:301–19.CrossRefGoogle Scholar
  42. 42.
    Halker R, Vargas B, Dodick DW. Cluster headache: diagnosis and treatment. Semin Neurol. 2010;30:175–85.CrossRefGoogle Scholar
  43. 43.
    Silberstein SD, Schulman EA, Hopkins MM. Repetitive intravenous DHE in the treatment of refractory headache. Headache. 1990;30:334–9.CrossRefGoogle Scholar
  44. 44.
    Hering R, Kuritzky A. Sodium valproate in the treatment of cluster headache: an open clinical trial. Cephalalgia. 1989;9(3):195–8.CrossRefGoogle Scholar
  45. 45.
    Freitag FG, Diamond S, Diamond ML, Urban GJ. Divalproex in the long-term treatment of chronic daily headache. Headache. 2001;41:271–8.CrossRefGoogle Scholar
  46. 46.
    Gallagher RM, Mueller LL, Freitag FG. Divalproex sodium in the treatment of migraine and cluster headaches. J Am Osteopath Assoc. 2002;102:92–4.PubMedGoogle Scholar
  47. 47.
    El Amrani M, Massiou H, Bousser MG. A negative trial of sodium valproate in cluster headache: methodological issues. Cephalalgia. 2002;22:205–8.CrossRefGoogle Scholar
  48. 48.
    Negro A, Delaruelle Z, Ivanova TA, Khan S, Ornello R, Raffaelli B, Terrin A, Reuter U, Mitsikostas DD, European Headache Federation School of Advanced Studies (EHF-SAS). Headache and pregnancy: a systematic review. J Headache Pain. 2017;18:106.CrossRefGoogle Scholar
  49. 49.
    Bruera O, Sances G, Leston J, Levin G, Cristina S, Medina C, Barontini M, Nappi G, Figuerola MA. Plasma melatonin pattern in chronic and episodic headaches: evaluation during sleep and waking. Funct Neurol. 2008;23:77–81.PubMedGoogle Scholar
  50. 50.
    Leone M, D’Amico D, Moschiano F, Fraschini F, Bussone G. Melatonin versus placebo in the prophylaxis of cluster headache: a double-blind pilot study with parallel groups. Cephalalgia. 1996;16:494–6.CrossRefGoogle Scholar
  51. 51.
    Pringsheim T, Magnoux E, Dobson CF, Hamel E, Aubé M. Melatonin as adjunctive therapy in the prophylaxis of cluster headache: a pilot study. Headache. 2002;42(8):787–92.CrossRefGoogle Scholar
  52. 52.
    Ekbom K. Prophylactic treatment of cluster headache with a new serotonin antagonist, BC 105. Acta Neurol Scand. 1969;45:601–10.CrossRefGoogle Scholar
  53. 53.
    Sicuteri F, Fusco BM, Marabini S, Campagnolo V, Maggi CA, Geppetti P, Fanciullacci M. Beneficial effect of capsaicin application to the nasal mucosa in cluster headache. Clin J Pain. 1989;5:49–53.CrossRefGoogle Scholar
  54. 54.
    Fusco BM, Marabini S, Maggi CA, Fiore G, Geppetti P. Preventative effect of repeated nasal applications of capsaicin in cluster headache. Pain. 1994;59:321–5.CrossRefGoogle Scholar
  55. 55.
    Marks DR, Rapoport A, Padla D, Weeks R, Rosum R, Sheftell F, Arrowsmith F. A double-blind placebo-controlled trial of intranasal capsaicin for cluster headache. Cephalalgia. 1993;13:114–6.CrossRefGoogle Scholar
  56. 56.
    Hering-Hanit R, Gadoth N. Baclofen in cluster headache. Headache. 2000;40:48–51.CrossRefGoogle Scholar
  57. 57.
    Saper JR, Klapper J, Mathew NT, Rapoport A, Phillips SB, Bernstein JE. Intranasal civamide for the treatment of episodic cluster headaches. Arch Neurol. 2002;59:990–4.CrossRefGoogle Scholar
  58. 58.
    Leandri M, Luzzani M, Cruccu G, Gottlieb A. Drug-resistant cluster headache responding to gabapentin: a pilot study. Cephalalgia. 2001;21:744–6.CrossRefGoogle Scholar
  59. 59.
    Schuh-Hofer S, Israel H, Neeb L, Reuter U, Arnold G. The use of gabapentin in chronic cluster headache patients refractory to first-line therapy. Eur J Neurol. 2007;14:694–6.CrossRefGoogle Scholar
  60. 60.
    D’Andrea G, Perini F, Granella F, Cananzi A, Sergi A. Efficacy of transdermal clonidine in short-term treatment of cluster headache: a pilot study. Cephalalgia. 1995;155:430–3.CrossRefGoogle Scholar
  61. 61.
    Leone M, Attanasio A, Grazzi L, Libro G, D’Amico D, Moschiano F, Bussone G. Transdermal clonidine in the prophylaxis of episodic cluster headache: an open study. Headache. 1997;379:559–60.Google Scholar
  62. 62.
    Sostak P, Krause P, Förderreuther S, Reinisch V, Straube A. Botulinum toxin type-A therapy in cluster headache: an open study. J Headache Pain. 2007;84:236–41.CrossRefGoogle Scholar
  63. 63.
    US National Library of Medicine. Accessed 11 Dec 2017.
  64. 64.
    US National Library of Medicine. Accessed 11 Dec 2017.
  65. 65.
    US National Library of Medicine. Accessed 11 Dec 2017.
  66. 66.
    US National Library of Medicine. Accessed 11 Dec 2017.
  67. 67.
    US National Library of Medicine. Accessed 11 Dec 2017.
  68. 68.
    US National Library of Medicine. Accessed 11 Dec 2017.
  69. 69.
    Couch JR Jr, Ziegler DK. Prednisone therapy for cluster headache. Headache. 1978;18:219–21.CrossRefGoogle Scholar
  70. 70.
    Antonaci F, Costa A, Candeloro E, Sjaastad O, Nappi G. Single high-dose steroid treatment in episodic cluster headache. Cephalalgia. 2005;254:290–5.CrossRefGoogle Scholar
  71. 71.
    Mir P, Alberca R, Navarro A, Montes E, Martínez E, Franco E, Cayuela A, Lozano P. Prophylactic treatment of episodic cluster headache with intravenous bolus of methylprednisolone. Neurol Sci. 2003;245:318–21.CrossRefGoogle Scholar
  72. 72.
    Mather PJ, Silberstein SD, Schulman EA, Hopkins MM. The treatment of cluster headache with repetitive intravenous dihydroergotamine. Headache. 1991;318:525–32.CrossRefGoogle Scholar
  73. 73.
    Magnoux E, Zlotnik G. Outpatient intravenous dihydroergotamine for refractory cluster headache. Headache. 2004;443:249–55.CrossRefGoogle Scholar
  74. 74.
    Mathew NT. Dosing and administration of ergotamine tartrate and dihydroergotamine. Headache. 1997;37(Suppl 1):S26–32.PubMedGoogle Scholar
  75. 75.
    Ekbom K, Krabbe AE, Paalzow G, Paalzow L, Tfelt-Hansen P, Waldenlind E. Optimal routes of administration of ergotamine tartrate in cluster headache patients. A pharmacokinetic study. Cephalalgia. 1983;3:15–20.CrossRefGoogle Scholar
  76. 76.
    Martelletti P, Giamberardino MA, Mitsikostas DD. Greater occipital nerve as target for refractory chronic headaches: from corticosteroid block to invasive neurostimulation and back. Expert Rev Neurother. 2016;16:865–6.CrossRefGoogle Scholar
  77. 77.
    Peres MF, Stiles MA, Siow HC, Rozen TD, Young WB, Silberstein SD. Greater occipital nerve blockade for cluster headache. Cephalalgia. 2002;22:520–2.CrossRefGoogle Scholar
  78. 78.
    Lambru G, Lagrata S, Matharu MS. Cutaneous atrophy and alopecia after greater occipital nerve injection using triamcinolone. Headache. 2012;52:1596–9.CrossRefGoogle Scholar
  79. 79.
    Lambru G, Abu Bakar N, Stahlhut L, McCulloch S, Miller S, Shanahan P, Matharu MS. Greater occipital nerve blocks in chronic cluster headache: a prospective open-label study. Eur J Neurol. 2014;21:338–43.CrossRefGoogle Scholar
  80. 80.
    Ambrosini A, Vandenheede M, Rossi P, Aloj F, Sauli E, Pierelli F, Schoenen J. Suboccipital injection with a mixture of rapid- and long-acting steroids in cluster headache: a double-blind placebo-controlled study. Pain. 2005;118(1–2):92–6.CrossRefGoogle Scholar
  81. 81.
    Leroux E, Valade D, Taifas I, Vicaut E, Chagnon M, Roos C, Ducros A. Suboccipital steroid injections for transitional treatment of patients with more than two cluster headache attacks per day: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2011;10:891–7.CrossRefGoogle Scholar

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© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Department of Clinical and Molecular Medicine, Regional Referral Headache Centre, Sant’Andrea HospitalSapienza University of RomeRomeItaly

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