Skip to main content

Advertisement

SpringerLink
Log in

Cluster Headache: A Review and Update in Treatment

  • Headache (R.B. Halker Singh and J. VanderPluym, Section Editors)
  • Published:
Current Neurology and Neuroscience Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

The treatment of cluster headache has evolved to include a handheld neuromodulation device and a monoclonal antibody in addition to more traditional agents.

Recent Findings

Galcanezumab is an approved treatment for episodic cluster headache. The non-invasive vagal nerve stimulator has been shown to be effective as a treatment for episodic cluster headache. Dedicated pituitary imaging may not be necessary with a normal MRI of the brain.

Summary

Cluster headache is the most common trigeminal-autonomic cephalalgia, characterized by unilateral, frequent, debilitating attacks associated with ipsilateral autonomic symptoms. Attacks have a circadian and, often, seasonal pattern with periods of remission that can last months to years in episodic patients. Though a rare disease, an increasing number of studies have revealed novel targets for treatment. Treatment in cluster headache should focus on early intervention to reduce frequency of attacks and the length of the cycle, which improves outcomes and disability. Acute therapy is used to treat attacks, while bridging and preventive therapies are combined to reduce cycle length.

Case 1: A 43-year-old man presents with the chief complaint of severe headaches. Upon general examination, he seems uncomfortable, agitated, and exhausted. He states that he hasn’t “slept in over a week because of debilitating headaches.” His headaches start around the same time every night: when he lays down to go to sleep. The pain is described as sharp, like a “hot poker” to his left eye. His partner has noticed that his eye droops and turns red when the pain starts. The attacks come on abruptly and prevent him from sleeping. The severe pain lasts 30 to 45 min, but he has mild-to-moderate pain that lingers for the rest of the night.

He has seen his primary care physician, an allergist, and an ear, nose, and throat (ENT) specialist before coming to see a neurologist.

Similar headaches occurred last year during the month of October as well. On further questioning, he reports that these headache attacks have been occurring almost yearly for the past 7 years. Each year, these headaches come on as the weather is changing and occur on a nightly basis for about 3 to 4 weeks.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

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

  1. Kandel SA, Mandiga P. Cluster headache. [Updated 2020 Jun 30]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK544241/Great overview of CH

  2. Fischera M, Marziniak M, Gralow I, Evers S. The incidence and prevalence of cluster headache: a meta-analysis of population-based studies. Cephalalgia. 2008 Jun;28(6):614–8. https://doi.org/10.1111/j.1468-2982.2008.01592.x.

    Article  CAS  PubMed  Google Scholar 

  3. Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition. Cephalalgia. 2018 Jan;38(1):1-211 Diagnostic Criteria by IHS

  4. Hoffmann J, May A. Diagnosis, pathophysiology, and management of cluster headache. Lancet Neurol. 2018;17(1):75–83. https://doi.org/10.1016/S1474-4422(17)30405-2Detailed source for CH.

    Article  PubMed  Google Scholar 

  5. Goadsby PJ. Pathophysiology of cluster headache: a trigeminal autonomic cephalgia. Lancet Neurol. 2002;1(4):251–7. https://doi.org/10.1016/s1474-4422(02)00104-7.

    Article  PubMed  Google Scholar 

  6. Ekbom K, Greitz T. Carotid angiography in cluster headache. Acta Radiol Diagn (Stockh). 1970;10(3):177–86. https://doi.org/10.1177/028418517001000302.

    Article  CAS  Google Scholar 

  7. Goadsby PJ, Edvinsson L. Human in vivo evidence for trigeminovascular activation in cluster headache. Neuropeptide changes and effects of acute attacks therapies. Brain. 1994;117(Pt 3):427–34. https://doi.org/10.1093/brain/117.3.427.

    Article  PubMed  Google Scholar 

  8. Carmine Belin A, Ran C, Edvinsson L. Calcitonin gene-related peptide (CGRP) and cluster headache. Brain Sci. 2020;10(1):30. https://doi.org/10.3390/brainsci10010030Great paper on CGRP and its role in CH.

    Article  CAS  PubMed Central  Google Scholar 

  9. ALH V, Snoer A, Beske RP, Guo S, Hoffmann J, Jensen RH. Ashina M. Effect of infusion of calcitonin gene-related peptide on cluster headache attacks: a randomized clinical trial. JAMA Neurol. 2018;75(10):1187–97. https://doi.org/10.1001/jamaneurol.2018.1675Great trial showing CGRP’s role in acute CH attack.

    Article  Google Scholar 

  10. Barbanti P, Fabbrini G, Pesare M, Vanacore N, Cerbo R. Unilateral cranial autonomic symptoms in migraine. Cephalalgia. 2002;22(4):256–9. https://doi.org/10.1046/j.1468-2982.2002.00358.x.

    Article  CAS  PubMed  Google Scholar 

  11. Dousset V, Laporte A, Legoff M, Traineau MH, Dartigues JF, Brochet B. Validation of a brief self-administered questionnaire for cluster headache screening in a tertiary center. Headache. 2009;49(1):64–70.

    Article  Google Scholar 

  12. Weaver-Agostoni J. Cluster headache. Am Fam Physician. 2013;88(2):122–8.

    PubMed  Google Scholar 

  13. Romiti A, Martelletti P, Gallo MF, Giacovazzo M. Low plasma testosterone levels in cluster headache. Cephalalgia. 1983;3(1):41–4. https://doi.org/10.1046/j.1468-2982.1983.0301041.x.

    Article  CAS  PubMed  Google Scholar 

  14. Stillman MJ. Testosterone replacement therapy for treatment refractory cluster headache. Headache. 2006;46(6):925–33. https://doi.org/10.1111/j.1526-4610.2006.00436.x.

    Article  PubMed  Google Scholar 

  15. Holle D, Obermann M. The role of neuroimaging in the diagnosis of headache disorders. Ther Adv Neurol Disord. 2013;6(6):369–74. https://doi.org/10.1177/1756285613489765.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Grangeon L, O'Connor E, Danno D, TMP N, Cheema S, Tronvik E, et al. Is pituitary MRI screening necessary in cluster headache? Cephalalgia. 2021:333102420983303. doi: 10.1177/0333102420983303 New findings regarding work up for CH.

  17. Graff-Radford SB, Teruel A. Cluster headache and obstructive sleep apnea: are they related disorders? Curr Pain Headache Rep. 2009;13(2):160–3. https://doi.org/10.1007/s11916-009-0027-8.

    Article  PubMed  Google Scholar 

  18. Kudrow L, McGinty DJ, Phillips ER, Stevenson M. Sleep apnea in cluster headache. Cephalalgia. 1984;4(1):33–8. https://doi.org/10.1046/j.1468-2982.1984.0401033.x.

    Article  CAS  PubMed  Google Scholar 

  19. Graff-Radford SB, Newman A. Obstructive sleep apnea and cluster headache. Headache. 2004;44(6):607–10. https://doi.org/10.1111/j.1526-4610.2004.446010.x.

    Article  PubMed  Google Scholar 

  20. Fogan L. Treatment of cluster headache. A double-blind comparison of oxygen v air inhalation. Arch Neurol. 1985;42(4):362–3. https://doi.org/10.1001/archneur.1985.04060040072015.

    Article  CAS  PubMed  Google Scholar 

  21. Cohen AS, Burns B, Goadsby PJ. High-flow oxygen for treatment of cluster headache: a randomized trial. JAMA. 2009;302(22):2451–7. https://doi.org/10.1001/jama.2009.1855.

    Article  CAS  PubMed  Google Scholar 

  22. Pearson SM, et al. Effectiveness of oxygen and other acute treatments for cluster headache: results from the cluster headache questionnaire, an International Survey. Headache. 2019;0:l–15 Population survey to CH therapies.

    Google Scholar 

  23. Robbins MS, Starling AJ, Pringsheim TM, Becker WJ, Schwedt TJ. Treatment of cluster headache: the American Headache Society Evidence-Based Guidelines. Headache. 2016;56(7):1093–106. https://doi.org/10.1111/head.12866.

    Article  PubMed  Google Scholar 

  24. AMF/AHS statement on oxygen therapy for cluster headache. American Migraine Foundation and American Headache Society. (Published 2020 14 Sept). 2021 Mar- Available from: americanmigrainefoundation.org/resource-library/joint-statement-oxygen-therapy/ AHS/AMF statement in support of CH patients

  25. Ekbom K, Monstad I, Prusinski A, Cole JA, Pilgrim AJ, Noronha D. Subcutaneous sumatriptan in the acute treatment of cluster headache: a dose comparison study. The Sumatriptan Cluster Headache Study Group. Acta Neurol Scand. 1993;88(1):63–9. https://doi.org/10.1111/j.1600-0404.1993.tb04189.x.

    Article  CAS  PubMed  Google Scholar 

  26. Matharu MS, Levy MJ, Meeran K, Goadsby PJ. Subcutaneous octreotide in cluster headache: randomized placebo-controlled double-blind crossover study. Ann Neurol. 2004;56(4):488–94. https://doi.org/10.1002/ana.20210 Erratum in: Ann Neurol. 2004 Nov;56(5):751.

    Article  CAS  PubMed  Google Scholar 

  27. Cittadini E, May A, Straube A, Evers S, Bussone G, Goadsby PJ. Effectiveness of intranasal zolmitriptan in acute cluster headache: a randomized, placebo-controlled, double-blind crossover study. Arch Neurol. 2006 Nov;63(11):1537–42. https://doi.org/10.1001/archneur.63.11.nct60002.

    Article  PubMed  Google Scholar 

  28. Rapoport AM, Mathew NT, Silberstein SD, Dodick D, Tepper SJ, Sheftell FD, et al. Zolmitriptan nasal spray in the acute treatment of cluster headache: a double-blind study. Neurology. 2007;69(9):821–6. https://doi.org/10.1212/01.wnl.0000267886.85210.37 Erratum in: Neurology. 2007 Nov 20;69(21):2029.

    Article  CAS  PubMed  Google Scholar 

  29. van Vliet JA, Bahra A, Martin V, Ramadan N, Aurora SK, Mathew NT, et al. Intranasal sumatriptan in cluster headache: randomized placebo-controlled double-blind study. Neurology. 2003 Feb 25;60(4):630–3. https://doi.org/10.1212/01.wnl.0000046589.45855.30.

    Article  PubMed  Google Scholar 

  30. Nicolas S, Nicolas D. Triptans. [Updated 2020 May 26]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK554507/ **Great overview of triptans and their use

  31. Negro A, Koverech A, Martelletti P. Serotonin receptor agonists in the acute treatment of migraine: a review on their therapeutic potential. J Pain Res. 2018;11:515–26.

    Article  CAS  Google Scholar 

  32. Silberstein SD, Mechtler LL, Kudrow DB, Calhoun AH, McClure C, Saper JR, et al. Tepper SJ; ACT1 Study Group. Non-invasive vagus nerve stimulation for the acute treatment of cluster headache: findings from the randomized, double-blind, sham-controlled ACT1 study. Headache. 2016;56(8):1317–32. https://doi.org/10.1111/head.12896.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Bahra A, Gawel MJ, Hardebo JE, Millson D, Breen SA, Goadsby PJ. Oral zolmitriptan is effective in the acute treatment of cluster headache. Neurology. 2000;54(9):1832–9. https://doi.org/10.1212/wnl.54.9.1832.

    Article  CAS  PubMed  Google Scholar 

  34. Schoenen J, Jensen RH, Lantéri-Minet M, Láinez MJ, Gaul C, Goodman AM, et al. Stimulation of the sphenopalatine ganglion (SPG) for cluster headache treatment. Pathway CH-1: a randomized, sham-controlled study. Cephalalgia. 2013;33(10):816–30. https://doi.org/10.1177/0333102412473667.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Barloese M, Petersen A, Stude P, Jürgens T, Jensen RH, May A. Sphenopalatine ganglion stimulation for cluster headache, results from a large, open-label European registry. J Headache Pain. 2018;19(1):6. https://doi.org/10.1186/s10194-017-0828-9Key results of SPG blocks in CH.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Kingston WS, Dodick DW. Treatment of cluster headache. Ann Indian Acad Neurol. 2018;21(Suppl 1):S9–S15. https://doi.org/10.4103/aian.AIAN_17_18Wonderful review of CH treatments.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Obermann M, Nägel S, Ose C, Sonuc N, Scherag A, Storch P, et al. Safety and efficacy of prednisone versus placebo in short-term prevention of episodic cluster headache: a multicentre, double-blind, randomised controlled trial. Lancet Neurol. 2021;20(1):29–37. https://doi.org/10.1016/S1474-4422(20)30363-XObjective findings of steroid use in CH.

    Article  CAS  PubMed  Google Scholar 

  38. Leroux E, Valade D, Taifas I, Vicaut E, Chagnon M, Roos C, et al. 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(10):891–7. https://doi.org/10.1016/S1474-4422(11)70186-7.

    Article  CAS  PubMed  Google Scholar 

  39. Ambrosini A, Vandenheede M, Rossi P, Aloj F, Sauli E, Pierelli F, et al. 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. https://doi.org/10.1016/j.pain.2005.07.015.

    Article  CAS  PubMed  Google Scholar 

  40. Devoghel JC. Cluster headache and sphenopalatine block. Acta Anaesthesiol Belg. 1981;32(1):101–7.

    CAS  PubMed  Google Scholar 

  41. Sanders M, Zuurmond WW. Efficacy of sphenopalatine ganglion blockade in 66 patients suffering from cluster headache: a 12- to 70-month follow-up evaluation. J Neurosurg. 1997;87(6):876–80. https://doi.org/10.3171/jns.1997.87.6.0876.

    Article  CAS  PubMed  Google Scholar 

  42. Fang L, Jingjing L, Ying S, Lan M, Tao W, Nan J. Computerized tomography-guided sphenopalatine ganglion pulsed radiofrequency treatment in 16 patients with refractory cluster headaches: twelve- to 30-month follow-up evaluations. Cephalalgia. 2016 Feb;36(2):106–12. https://doi.org/10.1177/0333102415580113.

    Article  PubMed  Google Scholar 

  43. Bendersky DC, Hem SM, Yampolsky CG. Unsuccessful pulsed radiofrequency of the sphenopalatine ganglion in patients with chronic cluster headache and subsequent successful thermocoagulation. Pain Pract. 2015;15(5):E40–5. https://doi.org/10.1111/papr.12288.

    Article  PubMed  Google Scholar 

  44. Burish M. Cluster headache and other trigeminal autonomic cephalalgias. Continuum (Minneap, Minn). 2018;24(4, Headache):1137–56 **Great source for review of CH and other TACs.

    Google Scholar 

  45. Hakim SM. Warfarin for refractory chronic cluster headache: a randomized pilot study. Headache. 2011;51(5):713–25. https://doi.org/10.1111/j.1526-4610.2011.01856.x.

    Article  PubMed  Google Scholar 

  46. Leone M, D'Amico D, Frediani F, Moschiano F, Grazzi L, Attanasio A, et al. Verapamil in the prophylaxis of episodic cluster headache: a double-blind study versus placebo. Neurology. 2000;54(6):1382–5. https://doi.org/10.1212/wnl.54.6.1382.

    Article  CAS  PubMed  Google Scholar 

  47. Fahie S, Cassagnol M. Verapamil. [Updated 2021 Mar 2]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK538495/Guidelines for verapamil therapy

  48. Koppen H, Stolwijk J, Wilms EB, van Driel V, Ferrari MD, Haan J. Cardiac monitoring of high-dose verapamil in cluster headache: an international Delphi study. Cephalalgia. 2016;36(14):1385–8. https://doi.org/10.1177/0333102416631968.

    Article  CAS  PubMed  Google Scholar 

  49. Bussone G, Leone M, Peccarisi C, Micieli G, Granella F, Magri M, et al. Double blind comparison of lithium and verapamil in cluster headache prophylaxis. Headache. 1990;30(7):411–7. https://doi.org/10.1111/j.1526-4610.1990.hed3007411.x.

    Article  CAS  PubMed  Google Scholar 

  50. Chokhawala K, Lee S, Saadabadi A. Lithium. [Updated 2020 Jul 10]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK519062/Guidelines for lithium therapy

  51. Gaul C, Diener HC, Silver N, Magis D, Reuter U, Andersson A, et al. Non-invasive vagus nerve stimulation for PREVention and Acute treatment of chronic cluster headache (PREVA): A randomised controlled study. Cephalalgia. 2016;36(6):534–46. https://doi.org/10.1177/0333102415607070

    Article  PubMed  Google Scholar 

  52. Goadsby PJ, Dodick DW, Leone M, Bardos JN, Oakes TM, Millen BA, et al. Martinez JM. Trial of galcanezumab in prevention of episodic cluster headache. N Engl J Med. 2019;381(2):132–41. https://doi.org/10.1056/NEJMoa1813440Trial for novel treatment of CH.

    Article  CAS  PubMed  Google Scholar 

  53. Dodick DW, Goadsby PJ, Lucas C, Jensen R, Bardos JN, Martinez JM, et al. Phase 3 randomized, placebo-controlled study of galcanezumab in patients with chronic cluster headache: results from 3-month double-blind treatment. Cephalalgia. 2020;40(9):935–48. https://doi.org/10.1177/0333102420905321Results of failed trial for CGRP monoclonal antibody therapy as treatment for CCH.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Teva Branded Industries. ClinicalTrials.gov [Internet]. Bethesda (MD): U.S. National Library of Medicine; Sept 18, 2019. A study comparing the efficacy and safety of fremanezumab (TEV-48125) for the prevention of chronic cluster headache (CCH). [cited 2021 March 14; Last update posted: 2021 Feb 16] Available from: https://www.clinicaltrials.gov/ct2/show/NCT02797951?cond=LY2951742&draw=1&rank=12. Identifier: NCT02964338 Clinical trial for another new, yet failed CGRP monoclonal antibody therapy as treatment for CCH

  55. Nowacki A, Moir L, Owen SL, Fitzgerald JJ, Green AL, Aziz TZ. Deep brain stimulation of chronic cluster headaches: posterior hypothalamus, ventral tegmentum and beyond. Cephalalgia. 2019;39(9):1111–20. https://doi.org/10.1177/0333102419839992Long-term results of effective treatment with DBS in patients with CCH.

    Article  PubMed  Google Scholar 

  56. Seijo-Fernandez F, Saiz A, Santamarta E, Nader L, Alvarez-Vega MA, Lozano B, et al. Long-term results of deep brain stimulation of the mamillotegmental fasciculus in chronic cluster headache. Stereotact Funct Neurosurg. 2018;96(4):215–22. https://doi.org/10.1159/000489937another long-term study with DBS as potential treatment for CCH.

    Article  PubMed  Google Scholar 

  57. Nilson N. Mendes Neto, Jessika Thais da Silva Maia, Juliano Jose da Silva, Sergio Adrian Fernandes Dantas, Marcelo Rodrigues Zacarkim, Daniel Duarte Rolim, Erich T Fonoff. The treatment of chronic cluster headache with deep brain stimulation of the posterior hypothalamus. Neurosurgery. 2018 Sept;65(CN_suppl_1):115. Available from: 10.1093/neuros/nyy303.200 Another DBS trial for CCH, unfortunately death noted

  58. Allena M, De Icco R, Sances G, Ahmad L, Putortì A, Pucci E, et al. Gender differences in the clinical presentation of cluster headache: a role for sexual hormones? Front Neurol. 2019;10:1220. https://doi.org/10.3389/fneur.2019.01220Important study highlighting the possibility of hormones as a cause for CH.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Chung PW, Lee MJ, Park JW, Sohn JH, Kim BK, Chu MK, et al. Differences of cluster headache on the basis of sex in the Korean Cluster Headache Registry. Headache. 2019;59(10):1722–30. https://doi.org/10.1111/head.13637Overview of differences in male and female presentation/experience of CH.

    Article  PubMed  Google Scholar 

  60. Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia. 2013;33(9):629–808.

    Article  Google Scholar 

  61. Paemeleire K, Bahra A, Evers S, Matharu MS, Goadsby PJ. Medication-overuse headache in patients with cluster headache. Neurology. 2006;67(1):109–13. https://doi.org/10.1212/01.wnl.0000223332.35936.6e.

    Article  CAS  PubMed  Google Scholar 

  62. Paemeleire K, Evers S, Goadsby PJ. Medication-overuse headache in patients with cluster headache. Curr Pain Headache Rep. 2008;12(2):122–7. https://doi.org/10.1007/s11916-008-0023-4.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurology, MedStar Georgetown University Hospital, 3800 Reservoir Rd, PHC-7, Washington, DC, 20007, USA

    Himanshu Suri & Jessica Ailani

Authors
  1. Himanshu Suri
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jessica Ailani
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Himanshu Suri.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of

interest.

Human and Animal Rights

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

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Headache

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Suri, H., Ailani, J. Cluster Headache: A Review and Update in Treatment. Curr Neurol Neurosci Rep 21, 31 (2021). https://doi.org/10.1007/s11910-021-01114-1

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11910-021-01114-1

Keywords

Search

Navigation