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July 9, 2018

Cluster Headache and Calcitonin Gene-Related Peptide—More on Quantum Therapeutics in Headache Medicine

Author Affiliations
  • 1Department of Neurology, University of California, San Francisco, San Francisco
  • 2Section Editor, JAMA Neurology
  • 3National Institute for Health Research–Wellcome Trust, King’s Clinical Research Facility, King’s College London, London, United Kingdom
JAMA Neurol. Published online July 9, 2018. doi:10.1001/jamaneurol.2018.1428

Cluster headache is an exceptionally painful disorder that is one of the trigeminal autonomic cephalalgias.1 It can come in 2 forms: episodic or chronic. Most patients have the episodic form, wherein they enter periods or bouts of weeks to months of cluster activity followed by remission. Those with chronic cluster headache have either no remission, or if they do have any reprieve, it is for less than 3 months a year.2 In a bout, patients experience acute attacks of strictly unilateral headache with associated cranial autonomic features. These attacks may happen several times per day, often with a circadian predictability, and manifest as horrifically severe pain, likened to a hot poker being stabbed in the eye. Activation of the trigeminal autonomic reflex leads to ipsilateral cranial autonomic symptoms, eg, conjunctival redness, nasal rhinorrhea, a sense of fullness in the ear. In contrast to migraine, during acute cluster, the person is often highly agitated and may pace or bang their head. Both the pain and the cranial autonomic symptoms are strictly lateralized, and side-shifting within bouts is relatively uncommon, making cluster headache a generally lateralized disorder.

Given the duration of acute cluster attacks (15 minutes to 3 hours), oral treatments are generally too slow to be useful acutely. Oxygen and injectable sumatriptan can be effective in some patients,3,4 but insurance access and sometimes medical comorbidities can make these treatments impractical. Preventing the attacks altogether would therefore be much preferable. However, to date, no disease-specific treatment has ever been developed for cluster headache, and there remains a substantial unmet treatment need.

A greater occipital nerve injection of corticosteroid, with or without admixed local anesthetic, can be helpful in shortening a cluster period.5,6 Verapamil,7 lithium,8 and melatonin9 have their use in some, although here too tolerability issues abound,8,10 and the proportion of nonresponders, particularly among those with chronic cluster headache, is high. Moreover, for those with episodic cluster headache—these treatments have only ever been shown to prevent attacks during a given cluster period—preventing the next cluster period itself remains a significant unmet therapeutic need.

Improving our understanding of cluster headache pathophysiology has the potential to help identify novel therapeutic targets and treatments. In this issue of JAMA Neurology, Vollesen et al11 extend our understanding of cluster headache by demonstrating that infusion of a neuropeptide called calcitonin gene-related peptide (CGRP) can trigger cluster attacks. Previous to this study, it was already known that serum CGRP levels are elevated during both spontaneous cluster attacks12 and those triggered by nitroglycerin infusion.13 In addition, effective treatment of acute cluster has been observed to normalize CGRP levels.12 Here we learn that infusion of CGRP can also trigger cluster attacks, interestingly only in those patients whose cluster disorder was already active. Using a rigorous double-blind placebo-controlled crossover study design, patients with episodic or chronic cluster headache were, in a random order, infused with CGRP or placebo and observed for development of a cluster attack in the ensuing 90 minutes. Of 9 patients with episodic cluster who were currently in a bout, 8 were triggered after the CGRP infusions vs 1 after placebo. Of those who were currently outside of a bout, none of the 9 participants were triggered after either CGRP or placebo. Seven of 14 patients with chronic cluster headache had an attack trigger after CGRP infusion vs none after placebo.

The fact that attacks could be triggered by peripheral infusion of CGRP in those whose cluster disorder was already active but not in those in whom it was not points to the brain’s role in cluster headache pathophysiology. It is not simply a matter of a peripheral trigger followed reflexively by trigeminal response. The brain’s susceptibility to cluster attacks varies. As the authors point out,11 functional neuroimaging data and the frequently circadian nature of cluster both point to the posterior hypothalamic region as the likely mediator of this central susceptibility.14 Individual brains may have different thresholds to trigger a cluster attack, even among those whose cluster disorder is active. For example, in this study,11 those with a higher natural attack frequency were more likely to be triggered than those with a lower attack frequency.

In migraine research, monoclonal antibodies to CGRP, or its receptor, have been shown in phase III trials to be effective for migraine prevention in both episodic and chronic migraine and the first of these has now been approved by the US Food and Drug Administration for this indication in the United States.15 Given the totality of the evidence, including the current study,11 that CGRP is involved in cluster headache, there is reason for optimism that these agents could also prove fruitful for cluster headache treatment. In fact, a phase III study of one of the anti-CGRP monoclonal antibodies for episodic cluster headache has reportedly hit its primary end point, although another trial for patients with chronic cluster headaches reportedly did not (ClinicalTrials.gov Identifiers: NCT02797951, NCT02964338, and NCT02945046).

An intriguing question now arises as to whether use of CGRP receptor antagonists, gepants,16 would work immediately. The CGRP pathway represents a quantum therapeutics approach to migraine, having a duality of mechanism: immediate and preventive treatment, which is resolved when appropriately measured. We are at the end of truly epoch-making changes for patients who experience what they describe as simply the worst pain there is.

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Article Information

Corresponding Author: Amy A. Gelfand, MD, MAS, Department of Neurology, University of California, San Francisco, 550 16th St, San Francisco, CA 94158 (amy.gelfand@ucsf.edu).

Published Online: July 9, 2018. doi:10.1001/jamaneurol.2018.1428

Conflict of Interest Disclosures: Dr Gelfand has received consulting fees from Zosano Pharma Corp, Eli Lilly and Company, and Biohaven Pharmaceutical; honoraria from UpToDate (for authorship) and JAMA Neurology (as an associate editor); consulting payments for work done through the University of California, San Francisco, Pediatric Headache program from eNeura, Inc; and personal compensation for medical-legal consulting. Dr Goadsby reports receiving grants and personal fees from Amgen Inc and Eli Lilly and Company; personal fees from Alder BioPharmaceuticals, Allergan, Autonomic Technologies Inc, Dr Reddy’s Laboratories, electroCore LLC, eNeura, Novartis, Scion, Teva Pharmaceutical Industries, and Trigemina Inc; and personal fees from MedicoLegal work, Journal Watch, UpToDate, Oxford University Press, Massachusetts Medical Society, and Wolters Kluwer; and a patent Magnetic stimulation for headache assigned to eNeura without fee. Both authors consult for companies developing products that act on the calcitonin gene-related peptide pathway for treatment of primary headache disorders.

Goadsby  PJ, Lipton  RB.  A review of paroxysmal hemicranias, SUNCT syndrome and other short-lasting headaches with autonomic feature, including new cases.  Brain. 1997;120(Pt 1):193-209. doi:10.1093/brain/120.1.193PubMedGoogle ScholarCrossref
 Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition.  Cephalalgia. 2018;38(1):1-211.PubMedGoogle ScholarCrossref
Nesbitt  AD, Goadsby  PJ.  Cluster headache.  BMJ. 2012;344:e2407. doi:10.1136/bmj.e2407PubMedGoogle ScholarCrossref
Cohen  AS, Burns  B, Goadsby  PJ.  High-flow oxygen for treatment of cluster headache: a randomized trial.  JAMA. 2009;302(22):2451-2457. doi:10.1001/jama.2009.1855PubMedGoogle ScholarCrossref
Ambrosini  A, Vandenheede  M, Rossi  P,  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):92-96. doi:10.1016/j.pain.2005.07.015PubMedGoogle ScholarCrossref
Afridi  SK, Shields  KG, Bhola  R, Goadsby  PJ.  Greater occipital nerve injection in primary headache syndromes: prolonged effects from a single injection.  Pain. 2006;122(1-2):126-129. doi:10.1016/j.pain.2006.01.016PubMedGoogle ScholarCrossref
Leone  M, D’Amico  D, Frediani  F,  et al.  Verapamil in the prophylaxis of episodic cluster headache: a double-blind study versus placebo.  Neurology. 2000;54(6):1382-1385. doi:10.1212/WNL.54.6.1382PubMedGoogle ScholarCrossref
Bussone  G, Leone  M, Peccarisi  C,  et al.  Double blind comparison of lithium and verapamil in cluster headache prophylaxis.  Headache. 1990;30(7):411-417. doi:10.1111/j.1526-4610.1990.hed3007411.xPubMedGoogle ScholarCrossref
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(7):494-496.PubMedGoogle ScholarCrossref
Cohen  AS, Matharu  MS, Goadsby  PJ.  Electrocardiographic abnormalities in patients with cluster headache on verapamil therapy.  Neurology. 2007;69(7):668-675. doi:10.1212/01.wnl.0000267319.18123.d3PubMedGoogle ScholarCrossref
Vollesen  ALH, Snoer  A, Beske  RP,  et al.  Effect of infusion of calcitonin gene-related peptide on cluster headache attacks: a randomized clinical trial  [published online July 9, 2018].  JAMA Neurol. doi:10.1001/jamaneurol.2018.1675PubMedGoogle Scholar
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):427-434. doi:10.1093/brain/117.3.427PubMedGoogle ScholarCrossref
Fanciullacci  M, Alessandri  M, Figini  M, Geppetti  P, Michelacci  S.  Increase in plasma calcitonin gene-related peptide from the extracerebral circulation during nitroglycerin-induced cluster headache attack.  Pain. 1995;60(2):119-123. doi:10.1016/0304-3959(94)00097-XPubMedGoogle ScholarCrossref
May  A, Bahra  A, Büchel  C, Frackowiak  RS, Goadsby  PJ.  Hypothalamic activation in cluster headache attacks.  Lancet. 1998;352(9124):275-278. doi:10.1016/S0140-6736(98)02470-2PubMedGoogle ScholarCrossref
Ong  JJY, Wei  DY, Goadsby  PJ.  Recent advances in pharmacotherapy for migraine prevention: from pathophysiology to new drugs.  Drugs. 2018;78(4):411-437. doi:10.1007/s40265-018-0865-yPubMedGoogle ScholarCrossref
Goadsby  PJ.  Bench to bedside advances in the 21st century for primary headache disorders: migraine treatments for migraine patients.  Brain. 2016;139(Pt 10):2571-2577. doi:10.1093/brain/aww236PubMedGoogle ScholarCrossref