Emerging Therapies for Cluster Headache

depressed woman on bed
depressed woman on bed
Recent studies have focused on the role of calcitonin gene-related peptides in cluster headache.

Cluster headache is a debilitating form of primary headache that affects an estimated 1 in 1000 people, with a higher prevalence among men vs women (2.5:1 ratio).1 The episodic form affects between 85% and 90% of individuals with the disorder, with periods of remission between bouts. Those with chronic cluster headache do not experience remission or have remission periods of <3 months.2,3

“Cluster headache is 1 of the most painful conditions that humans can experience, and it has been linked to suicidality,” Nathaniel M. Schuster, MD, a pain management specialist, headache neurologist, and assistant professor of anesthesiology at the University of California, San Francisco, School of Medicine, told Neurology Advisor. “Some of the preventive medicines, such as lithium and valproic acid, have safety concerns, and patients often do not have adequate access to the first-line acute treatments (subcutaneous sumatriptan and high-flow oxygen) due to insurance policies.”

The Role of CGRP

These issues further highlight the need for safe and accessible treatments for this debilitating condition. It is likely this need will soon be at least partly fulfilled, as emerging evidence shows promise for medications targeting calcitonin gene-related peptides (CGRP) as therapy for cluster headache. Previously, CGRP was found to induce migraine attacks, and anti-CGRP drugs have demonstrated efficacy in aborting and preventing migraine attacks.2 In September 2018, galcanezumab became the third anti-CGRP drug to receive US Food and Drug Administration (FDA) approval for migraine prevention, after fremanezumab and erenumab earlier in the year.4

Other recent studies have focused on the role of CGRP in cluster headache. A randomized, double-blind, placebo-controlled, crossover study of 32 adults showed that CGRP induced attacks in patients with chronic cluster headache and in those with episodic cluster headache during active phase, but not during the remission phase.2 In several earlier studies, patients with cluster headache showed elevated saliva and blood concentrations of CGRP during attacks compared with their baseline levels and those of healthy control patients.1

“When infusion of CGRP was found to trigger cluster headache, that sparked some interest in whether CGRP therapies would be effective treatments for the disorder, but it turns out that it is very difficult to create a proper trial design and recruit an adequate number of participants because of the relative rarity of cluster headache,” explained Stuart J. Tepper, MD, neurologist at Dartmouth-Hitchcock Medical Center and professor of neurology at the Giesel School of Medicine at Dartmouth, Hanover, New Hampshire. “The FDA accommodated that by saying that no more than 1 trial each was needed for chronic and episodic cluster headache.”

Results of Phase 3 Trials

Several phase 3 studies are investigating the efficacy and safety of 2 anti-CGRP monoclonal antibodies (fremanezumab and galcanezumab) as preventive therapies for cluster headache.1 At the American Headache Society (AHS) 60th Annual Scientific Meeting held in San Francisco in June 2018, data were presented from a trial evaluating galcanezumab for episodic cluster headache (ECH) prevention (ClinicalTrials.gov identifier: NCT02397473). Patients were randomly assigned to placebo or galcanezumab 300 mg subcutaneous. The primary outcome was the mean change from the baseline frequency of weekly attacks (17.3 and 17.8 for each group, respectively).

It was reported that attacks decreased by −5.2 to 12.1 attacks per week for placebo and by −8.7 to 9.1 attacks per week for galcanezumab (galcanezumab vs placebo; P =.036) by week 3. A key secondary endpoint, the ≥50% responder rate for patients showing a weekly reduction in attacks at week 3 was found to be 57% for placebo and 76% for galcanezumab (P =.04).

Galcanezumab was not effective for prevention of chronic cluster headache (ClinicalTrials.gov identifier: NCT02438826), and a trial evaluating fremanezumab for the same indication was halted in July 2018 because of futility (ClinicalTrials.gov identifier: NCT02964338). An ongoing trial is investigating fremanezumab for prevention of episodic cluster headache (ClinicalTrials.gov identifier: NCT02945046). According to Dr Tepper, Peter J Goadsby, MD, PhD, spoke about this trial at the AHS annual Scottsdale symposium, held in November 2018, and he implied that fremanezumab has demonstrated efficacy for prevention of episodic cluster headache.

“Cluster headache is not that uncommon. Its prevalence is similar to that of multiple sclerosis, but there is much less research being done for cluster headache,” said Dr Schuster. Future research should attempt to “replicate the results of the galcanezumab study, as having 2 studies with positive results will increase our confidence that the treatment is truly effective.”

Related Articles

Neurology Advisor spoke further with Dr Tepper about the recent trial results and future directions in cluster headache treatment.

Neurology Advisor: When do you expect these anti-CGRP therapies to become available for cluster headache prevention?

Dr Tepper: I expect that the application for galcanezumab will be submitted to the FDA within the next 6 months, and that it will receive approval. Also, if we trust what Dr Goadsby said at the meeting, we will also have a second preventive therapy (fremanezumab) for cluster headache in the near future. Right now, there are no pharmacologic therapies of any sort that are approved for prevention of cluster headache, so this is very exciting.

Neurology Advisor: Do you anticipate any challenges regarding access to these therapies if and when they are approved?

Dr Tepper: The biggest obstacle will be getting coverage from payers. The Centers for Medicaid & Medicare Services has refused to pay for oxygen as acute treatment for cluster headache, which is really shameful and indefensible. When I present internationally, it is an embarrassment.5 The AHS and the American Academy of Neurology have gone to the Centers for Medicaid & Medicare Services and presented the results of the randomized controlled trial supporting its efficacy. They explained that this is the standard of care worldwide and that it’s effective and inexpensive. But the Centers for Medicaid & Medicare Services refuses to negotiate. One of their excuses was that it hasn’t been studied in enough Medicare patients.

Neurology Advisor What can physicians do to address this situation and advocate for patients?

Dr Tepper: Write the prescriptions and write letters to your congresswomen and congressmen to let them know there’s no excuse to withhold a safe, proven treatment for cluster headache.

Payers have also been reluctant to pay for noninvasive modulatory devices, typically because of ignorance about the severity of the illness. We have a device approved for the acute treatment of episodic cluster headache (gammaCore), but no payer is covering it.7 We need to lobby payers to cover FDA-approved treatments for cluster headache; some don’t adequately cover sumatriptan, either.

As a result of this limited access to treatment, patients with cluster headache sometimes become so desperate that they try things that are not evidence-based, such as hallucinogens.

Neurology Advisor: What are some of the remaining research needs in this area?

Dr Tepper: We don’t have a medical therapy for chronic cluster headache. We are likely to soon have these 2 monoclonal antibodies for prevention of episodic cluster headache, and we will likely [ultimately] use gammaCore or Pulsante for acute treatment in chronic cluster headache. [Editors’ note: Pulsante is a neuromodulation device implanted in the pterygopalatine fossa to provide on-demand stimulation of the sphenopalatine ganglion. The device is manufactured by Autonomic Technologies Inc, and has been used in Europe for several years.8 A trial currently underway in the United States is evaluating its safety and efficacy as an acute treatment for attacks in patients with chronic cluster headache (ClinicalTrials.gov identifier: NCT02168764).]

We need to do some creative thinking about how to prevent cluster attacks, and some basic research is needed to explore why the 2 types of cluster headache are so different, unexpectedly. On the basis of the [divergent] results for episodic and cluster headache, it is clear that there are bigger differences between the 2 types than we realized.

I always tell people who are developing treatments for cluster headache that they’re doing extremely important work. It is such a severe illness that anything we can do to help these patients should be tried.

Disclosures: Dr Tepper has received consultancy fees and research support from Autonomic Technologies Inc and Teva Pharmaceutical Industries Ltd, and stock options from Autonomic Technologies Inc.


  1. Doesborg P, Haan J. Cluster headache: new targets and options for treatment. F1000Res. 2018;7:339.
  2. Vollesen ALHSnoer ABeske RP, et al. Effect of infusion of calcitonin gene-related peptide on cluster headache attacks: a randomized clinical trial. JAMA Neurol. 2018;75(10):1187-1197.
  3. Leone M. Evidence mounts for anti-CGRP treatment in cluster headache. Nat Rev Neurol. 2018; 14(11):636-637.
  4. American Migraine Foundation. 3rd anti-CGRP treatment approved for migraine. https://americanmigrainefoundation.org/resource-library/3rd-anti-cgrp-treatment-approved-for-migraine. Accessed November 19, 2018.
  5. Tepper SJDuplin JNye BTepper DE. Prescribing oxygen for cluster headache: a guide for the provider. Headache. 2017;57(9):1428-1430.
  6. Mwamburi MLiebler EJTenaglia AT. Review of non-invasive vagus nerve stimulation (gammaCore): efficacy, safety, potential impact on comorbidities, and economic burden for episodic and chronic cluster headache. Am J Manag Care. 2017;23(17 Suppl):S317-S325.
  7. Fontaine D, Santucci S, Lanteri-Minet M. Managing cluster headache with sphenopalatine ganglion stimulation: a review. J Pain Res. 2018;11:375-381.