Many treatments commonly used in cluster headache are based on evidence from a small number of trials or on therapeutic evidence for migraine, which is more prevalent. The relative rarity of cluster headache presents challenges for identifying patients with the disorder and optimizing their care. The unique characteristics of cluster headache, however, present clinicians and researchers with a clear means to contemplate the mechanisms of action of existing treatments and consider novel or optimized targets for improved prophylaxis. For example, the circadian nature of daily attacks and annual periods in patients with episodic cluster headache suggests the hypothalamus as a core structure in the generation of cluster headache.1 Diagnostic and treatment challenges encountered by many patients with cluster headache have also led to patient-identified preventive measures, including unconventional therapies and lifestyle factors2 that could provide additional sources for improved management of this most severe form of headache.

We present evidence-based forms of preventive treatment for cluster headache as well as unconventional therapies and lifestyle factors. Table 1 summarizes the most commonly used medical therapies that have the most evidence.

Established Prophylactic Therapies

As with any headache or pain condition, effective acute and preventive therapies are both required for optimal disease management. Patients with chronic cluster headache (CCH) may require continual preventive therapy if their attack burden is high. Individuals with episodic cluster headache (ECH) with predictable cluster periods may start preventives prior to an anticipated period or at the prodromal stage attempting to limit period duration and attack severity. Patients with ECH who have unpredictable cycles ideally should have quick access to preventive therapy as soon as attacks begin.

Verapamil

Verapamil is the mainstay preventive therapy for cluster headache. In controlled trials, verapamil immediate release (IR) 120 mg 3 times daily reduced patients’ headache burden by at least 50% after 1 to 2 weeks of treatment for both participants with ECH and with CCH.3,4 The dose of verapamil may be cautiously increased to achieve efficacy; however, increased doses may cause constipation and prolongation of the cardiac PR interval. Cardiac monitoring with ECG is recommended prior to initiation of and approximately 1 week after dose increases. Although a sustained release (SR) formulation of verapamil is available, it has not been formally investigated for cluster headache, nor is it generally believed to be as effective as the IR formulation. The effect of verapamil on monoaminergic neurotransmitter systems and the hypothalamus are likely related to its therapeutic effect in cluster headache.5

Lithium Carbonate

Lithium is effective in cluster headache prevention, although its narrow therapeutic range and undesirable side effect profile make it a less common choice. A clinical trial of 300 mg of lithium 3 times daily showed a 50% reduction in headache burden after 2 weeks.3 Another study, however, failed to show a significant difference between treatment with lithium and placebo, although this study used 800 mg of slow-release lithium once nightly.6 Lithium interrupts G-protein signaling, implicating several neurotransmitter systems involved in cluster headache,5 and affects hypothalamic function and sleep rhythms, which are pathophysiologic factors in cluster headache.5

Melatonin

The relatively mild side effect profile of melatonin makes it a good choice for patients with cluster headache who are unable to tolerate other options. Melatonin may also be used as adjunctive therapy. A placebo-controlled trial reported a termination of attacks in 50% of participants with ECH after 5 days of 10 mg melatonin taken every evening.7 Anecdotal patient reports of using higher doses (up to 30 mg) exist, suggesting that higher doses may be required for efficacy in those with CCH. There is a case report of the melatonin receptor agonist ramelteon eliminating nighttime cluster attacks8 but ramelteon has not been formally studied for cluster headache. Patient with cluster headache have reduced levels and phase-shifted release of endogenous melatonin, making the timing of supplementation (ideally a couple hours before bed) essential for proper treatment.1

Civamide

Civamide is a synthetic congener of capsaicin (the active compound of hot peppers), which is commonly used as a topical agent for treating pain. In a randomized, double-blind, placebo-controlled study, participants with ECH who applied 25 µg civamide intranasally (100 µL volume) daily for 5 to 7 days had a 61.4% reduction from baseline in the number of attacks for the 20-day posttreatment period compared with a 30.9% reduction for those who took placebo. Although promising, this result was not statistically significant, most likely because of the small number of people completing the trial (n = 24).9 Civamide depletes 2 inflammatory molecules associated with cluster and other headache disorders: calcitonin gene-related peptide (CGRP) and substance P.9

Warfarin

Warfarin therapy (international normalized ratio [INR] 1.5-1.9) induced remission in 50% of participants with CCH during a 12-week treatment period in a placebo-controlled, crossover pilot study.10 The need for laboratory monitoring during warfarin use and potential for bleeding may explain why warfarin has not been further pursued, especially considering that some patients with cluster headache carry out self-injurious behaviors during severe attacks. The mechanism of warfarin for cluster headache may be related to blocking vitamin K effects on nitric oxide, a potent inducer of cluster attacks.10

Antiepileptics

Several open-label trials have shown some efficacy for topiramate, gabapentin, and valproic acid for cluster headache, although these medications are not considered first-line for prevention.5 Standard risk-benefit assessments should be performed prior to starting any of these medications, either as monotherapy or adjunctive therapy.

Triptans

The use of triptans, particularly those with long half-lives (eg, naratriptan [8 hrs] or frovatriptan [26 hrs]), as prophylactic agents for cluster headache has been considered.5 Some patients report nighttime dosing with a triptan to prevent nocturnal attacks; short-term daily use may also benefit patients in difficult times.

Neuromodulation

Noninvasive vagal nerve stimulation with a handheld external device is FDA-approved for both acute and preventive treatment of cluster headache11,12 (see Neuromodulation Therapies for Headache in this issue). Modulation of trigeminocervical nociception is suggested as a mechanism for the therapeutic effect.11 The ipsilateral sphenopalatine ganglion (SPG), also known as the pterygopalatine ganglion, is a target for anesthetic blockade or selective electrical stimulation for cluster headache, as is chronic stimulation of the occipital nerve.5 Overlap of trigeminal (SPG) and cervical (occipital) afferents in the trigeminocervical complex (TCC), which spans the lower medulla and upper cervical region, supports the value of these targets in cluster headache treatment5

Because invasive procedures carry higher risk, deep brain stimulation (DBS) of the ipsilateral posterior hypothalamus is reserved for patients with the most refractory cluster headache.5 Modulation of connections between the post-erior hypothalamus and TCC are likely to underlie this therapeutic effect.5

Transitional Therapies

Given the need to uptitrate preventive therapies, transitional or bridge therapy may be needed. Such transitional treatments may also be used during exacerbations (eg, acute increases in attack frequency) or to terminate cluster periods or induce a remission period in patients with CCH. These transitional treatments are not indicated for continuous monotherapy.

Subcutaneous Occipital Steroid Injection

A randomized controlled trial studied serial cortivazol (3.75 mg in 1 mL saline; approximately equivalent to 50 mg of methylprednisolone14) injections into the ipsilateral greater occipital nerve.13 The results showed that 95% of patients treated with cortivazol had an immediate reduction in daily attack frequency after the third injection vs 55% for those treated with placebo.15 However, by day 15 after the third injection, both the steroid and placebo groups reported similar reductions in attack frequency.13 Participants with ECH were concomitantly undergoing verapamil uptitration, and those with CCHwere maintained on their prophylactic regimens.13 Several open-label and retrospective analyses have reported therapeutic benefit of greater occipital nerve block with methylprednisolone, triamcinolone, or betamethasone, with or without anesthetic agent (eg, lidocaine or bupivacaine).5 Success with greater occipital nerve blockade for cluster headache is likely due to the effects on afferent signals to the TCC.5

Systemic Corticosteroids

In a retrospective analysis of oral prednisone tapers, 73% of patients had more than 50% relief and 58% of patients had complete relief.15 Conclusive recommendations are limited in this study because the sample size is small and there was significant variability in starting doses ranging from 10 mg to 80 mg and tapers ranging in duration from 10 to 30 days.15 It is not uncommon for cluster attacks to return after completion of an oral steroid taper or a single intravenous (IV) administration of methylprednisolone (30 mg/kg in 500 mL saline).16 A recent retrospective analysis suggested oral steroids may provide better relief than greater occipital nerve block in patients with cluster headache, although the side effect profile of systemic steroids is less favorable.14 There has not yet been a formal trial for head-to-head comparison of these 2 methods. Systemic anti-inflammatory effects of steroids are central to efficacy for cluster headache.5,16

Dihydroergotamine

Treatment with dihydroergotamine (DHE) is usually reserved for patients with refractory headache, cluster or otherwise, because of the potential cardiovascular, gastrointestinal, and proemetic effects of treatment. Given in a pulse regimen, DHE treatment is given over 3 days to 3 weeks via IV, subcutaneous, and intranasal administration in inpatient or outpatient settings. Initial doses are often given IV, pretreating patients with metoclopramide or ondansetron, followed by 0.5 mg DHE (in 100 mL of normal saline) infusion. If side effects are tolerable, an additional 0.5 mg may be given, followed by 1-mg doses (in 250 mL of normal saline) every 8 to 12 hours.17 Although there are no prospective, controlled studies of DHE for transitional treatment of cluster headache, several retrospective analyses provide supportive evidence.5 A retrospective analysis of patients with refractory cluster headache treated with DHE (0.5-1.0 mg IV 3 times/day over 5 days; 8.25-11.25 mg total) showed 84% (32 of 38) achieved freedom from pain during treatment and had a mean of 17 days before attack return.17 Serotonergic activity of DHE, as for many other headache medications, is believed to be central to therapeutic effect of DHE for cluster headache.5

Emerging Preventive Therapies

Inflammatory Neuropeptides

There are 3 monoclonal antibodies that bind CGRP or the CGRP receptor (erenumab, fremanezumab, and galcanezumab) recently approved and made available for migraine prevention. Studies of potential use to treat cluster headache are ongoing, although for fremanezumab and galcanezumab, trials for treating CCH were discontinued for futility.18 Because peripheral levels of CGRP are elevated during cluster attacks and normalize after acute treatment with sumatriptan and inhaled oxygen,5 CGRP remains a viable therapeutic target in cluster headache.5

Unconventional and Restricted Compounds

Because cluster headache is severe, extremely painful, underrecognized, and undertreated, patients have sought self-medication with a variety of treatments, including unconventional agents.2 This practice has led to anecdotal evidence for the therapeutic utility of certain drugs in the indoleamine 5-hydroxytryptamine 2A (5-HT2A) receptor agonist class.2 Although some of these compounds are better known as psychedelics (eg, lysergic acid diethylamide [LSD], psilocybin), others are nonpsychotropic (eg, 2-bromo-lysergic acid diethylamide, 5-methoxy-N,N-diallyl-tryptamine). In contrast to standard therapies, these drugs are reported to produce long-lasting preventive benefit for cluster headache after a single or few doses.2 Indoleamine 5-HT2A receptor agonists have several biologic targets relevant to cluster headache, including hypothalamic activity, circadian rhythm, hormone function, and inflammation.1 There is an ongoing randomized, double-blind, placebo-controlled clinical triala investigating the effects of psilocybin for cluster headache.

The anesthetic ketamine was shown in a case series (n = 2) to offer complete or partial relief from refractory CCH for 6 weeks after IV infusion in combination with magnesium sulfate.19 Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist, as is memantine, which is used primarily to improve cognitive function in dementia but is also identified as prophylactic treatment for migraine headache and presented in abstract form as an effective cluster headache preventive.20 Of note, magnesium sulfate (administered concomitantly with ketamine in the above case series) can also impair NMDA receptor function.19

Cannabis does not appear to act as a preventive therapy in cluster headache, though there are known antinociceptive effects of cannabis and its constituent compounds (eg, Δ9-tetrahydrocannabinol, cannabidiol). The effects of cannabinoids in headache disorders, including cluster headache, warrant further investigation.(see Cannabis and Cannabinoids Therapies for Headache in this issue).

Vitamin D

Patients with cluster headache have been reported to have low vitamin D levels, although the relevance of this finding is not clear.21 There are anecdotal reports from patients that high-dose vitamin D supplementation (starting at 50,000 IU daily) reduces the burden of cluster headache, but this has not yet been formally investigated.

Lifestyle and Other Factors

Circadian Rhythm and Sleep

A distinctive characteristic of cluster headache is the cyclical nature of attacks and periods, which is consistent with research identifying the hypothalamus, sleep, and melatonin as key factors in the disorder. The maintenance of circadian rhythms is of utmost importance for persons with cluster headache, as disrupted sleep patterns, changing work shifts, and jet lag may provoke attacks.1 Rates of sleep apnea are also higher in people with cluster headache vs the general population. Treatment of sleep-disordered breathing has resulted in reduced or resolved cluster headache burden.22 Daily schedules and sleep patterns must be reviewed with all cluster headache patients to optimize disease management (Table 2).

Contributing Lifestyle Factors

Cigarette smoking is more prevalent in patients with cluster headache than in the general population, although rates havedecreased in parallel. A history of cigarette smoking may influence medication response, although further study is needed to understand this association.23 For patients with CCH or those with ECH in a susceptible period, alcohol and high altitude (or altitude changes) are attack triggers that should be discussed and periodically revisited with patients to develop strategies for relevant circumstances (eg, ski trips, celebrations with alcohol; Table 2).

Aggravating Conditions

There are subpopulations of people with cluster headache who historically have poor responses or limitations to preventive therapies. In general, those with CCH do not respond to treatment as well as those with ECH, possibly due to central sensitization that occurs in the chronic state.23 Those whose cluster headache disorder begins after age 50 may also face challenges in successful treatment, hormonal functions potentially playing a role in this resistance.23

Special Populations

Although approximately 50% of women with cluster headache who have been pregnant report improvement during pregnancy,24 management of cluster headache when it does persist in pregnancy is essential. Lidocaine nerve blocks are safely used during pregnancy and lactation, although efficacy (particularly for nerve blocks without steroid) may be limited (Table 2).25 Cluster headache prevention in children is based on case reports and anecdotal evidence.25 Safety and efficacy of neuromodulatory devices in both of these populations will require further study (see Migraine in Children and Migraine During Pregnancy in this issue.)

Conclusion

Mainstay therapies for cluster headache prevention often lack rigorous evidence-based support for their use. Given the difficulties in formally studying treatment effects in cluster headache, patient reports and experiential or serendipitous evidence have helped form additional preventive regimens. Emerging preventive therapies are on the horizon and may offer an alternative or adjunctive therapy for those still seeking clinically meaningful relief. Clinicians and researchers should seek to capitalize on the unique nature of cluster headache in the discovery and optimization of care in this disorder, including lifestyle modification and consideration of patient-identified treatment measures.

Disclosures

ES has received research funding from the Wallace Research Foundation, Cluster Headache-Trigeminal Autonomic Cephalalgia (CH-TAC), LLC, and Clusterbusters. CG is a member of the scientific advisory board for Alder Biopharmaceuticals, Amgen/Novartis, Biohaven, and Cipla and on the speaker’s bureau for Amgen/Novartis, Lilly, and Promius. He is the principal investigator for the clinical trial of fremanezumab sponsored by Teva.

1. Schindler EAD, Wallace RM, Sloshower JA, D’Souza DC. Neuroendocrine associations underlying the persistent therapeutic effects of classic serotonergic psychedelics. Front Pharmacol. 2018;9:177.

2. Schindler EA, Gottschalk CH, Weil MJ, et al. Indoleamine hallucinogens in cluster headache: results of the clusterbusters medication use survey. J Psychoactive Drugs. 2015;47:372-381.

3. Bussone G, Leone M, Peccarisi C, et al. Double blind comparison of lithium and verapamil in cluster headache prophylaxis. Headache. 1990;30:411-417.

4. 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;54:1382-1385.

5. Costa A, Antonaci F, Ramusino MC, Nappi G. The neuropharmacology of cluster headache and other trigeminal autonomic cephalalgias. Curr Neuropharmacol. 2015;13:304-323.

6. Steiner TJ, Hering R, Couturier EG, Davies PT, Whitmarsh TE. Double-blind placebo-controlled trial of lithium in episodic cluster headache. Cephalalgia. 1997;17:673-675.

7. 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;16:494-496.

8. Imai N. A cluster headache responsive to ramelteon, a selective melatonin MT1/MT2 receptor agonist. Intern Med. 2016;55:2483-2485.

9. Saper JR, Klapper J, Mathew NT, et al. Intranasal civamide for the treatment of episodic cluster headaches. Arch Neurol. 2002;59:990-994.

10. Hakim SM. Warfarin for refractory chronic cluster headache: a randomized pilot study. Headache. 2011;51:713-725.

11. Goadsby PJ, de Coo IF, Silver N, et al. Non-invasive vagus nerve stimulation for the acute treatment of episodic and chronic cluster headache: A randomized, double-blind, sham-controlled ACT2 study. Cephalalgia. 2018;38:959-969.

12. Marin J, Giffin N, Consiglio E, et al. Non-invasive vagus nerve stimulation for treatment of cluster headache: early UK clinical experience. J Headache Pain. 2018;19:114.

13. Leroux E, Valade D, Taifas I, 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;10:891-897.

14. Wei J, Robbins MS. Greater occipital nerve injection versus oral steroids for short term prophylaxis of cluster headache: a retrospective comparative study. Headache. 2018;58:852-858.

15. Couch JR, Jr., Ziegler DK. Prednisone therapy for cluster headache. Headache. 1978;18:219-221.

16. Antonaci F, Costa A, Candeloro E, Sjaastad O, Nappi G. Single high-dose steroid treatment in episodic cluster headache. Cephalalgia. 2005;25:290-295.

17. Nagy AJ, Gandhi S, Bhola R, Goadsby PJ. Intravenous dihydroergotamine for inpatient management of refractory primary headaches. Neurology. 2011;77:1827-1832.

18. Tepper SJ. Anti-calcitonin gene-related peptide (CGRP) therapies: update on a previous review after the American Headache Society 60th Scientific Meeting, San Francisco, June 2018. Headache. 2018;58(suppl 3):276-290.

19. Moisset X, Clavelou P, Lauxerois M, Dallel R, Picard P. Ketamine infusion combined with magnesium as a therapy for intractable chronic cluster headache: report of two cases. Headache. 2017;57:1261-1264.

20. Venturelli E, Rao R, Charles A. Memantine for prevention of cluster headache: a possible new treatment? Abstracts of the 2nd European Headache and Migraine Trust International Congress (EHMTIC). October 28-31, 2010. Nice, France. J Headache Pain. 2010;11:S2-150.

21. Sohn JH, Chu MK, Park KY, Ahn HY, Cho SJ. Vitamin D deficiency in patients with cluster headache: a preliminary study. J Headache Pain. 2018;19:54.

22. Ludemann P, Frese A, Happe S, Evers S. Sleep disordered breathing in patients with cluster headache. Neurology. 2001;56:984.

23. Schindler EAD, Wright DA, Weil MJ, et al. Survey analysis of the use, effectiveness, and patient-reported tolerability of inhaled oxygen compared with injectable sumatriptan for the acute treatment of cluster headache. Headache. 2018;58:1568-1578.

24. Rozen TD, Fishman RS. Female cluster headache in the United States of America: what are the gender differences? Results from the United States Cluster Headache Survey. J Neurol Sci. 2012;317:17-28.

25. VanderPluym J. Cluster headache: special considerations for treatment of female patients of reproductive age and pediatric patients. Curr Neurol Neurosci Rep. 2016;16:5.