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Abstract

Background

The management of cluster headache is similar to that of other primary headache disorders and can be broadly divided into acute and preventive treatments. Acute treatments for cluster headache are primarily delivered via rapid, non-oral routes (such as inhalation, nasal, or subcutaneous) while preventives include a variety of unrelated treatments such as corticosteroids, verapamil, and galcanezumab. Neuromodulation is becoming an increasingly popular option, both non-invasively such as vagus nerve stimulation when medical treatment is contraindicated or side effects are intolerable, and invasively such as occipital nerve stimulation when medical treatment is ineffective. Clinically, this collection of treatment types provides a range of options for the informed clinician. Scientifically, this collection provides important insights into disease mechanisms.

Methods

Two authors performed independent narrative reviews of the literature on guideline recommendations, clinical trials, real-world data, and mechanistic studies.

Results

Cluster headache is treated with acute treatments, bridge treatments, and preventive treatments. Common first-line treatments include subcutaneous sumatriptan and high-flow oxygen as acute treatments, corticosteroids (oral or suboccipital injections) as bridge treatments, and verapamil as a preventive treatment. Some newer acute (non-invasive vagus nerve stimulation) and preventive (galcanezumab) treatments have excellent clinical trial data for episodic cluster headache, while other newer treatments (occipital nerve stimulation) have been specifically tested in treatment-refractory chronic cluster headache. Most treatments are suspected to act on the trigeminovascular system, the autonomic system, or the hypothalamus.

Conclusions

The first-line treatments have not changed in recent years, but new treatments have provided additional options for patients.

Keywords

medication neuromodulation CGRP hypothalamus trigeminovascular

Introduction

Cluster headache (CH) treatments are categorized as acute (which manage an ongoing attack), bridge (quick-acting preventives that cannot be used for long periods of time), and long-term preventive (hereafter simply referred to as “preventive”). All CH patients should be given acute treatments. For bridge and preventive treatments, usage depends on the type of CH. For episodic cluster headache (eCH) patients with short bouts (three weeks or less, defined as the period during which the patient experiences the CH attacks), bridge treatments without preventives may be sufficient, and the medications can be stopped when the patient is out of their headache bout. For eCH patients with longer bouts (more than three weeks) or with bouts of unpredictable duration, bridge treatments may be used while titrating up preventives so that the preventive is at a sufficient dose when the bridge medication wears off. When the headache bout is over, the treatments can be down titrated and stopped. For chronic cluster headache (cCH) patients, preventives are typically used year-round. Bridge medications are still useful in cCH during headache flares; some cCH patients, for example, can have a circannual pattern where the headaches are more frequent at certain times of the year (1,2).

The list of treatments for CH is shown in Table 1, along with their guideline recommendations and, in the case of acute treatments, their comparative effectiveness from a recent network meta-analysis (3). Often multiple acute, bridge, and preventive medications are prescribed concurrently: in the authors’ personal experiences, at the start of an eCH bout, we have at times prescribed two acute treatments (such as sumatriptan and oxygen), one bridge treatment (such as an occipital nerve block), and one preventive (such as verapamil).

Table 1.

Treatment of Cluster Headache based on European and American society guidelines as well as probability ranking of acute treatments from a network meta-analysis.

	European Federation of Neurological Societies Recommendation	American Headache Society Recommendation	Dose examined for network meta-analysis	Ranking in Network Meta-Analysis
Acute
Oxygen (high flow)	A	A	12 L/min	1
Sumatriptan subcutaneous	A	A	6 mg	2
Sumatriptan nasal	A	B	20 mg	3
Oxygen (low flow)	A	A	6–7 L/min	4
Zolmitriptan nasal	A	A	5–10 mg	5
Octreotide subctaneous	B	C	100 µg	6
Noninvasive vagus nerve stimulation (eCH only)	new*	new*	3 × 2 min stimulations	7
Zolmitriptan oral	B	B	5–10 mg	NR
Lidocaine nasal	B	C	10%	NR
-----------------	----------	---------	-------------	--------
Bridge			Dose used in clinical trials
Prednisone	A	new*	100 mg daily for 5 days, decreasing by 20 mg every 3 days until off
Ipsilateral greater occipital nerve block	NR	A	Multiple; all use steroids
-----------------	----------	---------	-------------
Preventive			Dose used in clinical trials
Verapamil	A	C	360 mg divided TID
Lithium	B	C	900 mg divided TID
Melatonin	C	C	10 mg at bedtime
Topiramate	B	NR	100–400 mg divided BID***
Baclofen	C	NR	15–30 mg divided TID***
Warfarin	NR	C	Titrated to INR 1.5–1.9
Galcanezumab (episodic only)	new*	new*	300 mg monthly
Valproic acid	C	unfavorable**	600–2000 mg divided BID
------------------	----------	---------
Refractory
Occipital nerve stimulation	new*	new*
Sphenopalatine ganglion stimulation	NR	B
Hypothalamic deep brain stimulation	NR	unfavorable**

eCH, episodic cluster headache; NR, not rated; TID, three times daily.

Several treatments are too new to be placed in the guidelines. **American Headache Society guidelines have negative ratings for sodium valproate and deep brain stimulation: both were found to be “probably ineffective.” ***Dose is based on clinical trials except for baclofen and topiramate, which are based on open-label prospective studies.

This review focuses on the first-line treatments (sumatriptan, oxygen, corticosteroids, and verapamil) as well as treatments that have emerged in the last few years (galcanezumab as well as invasive and non-invasive neuromodulation options). To arrive at these treatments, the authors independently examined the American and European guidelines for CH (4,5), performed a narrative review of the literature for all of these treatments, created summaries, and then compared notes.

Acute pharmacological treatments

Triptans: Sumatriptan and zolmitriptan

Triptans, as a class, consist of seven approved medications that activate serotonin receptors 5HT_1B, 5HT_1D, and in some cases 5HT_1F (6). Two of these triptans – sumatriptan and zolmitriptan – have fast non-oral routes of administration, and these are the ones recommended for CH. Randomized clinical trials (RCTs) have shown the effectiveness of subcutaneous sumatriptan 6 mg at 15 minutes and of intranasal sumatriptan 20 mg and intranasal zolmitriptan 5–10 mg at 30 minutes (7 –11). Of note oral zolmitriptan is also recommended for CH and is also effective at 30 minutes, but at a higher dose (10 mg) than for migraine (2.5–5 mg) (12,13).

Real-world data also supports the use of sumatriptan and zolmitriptan. In one study of 2031 attacks in 52 patients treated with subcutaneous sumatriptan, attacks were aborted 88% of the time. Additionally 42% of patients showed pain freedom at 15 minutes in over 90% of their attacks (14). Other real-world studies have noted that patients can obtain relief from less than 6 mg (15) and there appears to be no tachyphylaxis (14,16,17). Studies of predictors for triptan response have shown that patients with eCH (as opposed to cCH), younger patients, and patients with shorter and less frequent attacks may be more responsive to triptans (18 –20). One genetic study identified a common GNB3 variant as a predictor of triptan response in CH (21), though testing for GNB3 is not commonplace in clinical practice.

Real-world data further suggest a risk of medication overuse in cluster headache patients (both episodic and chronic). Offending medications include triptans, ergot derivatives, opioids, caffeine, non-steroidal anti-inflammatory drugs (NSAIDs), and paracetamol, which result in either an increased frequency of attacks or a milder background headache (22). In one large case series of 430 patients, medication overuse headache was found in 4% of patients and the headache was most commonly a headache similar to that experienced by migraine patients with medication overuse headache: a bilateral, dull headache with no associated features (23). A personal or family history of migraine is quite common in cluster headache patients with medication overuse headache (23).

Side effects from triptans include sedation, dizziness, transient hypertension, flushing, and tightening sensations (in the chest, throat/neck, or extremities) (24 –27) and many of these effects are more common in subcutaneous sumatriptan than in the nasal or oral formulations (24). The triptans can cause coronary vasoconstriction and thus chest tightness is a concern that should be evaluated (24,28), however it should also be noted that the majority of chest tightness cases appear to be non-cardiac in etiology (24). Selective 5HT_1F agonists (which are called ditans instead of triptans) are devoid of vasoconstrictive side effects and are effective in a preclinical model of CH (29). However, human data on the efficacy of ditans in the treatment of CH are still lacking. The current formulation of ditans also lacks the fast-acting, non-oral form typically needed for the treatment of CH.

Triptans are not recommended in patients with a history of stroke or myocardial infarction or with uncontrolled hypertension. They should not be used in combination with monoamine oxidase inhibitor antidepressants as some triptans (including sumatriptan and zolmitriptan) are degraded via monoamine oxidase pathways (30). However, there is less concern combining triptans with other antidepressants; observational studies have shown a low risk for serotonin syndrome when combining triptans with selective serotonin- or serotonin-norepinephrine reuptake inhibitors (31,32).

The mechanism of action of triptans is an interesting historical debate; it was initially thought that the vasoconstrictive function of these medications was the primary mechanism of action, while today the widely accepted theory is that triptans primarily work in neurons through 5HT_1B/5HT_1D receptors to prevent the release of vasoactive peptides during trigeminovascular activation including calcitonin gene-related peptide (CGRP) (33,34), substance P (34), neurokinin A (34), and the activation of transient receptor potential vanilloid 1 (TRPV1) channels (35). An ongoing debate is where the triptans act, as 5HT_1B and 5HT_1D receptors are found peripherally in the trigeminal ganglion and centrally in the brainstem, thalamus, and hypothalamus (36 –39). The subcutaneous formulation may have a more rapid uptake into the central nervous system (40). Evidence from a recent human study suggests that one target is the junction between the axons of the first-order sensory neurons and the cell body of the second-order sensory neurons in the brainstem (41). Furthermore, sumatriptan continued to produce a good response in a CH patient who underwent trigeminal gangliotomy, further supporting a potential central target of action (42).

Oxygen

Oxygen has been proposed as a CH treatment since 1952 (43). Randomized clinical trials (RCTs) have shown that it is effective at high flow rates (7–12 L/min) at 15 minutes (44 –46), and should be used with a non-rebreather mask or, in recent studies, a demand valve mask (47,48). Predictors of oxygen responsiveness have been examined in small studies and include eCH (as opposed to cCH), younger age, a lack of nausea/vomiting, a lack of restlessness, and possibly male sex (20,49 –51). Side effects are typically minimal with oxygen such as lightheadedness or dry mouth (45), but there are two issues to note. First, patients can have a rebound headache when they finish the oxygen treatment (52,53). Second, oxygen can ignite flammable substances and patients should not use it near sparks or open flames (54). The rate of cigarette smoking is higher in CH than in the general population, and patients should not smoke near the oxygen. There are few contraindications, but caution should be given to patients with severe pulmonary disease as high-flow supplemental oxygen can reduce the respiratory drive and cause hypercapnia (55).

Like triptans, oxygen was originally thought to work via vasoconstriction, but it is now thought to have a neuronal mechanism (43,56). However much less is known about the mechanism by which oxygen aborts CH attacks. Oxygen may modulate the autonomic system, as rodent studies show that oxygen reduces pain signaling in the trigeminocervical complex when the superior salivatory nucleus is stimulated but not when the trigeminal nerve (via the dura) is stimulated (57). Human studies activating the peripheral portion of the cranial autonomic system using intranasal kinetic oscillation stimulation, however, showed no modulatory effects of oxygen on provoked parasympathetic output (58) (for more details of the peripheral autonomic pathway, see the discussion of the trigeminal-autonomic reflex in the vagus nerve stimulation section below). Furthermore oxygen inhalation reduces plasma CGRP levels after spontaneous cluster attacks (59), although it is unclear whether oxygen directly inhibits CGRP release or whether this effect is secondary to headache termination. Oxygen also appears to block protein extravasation in the dura (60). In short, there is still no consensus on how oxygen works in CH.

Bridge treatment

Corticosteroids

Corticosteroids have two routes of administration, either as a daily oral tablet or as a suboccipital injection. It is often referred to as a suboccipital steroid injection, rather than a greater occipital nerve (GON) block, because the primary medication is the steroid and not the local anesthetic. However, the two terms are used interchangeably.

For oral tablets, the best studied is prednisone but the dose and titration schedule have long been debated due to a lack of large clinical trials. Fortunately, a recent RCT has shown the effectiveness of a 17-day taper consisting of 100 mg of prednisone daily for five days, followed by a 20 mg taper every three days until discontinuation (61). This study is notable because it is a higher dose than previous observational studies and perhaps a higher dose than what many clinicians previously used. The comparative effectiveness of oral versus suboccipital steroids is unclear precisely because this 100 mg prednisone clinical trial is new and is higher than most real-world comparisons.

For suboccipital steroid injections, the efficacy was first reported in 1985 in a small (n = 20) open-label study (62) and confirmed in two double-blind placebo-controlled RCTs (63,64). Ambrosini et al. (63) recruited 23 CH patients (16 eCH in a new cluster bout, defined as ≤ 7 days, and 7 cCH) and randomized them to receive either suboccipital steroid injections or placebo injections. After one week of follow-up, 11 out of 13 patients in the betamethasone group became attack-free, compared with 0 out of 10 in the placebo group. The effects were maintained for at least four weeks (63). Leroux et al. (64) investigated the efficacy of repeated injections of cortivazol as add-on therapy for CH patients. A total of 15 cCH and 28 eCH patients were recruited. The primary outcome was the proportion of patients reporting an attack frequency of ≤2/day after injection. Twenty of 21 patients in the cortivazol group had a met the primary outcome, compared to 12 of 22 in the control group (64). Both double-blind placebo-controlled RCTs (63,64) and other non-controlled clinical trials (65 –69) have consistently reported a good response rate, usually ≥ 80%, although a head-to-head comparison between trials is not easy due to different outcome measures and cohort characteristics.

Corticosteroids, both oral and injected, are considered bridge treatments because of the safety risks of extended use which include weight gain, osteoporosis, immunosuppression, peptic ulcer disease, avascular necrosis of the hip, and adrenal insufficiency. These side effects are more commonly studied with oral steroids, though suboccipital injections are limited to several times per year because of both local and systemic issues with high-dose steroid injections. The local or site-specific adverse events that may be associated with suboccipital injections include alopecia and cutaneous atrophy (70). There are also acute side effects with both oral and injected steroids, which include insomnia, hyperglycemia (especially in diabetic patients), and mood changes (including mania in bipolar patients).

The mechanism of corticosteroids in CH is unclear, partly because corticosteroids have multiple mechanisms that could target CH. In the circadian system corticosteroids signal daytime (and melatonin signals nighttime); CH patients have higher corticosteroid and lower melatonin levels, and CH patients often have a predictable clock-like pattern to their attacks (71). Corticosteroids have also been shown to alter CGRP levels in CH patients and endogenous opioid systems for pain relief (72 –74). The mechanism of suboccipital steroid injections may be more localized than systemic, based on the close functional connection between the cervical (C2/C3) somatosensory and trigeminal sensory systems (75) and the fact that occipital nerve blocks partially inhibit the trigeminal nerve (specifically the nociceptive blink reflex [76]), suboccipital steroid injections may provide a more specific trigeminal modulatory effect than systemic steroid administration.

Preventive pharmacological treatments

Verapamil

Verapamil was first proposed in 1983 (77), with the first RCTs in 1990 (for cCH [78]) and 2000 (for eCH [79]). Despite the relatively low number of patients enrolled in these trials (n = 30 each), verapamil is widely considered the first-line preventive for CH. These trials are supported by significant patient survey data showing that verapamil is one of the most effective preventives (50,80). In real-world studies, however, the proposed doses are typically higher than the 360 mg daily (divided three times daily (TID)) from the RCTs. One study found that CH patients used an average dose of 587 mg daily (81) leading to the idea of “neurologic doses” which can be twice that of “cardiovascular doses” (77,82). One possible reason for these high doses is that verapamil is a substrate for the P-glycoprotein pump, which transports drugs out of the brain. As verapamil is thought to act in the central nervous system, very high doses may be needed to overcome this drug pump (53,77,82).

Side effects from verapamil include constipation which in the authors’ experience is fairly common at higher doses. Others include lower extremity edema, bradycardia, fatigue, gastrointestinal upset, erectile dysfunction, and, at high doses, gingival hyperplasia (77). One of the most concerning adverse side effects is heart block, and an electrocardiogram (to monitor the PR interval) is recommended before treatment, one to two weeks after each dose increase, every one to two months thereafter out to six months, then every six months because delayed heart block has been documented (53,81,83). Additionally, verapamil is a CYP3A4 inhibitor and can increase the serum concentration of other medications sometimes used to treat CH such as ergot derivatives (ergotamine and dihydroergotamine), gepants, and lithium.

The mechanism of verapamil in CH is unclear, like steroids it has multiple potential mechanisms. Verapamil appears to modulate a variety of serotonergic, noradrenergic, dopaminergic, muscarinic, and opioid receptors (34,78). Verapamil may block CGRP release through calcium channel blockade (77); along these lines, other calcium channel blockers like nimodipine and nifedipine have been tried with possible effectiveness (77). Furthermore verapamil may alter circadian rhythms, as patients using verapamil had their headaches shifted forward by one hour (84) and one preclinical study found that verapamil alters core circadian gene expression in both the trigeminal ganglion and the hypothalamus in mice (85).

Anti-calcitonin gene-related peptide therapy

The idea of CGRP blockade as a treatment for headaches originally came from findings that plasma CGRP from the external jugular vein increases during attacks of both migraine (86) and CH (59), suggesting trigeminovascular activation in both cases. Indeed, migraine and CH share certain CGRP-related disease mechanisms. Intravenous infusion of CGRP triggers CH attacks (87) and migraine attacks (88), and anti-CGRP monoclonal antibodies (CGRP-mAbs) have emerged in recent years to become indispensable in the treatment of migraine (89). It would follow, then, that all CGRP-mAbs would be effective for CH as well as migraine, but the data are more complicated (Table 2). Galcanezumab, one of the four CGRP-mAbs currently available, showed efficacy in reducing attack frequency in RCT for patients with eCH (90), but not in patients with cCH (91). Three RCTs of fremanezumab in CH (clinicaltrials.gov number NCT03107052), eCH (NCT02945046), and cCH (NCT02964338) were terminated early due to the results of interim futility analyses, as was an eptinezumab study in eCH (NCT04688775). Several clinical trials are still ongoing, including eptinezumab in cCH (NCT05064397), erenumab in cCH (NCT04970355), and rimegepant (an oral small molecule CGRP antagonist rather than a monoclonal antibody) in CH (NCT05264714). In summary, for eCH, one RCT showed efficacy and two others were terminated early for futility. For cCH, no RCT has shown efficacy over placebo. Several case series showed potential clinical efficacy in a subset of cCH patients (92 –94), but how to identify these patients who are likely to benefit from the treatment requires further investigation. One explanation as to why CGRP-mAbs have not worked as well in CH as they have in migraine may lie in the attack mechanism. Up to 30% of migraine attacks may be CGRP-independent (95) and similar non-CGRP mechanisms may be at play in CH, as attacks triggered by infusion of vasoactive intestinal peptide or pituitary adenylate cyclase-activating polypeptide-38 did not lead to increased levels of CGRP (96). Indeed, the data using CGRP as a pharmacological trigger gave a success rate of 89% in eCH patients during their active period (cluster bout) and only 50% in cCH patients (87). In addition, baseline plasma CGRP levels are higher in eCH patients, compared to chronic patients (97). Taken together, this suggests a greater role for a CGRP-independent pathway, especially in cCH patients. The effect of triptans in aborting CH attacks may involve the inhibition of CGRP release in trigeminal neurons (98,99). Whether the response to triptans correlates with the response to CGRP-mAbs is of clinical interest. Future studies investigating the effect of anti-CGRP treatment in CH patients that include biological measurements of CGRP would help to better understand who benefits from the treatment.

Table 2.

The current landscape of CGRP inhibitor trials for cluster headache. One CGRP receptor inhibitor not listed - atogepant - is approved for migraine but is not currently being investigated for cluster headache.

	Episodic cluster headache			Chronic cluster headache
	Effective	In clinical trials	Ineffective	Effective	In clinical trials	Ineffective
Eptinezumab			✓		✓*
Erenumab					✓
Fremanezumab			✓			✓
Galcanezumab	✓					✓
Rimegepant		✓*			✓*

These studies are open-label, while all others are randomized and double-blinded.

Side effects for CGRP-mAbs are remarkably limited given the widespread functions of CGRP in multiple organ systems including cardiovascular, neurovascular, pulmonary, gastrointestinal, muscular, and immunologic (100). Common side effects from clinical trials were upper respiratory tract infections and injection site reactions. Of all of the CGRP-mAbs, erenumab has undergone the most clinical studies on adverse events and potential side effects, finding a risk of constipation, no risk of worsening angina in patients with stable angina, and a better adverse event profile than topiramate in a head-to-head trial (101 –103). While early trials of small molecule CGRP receptor inhibitors were plagued by hepatotoxicity, hepatoxicity has not been a concern with the CGRP-mAbs or the newer generation small molecule oral CGRP antagonists.

The mechanism of action for CGRP-mAbs is thought to be clear, as these antibodies are highly specific for either the CGRP ligand (eptinezumab, fremanezumab, and galcanezumab) or for the CGRP receptor (erenumab). It should be noted, however, that CGRP ligand blockers may have different effects than CGRP receptor blockers for the following two reasons: 1) CGRP binds not only to the CGRP receptor but also to the amylin-1 receptor (100), and 2) a functional magnetic resonance study showed ligand- and receptor-specific activation of networks in patients receiving galcanezumab versus erenumab (104). While the mechanism of action is clear, the site of action of CGRP-mAbs is, in contrast, still under debate. CGRP receptors have been found in intracranial arteries, peripheral neurons, and central neurons (100). In fact, CGRP is the most abundant neuropeptide in the trigeminal ganglion (105). Theoretically, due to the large molecular size of the antibody, the percentage of CGRP-mAbs that cross the blood-brain barrier is minuscule and an effect (at least direct) on the central nervous system is unlikely (106,107). Thus, the trigeminal ganglion, located outside the blood-brain barrier, would presumably be the primary target for CGRP-mAbs. However, the role of the trigeminal ganglion in CH may be less prominent than in migraine. In one case report, a CH patient still experienced attacks after trigeminal root resection (42). In another case series, ten CH patients underwent trigeminal root resection. Five of them continued to have their regular cluster attacks, while another five had periodic cranial autonomic symptoms without headache (108). Both studies suggest the importance of a central pain generator in the pathophysiology of CH. Cumulative evidence from functional imaging studies (109,110) and neurophysiological studies (111,112) suggests that there is a central effect of CGRP-mAbs, albeit probably secondary to peripheral drug modulation. Some even suggest a differential central effect of CGRP-mAbs between responders and non-responders (109,110).

There are several other options for CH prevention (Table 1), and here we will briefly discuss two commonly used ones, lithium and melatonin. The clinical trial dose of lithium was 900 mg divided TID (78), but it has multiple side effects that include weight gain, diabetes insipidus, hypothyroidism, and hyperparathyroidism (113), as well as a narrow therapeutic window with toxicity linked to elevated lithium levels. Recommended monitoring, from a variety of guidelines (114), includes lithium levels within a week of dose changes as well as every 3–12 months thereafter, as well as renal and thyroid labs every 6–12 months. Melatonin, in contrast, is a widely available supplement with lower side effects (primarily sedation) that was effective for CH when 10 mg is taken at bedtime (115). Both of these medications have known circadian effects (116) though lithium also affects several neurotransmitters (34).

Neuromodulation

Vagus nerve stimulation

CH is characterized by prominent unilateral cranial autonomic symptoms such as lacrimation, rhinorrhea, and ptosis. Cranial autonomic symptoms are due to the activation of the trigeminal autonomic reflex which consists of two arcs: the trigeminal nociceptive input and the parasympathetic output (117) (Figure 1). The concept of treating CH with non-invasive vagus nerve stimulation (nVNS) was based both on its known modulatory effect on the parasympathetic system and on an early case report of headache improvement as an incidental finding in patients receiving invasive VNS for treatment-resistant depression (118). In double-blind, randomized, sham-controlled trials, nVNS was superior to placebo in aborting acute cluster attacks exclusively in patients with eCH (119,120). Despite the lack of efficacy as an acute treatment in patients with cCH, early open-label studies suggested a potential prophylactic effect of nVNS – more than 50% of cCH patients had a ≥50% reduction in headache frequency (121). This prompted subsequent studies on the use of nVNS as a preventive treatment option. Two studies reported the clinical efficacy of nVNS as an adjunctive prophylactic treatment in cCH patients receiving standard of care therapy (122,123). eCH patients also benefit from nVNS as an adjunctive prophylactic treatment (122).

Figure 1.

Schematic representation of peripheral and central pathways summarizing potential targets for neuromodulation in the treatment of cluster headache. Trigeminal pain during cluster headache attacks (red) leads to the activation of the trigeminal pain pathway (black) and the activation of the parasympathetic output (green). The spinal trigeminal nucleus in the trigeminal cervical complex has a bidirectional connection to the hypothalamus, which may initiate cluster headache attacks and serve as a modulatory center for trigeminal nociception. Notably, a direct trigeminohypothalamic tract has been demonstrated in animal studies, but not yet in humans. Neuromodulatory treatments and their potential targets are shown in this figure. Other brain areas relevant to the pathophysiology of cluster headache, such as the insula, cerebellum, or occipital cortex, are not depicted in this figure because there is insufficient evidence that they are potential targets of currently available neuromodulation treatments for cluster headache. Solid lines: monosynaptic connections; dashed lines: multisynaptic connections. HT: hypothalamus; NTS: nucleus tractus solitarius; S1: primary sensory cortex; SPG: sphenopalatine ganglion; SSN: superior salivatory nucleus; TCC: trigeminal cervical complex; TG: trigeminal ganglion; Thal: thalamus. Figure created with BioRender.com.

Side effects from nVNS include a brief pulling sensation of the face or lip (possibly from platysma muscle contraction). Exclusion criteria used in the study, which could be considered suggestions for clinical contraindications, included an abnormal electrocardiogram (as the right vagus nerve innervates the sinoatrial node of the heart [124]); implanted electrical or neuromodulatory devices; cervical spine hardware or other metal near the neck; and diseases of the head (including seizures or syncope in the last year, brain tumors, or significant head trauma), the neck (carotid endarterectomy or severe carotid artery disease), or the heart (uncontrolled hypertension, severe coronary artery disease, recent myocardial infarction, or congestive heart failure).

Despite the clinical efficacy of nVNS, its mechanism of action is not fully understood. nVNS appears to modulate the trigeminal autonomic reflex, including the reduction of parasympathetic output (VNS reduces lacrimation in healthy control humans [125]), the reduction of trigeminal sensitivity in both an animal model (126) and a human model (127), and the link between the two (when the superior salivary nucleus is stimulated to increase firing in the trigeminal nucleus of rodents, the addition of VNS reduces the trigeminal nucleus firing [128]). It is not clear which part of this pathway is crucial for the clinical effect of nVNS. Provocation of cranial autonomic symptoms by induction of the trigeminal autonomic reflex in CH patients does not trigger CH attacks, suggesting that the parasympathetic output is a downstream phenomenon in CH attacks, and its suppression may only reduce the cranial autonomic symptoms but not headache (129). Therefore, the clinical efficacy of nVNS may involve a mechanism that is parallel to peripheral parasympathetic suppression. Potential candidates for this mechanism include a direct trigeminal nociceptive modulation or the involvement of other central structures such as the hypothalamus, thalamus, periaqueductal gray, cortex, or cerebellum (130,131). A recent functional imaging study showed altered activation in the spinal trigeminal nuclei, pons, parahippocampal gyri, and hypothalamus (132). The hypothalamus has long been implicated as a cluster generator (133), and its involvement provides a potential mechanism by which nVNS may modulate disease activity and subsequently reduce headache frequency. Similarly, involvement of the trigeminal nucleus provides an explanation for how nVNS may suppress acute attacks by directly modulating trigeminal pain processing. However, why patients with eCH and cCH respond somewhat differently to nVNS remains unknown.

Occipital nerve stimulation

The success of suboccipital steroid injections in the treatment of CH, whether episodic or chronic, has led to the idea of treating cCH patients with GON stimulation, as regular repeated nerve blocks are either inaccessible in the long term or carry risks because they need to be performed too frequently. The first cohort study was conducted in 2007, and in a cohort of eight refractory cCH patients, six achieved responses (25%–95%) in either frequency or intensity reduction (134). Subsequent open-label studies reported similar efficacy with approximately 50–70% reduction in either frequency or intensity of cluster attacks (135 –137). The first RCT was conducted in 2021 in medically refractory cCH patients (defined as failure, intolerance, or contraindications to verapamil, lithium, and at least one other preventive) (138). This RCT showed a more than 40% improvement in headache frequency at 21–24 weeks post-operatively, however the improvement was the same in the experimental group (100% stimulation) and the “sham” group (30% stimulation). A placebo effect thus cannot be ruled out in this study, though such a strong placebo effect in such a medically refractory group raises the question of whether the sham protocol is already sufficient to stimulate the occipital nerve in the current paradigm. Such cases are not uncommon with neuromodulatory devices: the sham device for nVNS can effectively reduce parasympathetic output and is not ideal for sham stimulation (125). Adverse events were similar in both open-label studies and the RCT and were primarily hardware-related issues (lead migration, battery depletion, infection, and wound healing issues). In the absence of adverse events, GON stimulation appears to be an effective long-term treatment option, with an open-label study showing that 66.7% remained responders (>50% improvement) for an average of 6.7 years of follow-up (139).

Patients with severe psychiatric comorbidity were less likely to respond to occipital nerve stimulation (140). In addition, response to suboccipital injections does not reliably predict the response to occipital nerve stimulation (140,141), making it unclear who is a good candidate for this relatively invasive treatment. Suggested criteria for surgical treatment of CH, i.e., occipital nerve stimulator placement, include cCH (as opposed to eCH) for at least two years, headache frequency between four per week and daily, failure of at least three if not all preventive medications including verapamil (138,142,143), and an unremarkable work-up (which includes an MRI brain and, potentially, MRA head and neck, pituitary hormone testing, chest X-ray, and sleep study [144]).

Pain in CH is primarily felt near the eye in the trigeminal nerve distribution, raising the question of how stimulation of the GON would be effective. Animal studies suggest a functional link between the trigeminal system and the C2/3 spinal system, where the GON originates, at the trigeminocervical complex (TCC). Stimulation of the GON leads to hyperexcitable dural afferents (145) and increased metabolic activity in the trigeminal nucleus caudalis (146). Anatomically, fibers from the C2/C3 ganglion also partially converge on the marginal part of two of the three subnuclei of the spinal trigeminal nucleus (the nucleus caudalis and nucleus interpolaris), providing an anatomical basis for crosstalk between the two systems at the TCC (147). In healthy humans, stimulation of the GON with capsaicin alters the pain thresholds of the dermatomes of all three branches of the trigeminal nerve; reciprocally, stimulation at V1 modulates pain thresholds in the occipital region (C2/3 dermatome) (75). Furthermore, the clinical efficacy of the suboccipital steroid injection outlasts the half-life of the injected drug, suggesting a pain modulatory effect rather than direct pain inhibition (148), and the TCC is most likely the site of the modulation.

Sphenopalatine ganglion simulation

As mentioned above, the trigeminal autonomic reflex plays a central role in the pathophysiology of cranial autonomic symptoms (117). While vagus nerve stimulation targets several components of the trigeminal autonomic reflex, the sphenopalatine ganglion (SPG) stimulation targets the parasympathetic portion of the trigeminal autonomic reflex (149). Like the GON, the SPG is a peripheral structure; peripheral stimulation carries a lower risk than the deep brain stimulation, which will be discussed in the next section. The efficacy of SPG stimulation as both an acute and prophylactic treatment has been demonstrated in two randomized, double-blind, sham-controlled trials (150,151). In the study by Schoenen et al. (150), 68% of cCH patients reported clinically significant improvement, defined as a 50% reduction in either attack frequency or pain intensity. An American study was conducted and reported similar efficacy of SPG stimulation in cCH patients (151). Long-term follow-up of SPG stimulation showed continued efficacy, 61–68% remained either acute responders (intensity reduction) or preventive responders (frequency reduction) (152,153). Despite the well-validated clinical efficacy, the company that manufactured the SPG stimulator had financial issues and the stimulator is currently unavailable (154).

The mechanism of SPG stimulation is not fully understood. SPG stimulation modulates the trigeminal autonomic reflex, but this may not fully explain how it works against headache. In SPG stimulation, low-frequency stimulation leads to increased parasympathetic outflow, whereas high-frequency stimulation, as the paradigm used in SPG stimulation clinical trials, leads to decreased parasympathetic outflow (155). Schytz et al. (155) successfully induced cluster-like attacks in three out of six CH patients with low-frequency stimulation and unexpectedly, in one out of six patients with high-frequency stimulation. Guo et al. (156) repeated low-frequency SPG stimulation in 20 CH patients in a double-blind, randomized, sham-controlled, crossover design, and low-frequency stimulation effectively induced autonomic symptoms but not headache. Intranasal kinetic oscillation is another method that effectively triggers the trigeminal autonomic reflex and leads to prominent parasympathetic output, i.e., lacrimation (125). However, it also failed to trigger headache attacks in patients with CH (129). Taken together, these two studies support a dissociation between the parasympathetic output and cluster headache triggers (129,156). Therefore, the acute pain-aborting/inhibitory effect of SPG stimulation, and the long-term disease-modulating effect, i.e., reduction in attack frequency, may involve a mechanism that is more complex than inhibition of the parasympathetic autonomic output. In animal models, the SPG projects not only to the lacrimal gland and nasal mucosa via parasympathetic postganglionic fibers, but also directly to the trigeminal ganglion, providing an anatomical basis for direct modulation of the trigeminal nociception by SPG stimulation (157). Alternatively, SPG stimulation shows modulatory effects on cerebral perfusion and alteration of blood-brain barrier permeability, but how this may affect pain perception requires further investigation (158).

Deep brain stimulation

For patients with medically refractory CH, deep brain stimulation (DBS) of the posterior hypothalamus was tried before other neuromodulatory treatment options were available. DBS is based on functional imaging studies showing posterior hypothalamic activation during CH attacks, so this site has been considered a potential headache generator in CH (159,160). In small case series, posterior hypothalamic DBS effectively reduced the attack intensity and attack frequency (161 –163). One double-blind, randomized, sham-controlled study (164) failed to show the superiority of DBS during the one-month randomized phase, but at the end of the open-label phase (one year after the randomized phase), 6/11 had a good response, similar to the previous studies (161 –163). However, the potentially fatal risk of intracranial hemorrhage renders this central nervous system treatment option less preferable to the peripheral nervous system alternatives such as SPG and GON stimulation (163). DBS is currently rarely used to treat refractory CH. Nevertheless, the potential success of hypothalamic DBS in the treatment of CH provides proof of concept that this region may be directly involved in the generation of cluster attacks. A neurophysiological study in patients receiving hypothalamic DBS showed that DBS increased the thermal pain threshold in dermatome V1 ipsilateral to the stimulation, suggesting a direct pain modulatory effect of DBS (165). In addition, both nVNS and CGRP-mAbs showed (possibly indirect) hypothalamic modulatory effects (109,110,132), further supporting the hypothalamus as a potential treatment target.

Conclusion

Common first-line treatments for CH – subcutaneous sumatriptan, oxygen, prednisone, suboccipital steroid injections, and verapamil – remain the mainstay for treatment of this disorder. The mechanisms of these treatments, either how they work or where they work, are still incompletely understood. Additionally, the advent of neuromodulation and the introduction of anti-CGRP treatment have brought new opportunities for CH patients. However, patients still suffer from inadequate access to these treatment options. In addition, some patients, particularly those with cCH, respond poorly to existing treatment options. A better understanding of the biological differences between eCH and cCH is essential to unravel the factors that determine clinical response.

Clinical implications

Cluster headache is treated with acute treatments (to manage an ongoing attack), bridge treatments (short-term preventives to be used while uptitrating preventives), and long-term preventive treatments.

Common first-line treatments include fast-acting triptans and high-flow oxygen as acute treatments, corticosteroids (oral or suboccipital injections) as bridge treatments, and verapamil as a long-term preventive treatment.

The mechanisms of oxygen, corticosteroids and verapamil are uncertain, whereas those of triptans and anti-CGRP treatments are clear but their site of action remains controversial. The mechanisms of neurostimulation devices are thought to target parts of the cluster headache pathways.

Footnotes

Declaration of conflicting interests

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article:

K-PP has received honoraria as speaker from TEVA and serves as Associate Editor of Cephalalgia and Cephalalgia Reports.

MJB was an unpaid medical advisor for Praxis Precision Medicines (in lieu of compensation a fee was paid to the University of Texas Health Science Center at Houston) and was an unpaid consultant for Beckley Psytech limited (in lieu of compensation a donation was made to the Will Erwin Headache Research Foundation). It should be noted, however, that Dr. Burish is employed by the University of Texas Health Science Center at Houston and receives research funding from the Will Erwin Headache Research Foundation. He is an unpaid member of the medical advisory board of Clusterbusters, and was a site investigator for a cluster headache clinical trial funded by Lundbeck.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Kuan-Po Peng

Mark J. Burish

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Management of cluster headache: Treatments and their mechanisms

Abstract

Background

Methods

Results

Conclusions

Keywords

Introduction

Acute pharmacological treatments

Triptans: Sumatriptan and zolmitriptan

Oxygen

Bridge treatment

Corticosteroids

Preventive pharmacological treatments

Verapamil

Anti-calcitonin gene-related peptide therapy

Neuromodulation

Vagus nerve stimulation

Occipital nerve stimulation

Sphenopalatine ganglion simulation

Deep brain stimulation

Conclusion

Clinical implications

Footnotes

Declaration of conflicting interests

Funding

ORCID iDs

References