Review

Cephalalgia
2023, Vol. 43(8) 1–15
Management of cluster headache: ! International Headache Society 2023
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DOI: 10.1177/03331024231196808
journals.sagepub.com/home/cep

Kuan-Po Peng1 and Mark J. Burish2

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
Date received: 22 June 2023; revised: 30 July 2023; accepted: 1 August 2023

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 pre-
ventive 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 suffi-
cient, 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
1
Department of Systems Neuroscience, University Medical Center
Hamburg-Eppendorf, Hamburg, Germany
2
Department of Neurosurgery, UTHealth Houston, Houston, Texas,
USA
Corresponding author:
Mark J. Burish, Department of Neurosurgery, UTHealth Houston, 6400
Fannin Street, Suite 2010, Houston, TX, USA 77006.
Email: mark.j.burish@uth.tmc.edu

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2 Cephalalgia

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 effective-
ness from a recent network meta-analysis (3). Often
multiple acute, bridge, and preventive medications are
prescribed concurrently: in the authors’ personal expe-
riences, 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).
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), per-
formed a narrative review of the literature for all of

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 American

of Neurological Headache Ranking in
Societies Society Dose examined for Network
Recommendation Recommendation network meta-analysis 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 mg 6
Noninvasive vagus nerve new* new* 3
2 min stimulations 7
stimulation (eCH only)
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 NR A Multiple; all use steroids
occipital nerve block
——————————————— ———————— ——————— ———————————
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.
Peng and Burish
these treatments, created summaries, and then com-
pared notes.
Acute pharmacological treatments
Triptans: Sumatriptan and zolmitriptan
Triptans, as a class, consist of seven approved medica-
tions that activate serotonin receptors 5HT1B, 5HT1D,
and in some cases 5HT1F (6). Two of these triptans –
sumatriptan and zolmitriptan – have fast non-oral
routes of administration, and these are the ones recom-
mended 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 sumatrip-
tan 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 trip-
tan response have shown that patients with eCH (as
opposed to cCH), younger patients, and patients with
shorter and less frequent attacks may be more respon-
sive 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-inflam-
matory 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 head-
ache: a bilateral, dull headache with no associated fea-
tures (23). A personal or family history of migraine is
quite common in cluster headache patients with medi-
cation overuse headache (23).
Side effects from triptans include sedation, dizziness,
transient hypertension, flushing, and tightening sensa-
tions (in the chest, throat/neck, or extremities) (24–27)
and many of these effects are more common in subcu-
taneous sumatriptan than in the nasal or oral
3
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
5HT1F agonists (which are called ditans instead of trip-
tans) 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 typical-
ly needed for the treatment of CH.
Triptans are not recommended in patients with a his-
tory of stroke or myocardial infarction or with uncon-
trolled hypertension. They should not be used in
combination with monoamine oxidase inhibitor antide-
pressants 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 stud-
ies 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 vaso-
constrictive function of these medications was the prima-
ry mechanism of action, while today the widely accepted
theory is that triptans primarily work in neurons through
5HT1B/5HT1D receptors to prevent the release of vasoac-
tive peptides during trigeminovascular activation includ-
ing calcitonin gene-related peptide (CGRP) (33,34),
substance P (34), neurokinin A (34), and the activation
of transient receptor potential vanilloid 1 (TRPV1) chan-
nels (35). An ongoing debate is where the triptans act, as
5HT1B and 5HT1D receptors are found peripherally in the
trigeminal ganglion and centrally in the brainstem, thal-
amus, and hypothalamus (36–39). The subcutaneous for-
mulation 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 gan-
gliotomy, 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
4 Cephalalgia
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 treat-
ment (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 auto-
nomic 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 stimu-
lated (57). Human studies activating the peripheral
portion of the cranial autonomic system using intrana-
sal kinetic oscillation stimulation, however, showed no
modulatory effects of oxygen on provoked parasympa-
thetic output (58) (for more details of the peripheral
autonomic pathway, see the discussion of the
trigeminal-autonomic reflex in the vagus nerve stimu-
lation 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 injec-
tion. 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 pre-
viously 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 ¼ 20) open-label
study (62) and confirmed in two double-blind place-
bo-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, com-
pared 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 consis-
tently 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 consid-
ered 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 ste-
roids, though suboccipital injections are limited to sev-
eral 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 cuta-
neous 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 bipo-
lar patients).
The mechanism of corticosteroids in CH is unclear,
partly because corticosteroids have multiple mecha-
nisms that could target CH. In the circadian system
corticosteroids signal daytime (and melatonin signals
Peng and Burish
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 injec-
tions 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 ¼ 30 each), verapamil is widely consid-
ered 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 (divid-
ed 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 docu-
mented (53,81,83). Additionally, verapamil is a
CYP3A4 inhibitor and can increase the serum concen-
tration of other medications sometimes used to treat
CH such as ergot derivatives (ergotamine and dihydro-
ergotamine), gepants, and lithium.
5
The mechanism of verapamil in CH is unclear, like
steroids it has multiple potential mechanisms.
Verapamil appears to modulate a variety of serotoner-
gic, 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 nimo-
dipine 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 gan-
glion and the hypothalamus in mice (85).
Anti-calcitonin gene-related peptide therapy
The idea of CGRP blockade as a treatment for head-
aches 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 fremane-
zumab 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), erenu-
mab in cCH (NCT04970355), and rimegepant (an oral
small molecule CGRP antagonist rather than a mono-
clonal 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
6 Cephalalgia
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
Effective In clinical trials
Eptinezumab
Erenumab
Fremanezumab
Galcanezumab  
Rimegepant *
*
These studies are open-label, while all others are randomized and double-blinded.
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 (clus-
ter bout) and only 50% in cCH patients (87). In addi-
tion, 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 meas-
urements of CGRP would help to better understand
who benefits from the treatment.
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 immuno-
logic (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 con-
stipation, 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 spe-
cific for either the CGRP ligand (eptinezumab, frema-
nezumab, 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
Chronic cluster headache
Ineffective Effective In clinical trials Ineffective
 *

 
*
reasons: 1) CGRP binds not only to the CGRP recep-
tor 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 trigem-
inal 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 gener-
ator in the pathophysiology of CH. Cumulative evi-
dence from functional imaging studies (109,110) and
neurophysiological studies (111,112) suggests that there
is a central effect of CGRP-mAbs, albeit probably sec-
ondary to peripheral drug modulation. Some even sug-
gest 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 common-
ly 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 tox-
icity linked to elevated lithium levels. Recommended
Peng and Burish 7

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 thy-
roid 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 medica-
tions 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 receiv-
ing 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 treat-
ment 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 subse-
quent studies on the use of nVNS as a preventive treat-
ment 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.
8 Cephalalgia
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 clin-
ical contraindications, included an abnormal electro-
cardiogram (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 dis-
ease), 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 can-
didates 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 poten-
tial mechanism by which nVNS may modulate disease
activity and subsequently reduce headache frequency.
Similarly, involvement of the trigeminal nucleus pro-
vides 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 stimu-
lation, as regular repeated nerve blocks are either inac-
cessible 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 suf-
ficient to stimulate the occipital nerve in the current
paradigm. Such cases are not uncommon with neuro-
modulatory 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 fre-
quency 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]).
Peng and Burish
Pain in CH is primarily felt near the eye in the tri-
geminal 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 cross-
talk between the two systems at the TCC (147). In
healthy humans, stimulation of the GON with capsai-
cin 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 inhibi-
tion (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 stimu-
lation 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 stimula-
tion carries a lower risk than the deep brain stimula-
tion, which will be discussed in the next section. The
efficacy of SPG stimulation as both an acute and pro-
phylactic 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 improve-
ment, defined as a 50% reduction in either attack fre-
quency or pain intensity. An American study was
conducted and reported similar efficacy of SPG stimu-
lation 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
9
autonomic reflex, but this may not fully explain how it
works against headache. In SPG stimulation, low-
frequency stimulation leads to increased parasympa-
thetic 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 stimu-
lation effectively induced autonomic symptoms but not
headache. Intranasal kinetic oscillation is another
method that effectively triggers the trigeminal auto-
nomic 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 dissocia-
tion 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 mecha-
nism that is more complex than inhibition of the para-
sympathetic 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 poten-
tially fatal risk of intracranial hemorrhage renders this
10 Cephalalgia

central nervous system treatment option less preferable Conclusion

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 treat-
ment 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 indi-
rect) hypothalamic modulatory effects (109,110,132),
further supporting the hypothalamus as a potential
treatment target.
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 addi-
tion, 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 deter-
mine 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, cor-
ticosteroids (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 neuro-
stimulation devices are thought to target parts of the cluster headache pathways.

Declaration of conflicting interests Mark J. Burish https://orcid.org/0000-0002-8931-6436

The authors declared the following potential conflicts of
interest with respect to the research, authorship, and/or pub-
lication 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, howev-
er, that Dr. Burish is employed by the University of Texas
Health Science Center at Houston and receives research fund-
ing 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 head-
ache 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 https://orcid.org/0000-0002-2718-3738
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