PRIMER

Cluster headache
Arne May1, Todd J. Schwedt2, Delphine Magis3, Patricia Pozo-Rosich4,5, Stefan Evers6
and Shuu-Jiun Wang7
Abstract | Cluster headache is an excruciating, strictly one-sided pain syndrome with attacks that
last between 15 minutes and 180 minutes and that are accompanied by marked ipsilateral cranial
autonomic symptoms, such as lacrimation and conjunctival injection. The pain is so severe that
female patients describe each attack as worse than childbirth. The past decade has seen
remarkable progress in the understanding of the pathophysiological background of cluster
headache and has implicated the brain, particularly the hypothalamus, as the generator of both
the pain and the autonomic symptoms. Anatomical connections between the hypothalamus
and the trigeminovascular system, as well as the parasympathetic nervous system, have also been
implicated in cluster headache pathophysiology. The diagnosis of cluster headache involves
excluding other primary headaches and secondary headaches and is based primarily on the
patient’s symptoms. Remarkable progress has been achieved in developing effective treatment
options for single cluster attacks and in developing preventive measures, which include
pharmacological therapies and neuromodulation.

Correspondence to A.M.
Department of Systems
Neuroscience, University
Medical Center Hamburg-
Eppendorf, Martinistrasse
52, D-20246 Hamburg,
Germany.
a.may@uke.de
Article number: 18006
doi:10.1038/nrdp.2018.6
Published online 1 Mar 2018
Headache is one of the most common pain symptoms in
humans. It is extremely rare to have never had a head‑
ache, even when experiencing influenza infection or a
mild head trauma. Headache is a normal physiological
reaction; however, when headaches occur regularly and
without adequate triggers, they are regarded not as a
symptom but as a disease, examples of which include
migraine and cluster headache. The International
Classification of Headache Disorders (ICHD‑3), which
was updated in 2018, uses explicit diagnostic criteria
based on symptoms and medical history for all head‑
ache disorders1. No single examination is able to define,
ensure or differentiate idiopathic headache syndromes2.
The ICHD‑3 summarizes one group of headache syn‑
dromes as the trigeminal-autonomic cephalalgias (TACs;
BOX 1)1, of which cluster headache is the most prominent
and common subtype.
Cluster headache is probably the most severe pain
known and is characterized by ipsilateral headache, with
pain localized to the orbit, supraorbital and/or temporal
regions and associated autonomic features. Autonomic
symptoms, such as lacrimation (tearing), conjunctival
injection (redness of the sclera), rhinorrhoea, nasal
congestion, hyperhidrosis (excessive sweating) and eye‑
lid oedema, usually occur on the ipsilateral side to the
pain3 and are absent in only 3% of cases. Cluster head‑
ache can be subclassified as either episodic or chronic,
of which the episodic form is more common and affects
80–90% of patients3. Based on the ICHD‑3 criteria,
diagnosis of episodic cluster headache requires at least
two cluster periods (also known as cluster bouts), each
lasting from 7 days to 1 year 1. These cluster periods are
separated by pain-free periods (also known as out-of-
bout periods or remission periods) that last ≥3 months.
Diagnosis of chronic cluster headache requires cluster
attacks that occur for >1 year without remission p ­ eriods
or with remission periods of <3 months in duration.
Cluster headache attacks usually also occur with clock‑
like r­ egularity during the day and are common during
the night.
The pathophysiology of cluster headache is not fully
understood but includes alterations in both the central
and peripheral nervous systems, including activation
of the trigeminovascular system (that is, divisions of
the trigeminal nerve that innervate the cranial blood
­vessels) and the parasympathetic nervous system, which
are speculated to underlie the pain and autonomic
­features of cluster headache, respectively. In addition,
the hypothalamus — which interacts with several com‑
ponents of the trigeminovascular system — is believed
to have an important role in the pathophysiology of
cluster headache.
This Primer focuses on the current evidence of
pathophysiology and diagnosis of cluster headache and
how to manage patients, including those who are diffi‑
cult to treat. This Primer also gives an up-to-date over‑
view of the clinical features of cluster headache and a
topical summary of the current state of research for this
debilitating disease that is, in principle, easily treatable
if certain principles are followed.

NATURE REVIEWS | DISEASE PRIMERS VOLUME 4 | ARTICLE NUMBER 18006 | 1

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Author addresses Cluster bout periods seem to be more frequent in

1
Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf,
Martinistrasse 52, D-20246 Hamburg, Germany.
2
Department of Neurology, Mayo Clinic, Phoenix, AZ, USA.
3
University Department of Neurology CHR, CHU de Liege, Belgium.
4
Headache and Craniofacial Pain Unit, Neurology Department, Hospital Universitari Vall
d’Hebron, Barcelona, Spain.
5
Headache Research Group, VHIR, Universitat Autònoma Barcelona, Barcelona, Spain.
6
Department of Neurology, Krankenhaus Lindenbrunn, Coppenbrügge, Germany.
7
Taipei Veterans General Hospital, National Yang-Ming University School of Medicine,
Taipei, Taiwan.
Epidemiology
Sociodemographic factors
Cluster headache is a rare headache disorder that occurs
globally in 0.1% of the general population but accounts for
<3% of all patients with headache in Asia4–6. Cluster head‑
ache has a male preponderance; the Cluster Headache
Survey completed by 1,134 individ­uals in the United States
confirmed earlier reports that ~72% of patients are male7.
A decreasing male to female ratio has been reported in the
past 30 years8. This difference is probably attributable to
better epidemio­logical tools, improved adherence to the
diagnostic criteria and increased knowledge of the dis‑
ease9; a lack of awareness of the disorder probably led to
frequent misdiagnosis as migraine10. Indeed, a large pro‑
portion of patients with cluster headache have migraine-
like f­ eatures, such as photophobia (sensitivity to light)
or osmophobia (hypersensitivity to odours), in addition
to the typical trigeminal-­autonomic symptoms, such as
­ptosis (drooping of the upper eyelid), sweating and miosis
(constriction of the pupils). These patients (up to 46% in
a large Italian study) also show a relatively younger age of
onset and attacks that are longer in duration than cluster
­headache attacks without migraineous features11.
The age at onset of cluster headache ranged from
10 years to 68 years of age in one study in Sweden, with
a peak between 20 years and 29 years of age for both
sexes12. In the United States, cluster headache onset has
been shown to occur before 20 years of age in 35% of
patients and between 21 years and 30 years of age in 36%
of patients7. Onset is less likely to occur between 31 years
and 40 years of age (observed in 16% of patients) and
between 41 years and 50 years of age (observed in 10%
of patients)7. Only 3% of patients were >51 years of age
at onset in the United States7. Other studies conducted in
the United States and Italy have shown an onset of cluster
headache before 50 years of age in 83.3% of women and
91.3% of men13,14. In a large Italian study, the mean age
at onset was 30.2 years. In this study, women with pri‑
mary chronic cluster headache (cluster headache that was
chronic from onset) had a mean age at onset of 42.8 years;
the age at onset in women with secondary chronic cluster
headache (cluster headache that was episodic at onset and
later became chronic) did not differ much from those
with episodic cluster headache. In patients with chronic
cluster headache who had onset prior to 16 years of age
or after 49 years of age, the traditional male to female
ratio was inverted15. Thus, the clear male predominance
in cases with onset in the central age groups became
­attenuated in the extreme age groups.
spring and autumn; although there are some reports in this
regard, data are not available from all countries. However,
one study in Taiwan stated that the cluster periods were
more likely to occur in autumn and winter and are
determined by the temperature of the preceding periods16.
In regard to life habits and possible risk factors, cigar­
ette smoking, head trauma and family history of head‑
ache were associated with cluster headache in an Italian
­epidemiological case–control study 17.
Genetic factors
Previous twin and family studies have highlighted the
importance of genetic factors in cluster headache4,18.
Individuals with first-degree and second-degree relatives
with cluster headache have an increased risk compared
with the general population19,20. Some studies suggest
that cluster headache is an autosomal recessive inherited
disorder, although others have suggested an autosomal
dominant or multifactorial inheritance pattern21.
Genetic association studies focusing on the identifi­
cation of candidate genes for cluster headache have
suggested a modulatory role for HCRTR2 (encoding
hypocretin (orexin) receptor type 2) in posterior hypo‑
thalamic neurons that are involved in the trigeminal pain
pathway 22–24; however, this hypothesis was contradicted
in a recent meta-analysis25. Other studies have associated
homozygosity for the 1246G>A allele of HCRTR2 with
an increased risk of cluster headache26,27, but this finding
was not confirmed in a large multinational study22. Given
the association between polymorphisms in HCRTR2 and
cluster headache as well as the role of the orexin system in
the pathophysiology (see Mechanisms/­pathophysiology,
below), sleep disorders such as narcolepsy have been
suggested to be associated with cluster headache28. Other
genetic association studies have revealed neg­ative or con‑
flicting results for the association of several genetic alter‑
ations with cluster headache, including mito­chondrial
DNA mutation29, genes encoding nitric oxide synthase
(NOS1, NOS2A and NOS3)30, CACNA1A (encoding
Box 1 | Trigeminal-autonomic cephalalgias
The trigeminal-autonomic cephalalgias (TACs) are a
group of headache disorders characterized by unilateral
headaches with autonomic symptoms ipsilateral to the
pain, such as miosis (constriction of the pupil), ptosis
(drooping of the upper eyelid), lacrimation (tearing) and
conjunctival injection (redness of the sclera). Individual
TACs have distinct patterns of duration, frequency,
periodicity and intensity of attacks. In the most current
International Classification of Headache Disorders
(ICHD‑3), the following syndromes are classified as TACs:
• Episodic and chronic cluster headaches
• Episodic and chronic paroxysmal hemicrania
• Hemicrania continua
• Short-lasting unilateral neuralgiform headache attacks
with cranial autonomic symptoms (SUNA-syndrome)
• Short-lasting unilateral neuralgiform headache
attacks with conjunctival injection and tearing
(SUNCT-syndrome)

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calcium voltage-gated, P/Q‑type, α-1A sub­unit) for Pathogenesis of peripheral origin

­paroxysmal characteristics31 and a number of clock genes
for rhythmicity, such as PER3, and the T3111C and
3092 T>C polymorphisms in CLOCK32–34.
ADH4 (encoding alcohol dehydrogenase 4) has
been studied in patients with cluster headache in light
of the identification of alcohol as a trigger for attacks35.
One study identified a positive association between the
ADH4 rs1126671 single nucleotide polymorphism (SNP)
and the risk of cluster headache in an Italian cohort 35;
another study reported an association between the ADH4
rs1800759 SNP and cluster headache36. However, these
findings were not confirmed in a recent large c­ ase–­control
cohort study in Sweden37.
A recent genome-wide association study in a cohort
of 99 Italian patients with cluster headache and 360 age-
matched, cigarette-smoking, healthy controls demon‑
strated that ADCYAP1R1 (encoding pituitary adenylyl
cyclase-activating polypeptide type I receptor, also known
as PACAP) and MME (encoding membrane metallo­
endopeptidase, also known as neprilysin) variants were
associ­ated with cluster headache susceptibility, suggesting
roles for genes implicated in pain processing 38. However,
a case–control study in Sweden did not find an association
between cluster headache and ADCYAP1R1, MME or an
intergenic variant on chromosome 14q21 (REF. 39). Thus,
additional exploration of specific gene abnormalities in
cluster headache is warranted, and additional studies with
larger sample sizes are needed; hitherto, no gene has been
clearly associated with cluster headache.
Mechanisms/pathophysiology
Our understanding of the pathophysiology of cluster
headache has advanced greatly owing to findings from
preclinical and clinical studies, clinical observations,
genetics and neuroimaging studies, but still remains
incompletely understood. Previously, cluster headache
was considered to be a type of vascular headache, but
more recent evidence suggests that the pathophysio­
logy of cluster headache involves the brain, trigemino‑
vascular system and cranial parasympathetic system9,40.
Whether cluster headache pain originates peripherally
or centrally remains controversial; both are hypotheses
of cluster headache pathophysiology. Collectively, the
pathophysiology of cluster headache seems to involve
the hypothalamus and pain-processing areas of the central
nervous system, as well as peripheral structures, such as
the trigeminal nerve, parasympathetic nerves and c­ ranial
vasculature. However, changes in peripheral structures
(such as peripheral blood vessels) have a secondary role
in cluster headache pathophysiology. Structural and
functional changes in the hypothalamus and other brain
networks that transmit nociceptive information have also
been implicated in cluster headache, and the functional
changes dynamically change between cluster-bout ­periods
and out-of-bout periods. Moreover, anatomical and func‑
tional links between the hypothalamus and brain areas
that are traditionally not considered as pain processing
(for example, the occipital cortex and cerebellum) are
altered in cluster headache and may also contribute to
the pathophysiology.
Proposed model of cavernous sinus involvement. Several
characteristics of cluster headache attacks are consistent
with pathology in the region of the cavernous sinus,
mainly the triad of a predominantly tri­geminal pain
distribution, parasympathetic hyperactivity and sympa­
thetic deficits. Indeed, the cavernous sinus is the only
peripheral site where trigeminal C‑fibres (which have
a role in the transmission of nociceptive information
to the central nervous system) and sympathetic fibres
can be affected by a single cause41. However, clinical
evidence for the involvement of the cavernous sinus in
cluster headache is lacking. For example, the frequency
of abnormal findings observed at orbital veno­graphy
in cluster headache was not higher than those in other
forms of headache42,43, suggesting that the caver­nous
sinus is unlikely to be the sole origin of pain in ­cluster
headache. Furthermore, no clinical or bio­chemical
evidence suggests a role of s­ ystemic inflammation in
patients with cluster headache44.
Proposed vascular model. Another, albeit ­obsolete,
hypothesis is that cluster headache is a variant of
migraine such that the vascular headaches in cluster
headache are related to changes in intracranial and extra­
cranial blood vessels. Indeed, vasoconstricting ergot
alkaloid deriv­atives are effective for the treatment of
cluster headache45. However, neuroimaging studies
using single-photon emission computed tomography
(SPECT) have yielded contradictory results, with stud‑
ies showing increased, decreased or unchanged cere‑
bral blood flow in patients with cluster headache44,46–49.
Furthermore, intra­cranial vasodilation has been pro‑
posed to occur in cluster headache, although this is not
specific as it also occurs in forehead pain50. Notably,
exogenous hista­mine and other vasodilators (for exam‑
ple, alcohol, nitro­glycerine and 5‑hydroxytryptamine 2B
(5‑HT2B) agonists) can trigger cluster headache attacks
during cluster‑bout periods in patients51,52. This finding
does not prove that vaso­dilatation is the initial event
of c­ luster headache but suggests that vascular or other
changes generate a permissive state in the cluster head‑
ache brain. Thus, vaso­dilation may be a trigger for the
onset of cluster headache attacks, but it does not seem to
be the primary cause.
Proposed trigeminal nerve model. According to the
trigeminal nerve model of cluster headache, activ­ation
of the first division of the trigeminal nerve (that is,
the ophthal­mic nerve) by headache triggers — such as
changes in weather, alcohol consumption, histamine
release and strong odours — produces severe uni­
lateral headache. This activation of the trigeminal nerve
leads to the reflex activation of parasympathetic effer‑
ents (through the trigeminal-autonomic reflex), which
produce autonomic symptoms, such as ­lacrimation,
­rhinorrhoea and nasal congestion53.
In support of this model, triptans (particularly, suma­
triptan), which activate postsynaptic 5‑HT1B (causing
intracranial vasoconstriction) and 5‑HT1D receptors
(inhibiting brainstem trigeminal neuron neurotransmitter

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PRIMER

release), have been successfully used to treat acute cluster
headache attacks54. However, to date, no evidence sup‑
ports that sumatriptan crosses the blood–brain b ­ arrier
during acute attacks55, and whether triptans act through
an effect on peripheral trigeminovascular neurons or
predominantly through a central nervous system effect
in the brainstem is debated56. Surgical lesioning of the
trigeminal nerve is not effective in patients with clus‑
ter headache57, suggesting that the potentially central
effects of sumatriptan on the trigeminal nucleus caudalis
(TNC; that is, the caudal region of the spinal trigeminal
nucleus)58 are partly responsible for the success of this
treatment in cluster headache, in ­addition to a possible
peripheral trigeminovascular effect59.
Other lines of evidence supporting the trigeminal
nerve model of cluster headache include increased ­levels
of markers of both trigeminal nerve and para­sympa­
thetic activation. For example, increased expression
of calcitonin gene-related peptide (CGRP; a marker of
trigeminal activation) and vasoactive intestinal peptide
(VIP; a marker of parasympathetic neuronal activ­ation)
have been found in jugular vein blood samples, ipsi‑
lateral to cluster headache attacks compared with out-
of-bout periods and in healthy individuals60. Moreover,
CGRP is increased in the plasma of patients during
acute cluster headache attacks compared with out-
of-bout periods61, and increased plasma CGRP l­evels
during nitroglycerine-­induced attacks can be attenu‑
ated by sumatriptan injection in patients62. In addition,
increased CGRP levels have been reported between
headaches (interictally) in patients during a cluster-­
bout period, which were reduced after short-term
Mechanical and nociceptive Higher brain
input from face and neck Trigeminal centres
ganglion
Vasodilation
TCC
TNC
Lacrimation
C1
C2 SSN
Rhinorrohea
SPG
Figure 1 | Schematic pathway representation summarizing the trigeminal-
Nature Reviews | Disease Primers
parasympathetic reflex. In patients with cluster headache, autonomic symptoms are
thought to be mediated through the trigeminal-autonomic reflex. The trigeminal nucleus
caudalis (TNC) is connected to the superior salivatory nucleus (SSN), from which
parasympathetic efferent fibres of the facial nerve arise. During the trigeminal-
autonomic reflex, activation of the trigeminal nerve is thought to lead to activation of
parasympathetic efferents, producing autonomic symptoms such as lacrimation,
rhinorrhoea and nasal congestion. These parasympathetic efferents originate in the SSN
synapse with postganglionic fibres that innervate the dural vessels in the sphenopalatine
ganglion (SPG), resulting in vasodilation. C1, C1 cervical nerve; C2, C2 cervical nerve;
TCC, trigeminocervical complex.
prophylaxis with cortico­steroids63. Pretreatment with
methylprednisolone could suppress IL‑1β, but not
prostaglandin E 2-induced CGRP release from cul‑
tured trigeminal ganglia neurons64, and a blockade of
cytokine-mediated trigeminal activation may medi‑
ate the preventive effect of methylprednisolone on
cluster headache pathophysiology 64. However, despite
increased levels of CGRP in cluster headache, similar
changes have been reported during migraine attacks
and during therapeutic lesioning of the tri­geminal
ganglion65,66. Thus, although the trigeminal nerve may
be involved in cluster headache, its activation alone
cannot account for the disorder, and other factors are
probably involved.
The neuropeptide PACAP is pharmacologically
similar to VIP, is involved in pain processing in animal
models and has been implicated in migraine patho‑
genesis67. Indeed, the intravenous administration of
PACAP in healthy individuals can induce migraine-like
headaches68. Interestingly, one study demonstrated the
presence of PACAP in plasma during acute attacks in
patients with cluster headache69. In addition, PACAP can
induce activation of neurons in regions that are thought
to be involved in cluster headache pathophysiology, such
as the superior salivatory nucleus, the sphenopalatine
ganglion (SPG; a parasympathetic ganglion) and the
trigeminal ganglion70.
Studies using animal models have shown that stimu­
lation of the pontine superior salivatory nucleus (SSN;
which is the origin of cells in the parasympathetic vaso­
dilator pathway and contains cell bodies of neurons
that innervate the salivary glands and a host of other
tissues) independently produces short-term neuronal
activ­ation in the trigeminocervical complex (TCC),
which is associ­ated with autonomic cranial symptoms,
such as lacrimation and rhinorrhoea, and is inhibited
by oxygen treatment in cluster headache71,72. The TCC
consists of the dorsal horn of cervical spinal cord level 1
and level 2 and the TNC and acts as a relay centre that
conveys nociceptive information from the head and
neck to higher brain regions, such as the thalamus.
In addition, the SSN receives direct projections from
the para­ventricular hypothalamic nucleus, which might
modulate trigeminovascular nociceptive processing 73.
Neurons from the SSN project to the SPG, which is
associated with cranial pain and autonomic symptoms,
such as lacrimation and rhinor­rhoea, and mediate the
trigeminal-autonomic reflex 40 (FIG. 1). Indeed, studies
have suggested that the activation of postganglionic
SPG neurons mediates the dilation of local meningeal
­vessels and the activation of trigeminal nociceptive
fibres40. The activation of trigeminal nociceptive fibres
can also ­trigger a reflex connection in the SSN, which
contributes to increased cranial parasympathetic activ‑
ity mediated by the SPG74,75. Consequently, SPG stimu‑
lation is minimally invasive and a potentially effective
treatment option for patients with intractable chronic
cluster headache (see Neuromodulation, below)76–79.
Of note, purely peripheral activation of the cranial
para­sympathetic system is not sufficient to cause cluster
headache attacks80–82.

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Although the above data suggest peripheral involve‑
ment in the pathogenesis of cluster headache, such
theories cannot explain the cyclical recurrence of this
disorder. Indeed, cluster headache‑specific features,
such  as circadian and circannual rhythmicity, and
behavi­oural features, such as agitation and restlessness,
during acute attacks might be attributable to central
rather than p
­ eripheral mechanisms.
Pathogenesis of central origin
The pain network. Pain is a complex, multifactorial and
subjective experience that involves a large distributed
brain network including both sensory–discriminatory
and affective–cognitive evaluative neuroanatomical
components83. Several neurophysiological studies have
shown altered pain perception and decreased pain
thresholds in patients with cluster headache, suggesting
dysfunction of the pain control system84–87. Furthermore,
neurophysio­logical studies have implicated deficits in
supraspinal pain control, such as the diffuse noxious
inhibitory controls (neuronal pathways that underlie
the physiological inhibition of pain by another pain‑
ful stimulus) in cluster headache88,89. Dysfunction of
the descending pain control system may facilitate pri‑
mary headache disorders, including cluster headache,
by ­disinhibiting or facilitating n­ ociceptive signalling 90.
Functional imaging studies have demonstrated dys‑
function of the pain modulatory system in cluster head‑
ache91,92. Indeed, studies using 18F-fluorodeoxyglucose
PET showed increased glucose metabolism in frontal
brain areas (such as the perigenual anterior cingulate
and prefrontal cortices) in addition to the thalamus,
pos­terior cingulate, insular cortex and temporal c­ ortex
during cluster-bout periods compared with out-of-
bout periods in patients with episodic cluster headache,
suggest­ing that dynamic functional differences in c­ entral
descending pain modulation between cluster‑bout
(interictally between headaches) and out‑of‑bout
­periods may ­facilitate attacks91.
In addition, studies using T1 voxel-based morpho‑
metry (VBM) have demonstrated grey matter volume
reductions in the middle frontal gyrus, left superior
gyrus and medial frontal gyrus during cluster-bout
periods in patients compared with healthy controls93.
Further­m ore, grey matter volume increases were
observed in the left anterior cingulate, insular cortex and
fusiform gyrus during cluster-bout periods compared
with out-of-bout periods. Thus, these dynamic changes
in grey matter volume may reflect insufficient capacity
for pain modulation in ­frontal areas in episodic clus‑
ter headache that are p ­ otentially associated with cluster
headache pathophysiology.
Studies using diffusion-tensor imaging (DTI) to
inves­ti­gate white matter microstructural changes in
patients with cluster headache have offered contradic‑
tory findings94–96. One study revealed the absence of
white matter diffusivity abnormalities compared with
healthy controls94, although two other studies reported
widespread white matter microstructural changes in the
brain, particularly in the pain network, such as the fron‑
tal lobe, parietal lobe, temporal lobe and thalamus95,96.
In addition, white matter microstructural differences
have been reported in frontal pain modulation areas
during the cluster-bout period in patients with cluster
headache compared with healthy controls, and these
changes mostly persisted during out-of-bout periods97.
Probabilistic tractography showed consistent anatom‑
ical connections between the altered areas (between
the cluster-­bout ­periods and out-of-bout periods) and the
hypothalamus, suggesting that these connections explain
the shift between the two periods. Further research is
required to determine the association. The discrepancies
in the DTI studies may be attributable to differences in
study populations at the time of scanning (for example,
during cluster bouts or between c­ luster-bout periods).
Hypothalamus. The regularity and seasonal pattern of
cluster headache (with a peak in occurrence of attacks in
the autumn and spring), in conjunction with a relapsing–
remitting presentation and ipsilateral cranial autonomic
features, suggest that cluster headache may be related
to alterations in the biological clock, such as that found
in the hypothalamus98,99. In addition, several other lines
of evidence, including data from anatomical, neuro­
imaging, hormonal and genetic studies implicate the
hypothalamus in the pathophysiology of cluster head‑
ache. For example, patients with cluster headache often
have neuro-endocrinological changes such as a blunted
circadian testosterone rhythmicity and abnormal l­evels
of other hormones regulated by the hypothalamus,
including cortisol, growth hormone, thyroid-stimulat‑
ing hormone, prolactin, melatonin, follicle-stimulating
­hormone and luteinizing hormone99,100.
Several neuronal connections exist between the hypo‑
thalamus and regions of the trigeminovascular system
(FIG. 2). Studies in rodents have shown that the hypothala­
mus receives sensory input, including nociceptive infor‑
mation, from areas of the face and cranium innervated
by the trigeminal nerve via the trigeminohypothalamic
tract 101,102. Additionally, the posterior hypothalamus is
a physiological modulator of TNC neuronal activity 103.
Interestingly, disturbances in the hypothalamic–orexin
system have been associated with cluster headache patho­
physio­logy 104. For example, injection of orexin A into
the posterior hypothalamus of rats activates neurons in the
TNC, whereas the injection of orexin B inhibits activity
in the TNC24. In addition, one study showed decreased
levels of orexin A in the cerebrospinal fluid of patients
with ­cluster headache during cluster-bout ­periods105,
which may be due to decreased function of the hypo‑
thalamic descending antinociceptive pathway or may
represent an epiphenomenon of pain affecting hypotha‑
lamic activity 105. The evidence for potential involvement
of the orexin system in cluster headache pathophysiology
is supported by human genetic associ­ation studies, which
have revealed an association between a polymorphism of
HCRT2 and risk of cluster headache26.
Increased ipsilateral posterior hypothalamic activ­
ation has been observed in patients with cluster head‑
ache during nitroglycerine-triggered attacks compared
with both out-of-bout periods and with healthy individ‑
uals106,107. In addition, similar hypothalamic activation

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Regions that are altered during acute attacks

Regions that are altered interictally
(between headaches) S1
Regions that are altered between cluster-bout
periods and out-of-bout periods

ACC

OCC
PFC INS
THA

AMYG
HYP

PAG CERE

Sensory and TG LC
nociceptive SSN
input from the
dural vessels, Trigeminal nerve NRM
face and head

TNC
Lacrimation,
rhinorrhoea and SPG
nasal congestion Parasympathetic division
of the facial nerve
Figure 2 | Schematic peripheral and central pathway representation summarizing the pathogenesis of cluster
headache. Pain and autonomic features in cluster headache probably arise from activation Nature Reviews structures,
of peripheral | Disease Primers
such as the trigeminovascular system. The pathophysiology initially involves structural and functional changes in the
hypothalamus and specific brain networks that transmit nociceptive input, and these functional changes can differ
between cluster‑bout and out-of-bout periods. In addition, anatomical and functional links between the hypothalamus
and brain areas that are traditionally not considered to be involved in pain processing (such as the occipital cortex
(OCC) and cerebellum (CERE)) are altered in cluster headache and may have contributory roles in its pathophysiology.
ACC, anterior cingulate cortex; AMYG, amygdala; HYP, hypothalamus; INS, insular cortex; LC, locus coeruleus; NRM,
nucleus raphe magnus; PAG, periaqueductal grey; PFC, prefrontal cortex; S1, primary sensory cortex; SPG, sphenopalatine
ganglion; SSN, superior salivatory nucleus; TG, trigeminal ganglion; THA, thalamus; TNC, trigeminal nucleus caudalis.
Adapted from REF. 111, Sage.

was observed in a patient with a spontaneous attack108,109.
In addition, bout-independent bilateral grey matter vol‑
ume increases have been reported in the hypothalamus
of patients with cluster headache106,110. These findings
are under debate as some groups could not repro‑
duce them111, whereas another study recently did110. The
use of different MRI sequences and procedures for image
processing may partly explain this discrepancy. Proton
magnetic reso­nance spectroscopy studies have prov­
ided additional evidence in support of hypothalamic
dysfunction in c­ luster headache: low N‑acetylaspartate
to creatine ratios in the hypothalamus of patients with
cluster headache were found, which again supports
­hypothalamic dysfunction in the pathophysiology 112,113.
Further evidence supporting the role of the hypothal‑
amus in cluster headache pathophysiology stems from
neuromodulation. Deep brain stimulation (DBS) of the
posterior hypothalamus has been evaluated for the treat‑
ment of intractable chronic cluster headache114–117 and
leads to improvement in ~60% of patients115, although
ongoing attacks are unaffected (see Neuromodulation,
below)118.
Other brain structures. Brainstem nuclei, including the
locus coeruleus and dorsal raphe nucleus (which modu‑
late vascular activity and pain input from the trigeminal
nucleus), have been implicated in cluster headache patho‑
genesis119,120. The dysfunction of related monoaminergic
pathways, which is related to brainstem descending pain
modulation (noradrenaline and 5‑HT as neurotrans­
mitters), may link the hypothalamus and brainstem in
cluster headache121 (FIG. 2).
Altered intrinsic fluctuations in sensorimotor and pri‑
mary visual networks have been reported in patients dur‑
ing out‑of‑bout periods, suggesting that these functional
changes extend beyond the antinociceptive system of the
brain122. In addition, abnormal functional connectivity
between the hypothalamus and areas associated with pain
processing and visual networks, such as the sensori­motor
and the primary visual networks, has been reported dur‑
ing and between attacks122. Bout-dependent changes in
hypothalamic dynamic functional connectivity with
regions of the frontal and occipital lobes and the cere‑
bellum and cerebellar areas have also been reported in
patients with cluster headache123. Additionally, a decrease

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in functional co‑activation of the hypothalamus and sali‑
ence network areas in patients with cluster headache has
been observed, suggesting the association with the defec‑
tive central pain control pathway and autonomic nervous
system dysregulation124. Dynamic functional connectiv‑
ity in the frontal and dorsal attention networks between
cluster‑bout periods and out-of-bout periods in patients
with cluster headache has also been reported, implicating
these changes in discrete cortical areas within networks
outside ­traditional ­pain-processing areas125.
As previously mentioned, behavioural disturbances,
including agitation and restlessness, are frequently
observed in patients during attacks9; these symptoms are
thought to be associated with the autonomic fight‑or‑
flight response rather than a reaction to pain126,127. Pre­
vious studies have suggested the association between the
cerebellum and the motor agitation128,129. Furthermore,
trigeminal nociceptive processing has been reported in
the cerebellar lobules V and VI, ipsilateral to the stimulus,
suggesting that the cerebellum might have a functional
influence on nociceptive and trigeminal processing 130.
Cluster headache‑related functional changes in the cere‑
bellum have been demonstrated in recent imaging studies
and implicated in acute attacks131. Thus, we hypothesize
that alterations in the activity or connectivity of the cere‑
bellum may be associated with agitation or restlessness in
cluster headache. Further research is required to confirm
this hypothesis and may reveal neuromodulatory targets
for specific symptoms.
Diagnosis, screening and prevention
Cluster headache features
The typical features of cluster headache have been
described in studies from Denmark, the United Kingdom,
Germany and the United States, collectively including
1,924 individuals7,132–134. These studies provide fairly con‑
sistent results regarding the age of onset of cluster head‑
ache, the number and duration of attacks, the number of
cluster periods per year, headache location and associated
symptoms. Cluster attacks might begin with premonitory
features that occur 10–20 minutes before the attack and
include pain symptoms in the same regions as the cluster
headache pain, cranial autonomic symptoms and general
symptoms, such as difficulty concentrating and restless‑
ness135. Pain intensity is consistently described as severe,
and the most common headache locations are peri­
orbital and retro-orbital, followed by temporal. The most
common symptom associated with cluster headache is
lacrimation (reported by >90% of patients), but other
common symptoms include conjunctival injection, nasal
congestion and rhinorrhoea, irritability, motor a­ gitation,
ptosis, eyelid swelling, forehead sweating and light sen‑
sitivity. Of note, in Asian individuals, lower frequencies
of restlessness (50%) have been reported c­ ompared to
western ­populations (>80%)5,6.
Circadian rhythmicity is reported by ~80% of
patients, and circannual rhythmicity is noted by >50%.
In the Danish study, the worsening of attacks or the onset
of cluster-bout periods was most common at the end of
autumn and the beginning of winter, but in the US study,
onset or worsening of attacks was most common in the
spring and autumn7. The circadian and circannual rhyth‑
micity is preserved in chronic cluster headache136. The
average number of daily attacks ranges from two to four,
with a mean duration of ~100 minutes for untreated
attacks. In individuals with episodic cluster headache,
the average duration of a cluster period is 8–9 weeks,
and patients experience an average of one to two cluster
periods per year.
Commonly reported trigger factors for cluster attacks
include sleep, alcohol consumption, relaxation, warmth,
stress, high altitude and changes in weather. Indeed,
in a questionnaire-based study of 275 individuals with
­cluster headache, 80% reported sleep as a trigger for their
attacks28. Alcohol can trigger cluster attacks in 50–80% of
patients and, accordingly, some individuals with c­ luster
headache avoid alcohol completely 137.
Diagnostic evaluation
Diagnostic criteria for cluster headache are available
from the ICHD‑3 (REF. 138) (BOX 2). Cluster headache is
subcategorized into episodic and chronic forms based on
whether cluster-bout periods are separated by pain-free
intervals (out-of-bout periods) that last at least 3 months.
The official classification, including several translations,
can also be found online139.
The diagnosis of cluster headache is based on the
patient’s symptoms and the exclusion of a secondary
headache. As secondary headaches that have a clus‑
ter headache phenotype and primary cluster headache are
difficult to differentiate according to symptoms alone140,
all patients with suspected cluster headache should
undergo brain imaging to determine whether condi‑
tions are present that could cause a secondary headache
with a cluster phenotype. The recommended technique is
MRI with or without contrast enhancement and with fine
slices through the region of the pituitary gland (as pitu‑
itary tumours can manifest with secondary headaches
with a cluster phenotype)141. If a pituitary gland lesion is
suspected or confirmed by imaging, laboratory testing
for levels of pituitary hormones is indicated. In addition,
as many patients with cluster headache have attacks that
wake them from sleep, some patients have sleep dis‑
turbances before the attacks142 and sleep disorders are
common comorbid conditions, investigations for sleep
disorders are often indicated (see Comorbidities, below).
Differential diagnosis. Cluster headache must be
differentiated from other headache types that have
over­lapping features, including other TACs (BOX 1), side-
locked migraine (in which every migraine attack occurs
on the same side of the head) and secondary headaches
manifesting with a cluster phenotype. Although the
symptoms of cluster headache are similar to those of
other TACs, they can be differentiated by the duration
and frequency of attacks and therapeutic response to
indomethacin (TABLE 1). Hemicrania continua consists of
continuous unilateral headache, although exacer­bations
of headache severity that are often associated with ipsi‑
lateral cranial autonomic features can occur episodi‑
cally; the continuous pain and the complete therapeutic
response to indomethacin in patients with hemicrania

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continua differentiate this disorder from cluster head‑
ache138. Attacks of paroxysmal hemicrania, short-lasting
unilateral neuralgiform headache attacks with conjunc‑
tival injection and tearing (SUNCT) and short-lasting
unilateral neuralgiform headache attacks with cranial
autonomic symptoms (SUNA) have key differences in
their duration, frequency and response to indomethacin
compared with cluster headache (TABLE 1).
Occasionally, phenotypic overlap is apparent between
migraine attacks and cluster headache, such as in side-
locked migraine, when migraine is associated with
ipsilateral cranial autonomic features and when cluster
headache is associated with photophobia, phonophobia,
nausea or vomiting 7,143. Characteristics that are consistent
with side-locked migraine rather than cluster headache
are the longer duration of untreated attacks with migraine
and the differences in patient activity during the attack
(TABLE 1). As previously mentioned, secondary headaches
with a cluster phenotype cannot be differentiated from
primary cluster headache based on clinical features alone,
and a diagnostic e­ valuation is required.
Diagnostic challenges. In patients with typical cluster
headache symptoms, the phenotype should be easily
recognized and the diagnosis of primary cluster head‑
ache should be made after the exclusion of a secondary
headache. However, patients with cluster headache often
experience delayed diagnosis or misdiagnosis, leading
to suboptimal and inappropriate treatments144,145. In one
study of 85 patients seen at the Danish Headache Center,
the average delay between onset and diagnosis was
9 years, whereas in another survey of 351 patients within
the Danish Headache Survey, the average time to diagno‑
sis was 6.2 years and half of the patients initially received
the wrong diagnosis132,146. In general, the time to diagnosis
Box 2 | ICHD‑3 diagnostic criteria for cluster headache
Cluster headache
At least five attacks that fulfil the following criteria:
• Severe or very severe unilateral orbital, supraorbital and/or temporal pain lasting
15–180 minutes (when untreated)
• Either or both of the following:
-- At least one of the following, ipsilateral to the headache: conjunctival injection
and/or lacrimation; nasal congestion and/or rhinorrhoea; eyelid oedema;
forehead and facial sweating; or miosis and/or ptosis
-- A sense of restlessness or agitation
• Attacks have a frequency between one every other day and eight per day for more
than half of the time when the disorder is active (during cluster bouts)
• Not better accounted for by another ICHD‑3 diagnosis
Episodic cluster headache
• Attacks fulfilling criteria for cluster headache and occurring in cluster bout periods
• At least two cluster-bout periods lasting from 7 days to 1 year (when untreated)
and separated by pain-free remission (out-of-bout) periods of at least 3 months
Chronic cluster headache
• Attacks fulfilling criteria for cluster headache
• Occurring without a remission period, or with remissions lasting <3 months,
for at least 1 year
ICHD‑3, International Classification of Headache Disorders138.
is variable between countries; the average time to diagno‑
sis was 2.6 years in the United Kingdom144, 4.6 years in
Spain147, 5 years in the United States7, 5.3 years in Italy 148,
8 years in Taiwan5 and 11 years in Norway 4. In the US
Cluster Headache Survey, 25% of patients were diagnosed
within 1 year of symptom onset and 58% of patients were
diagnosed within 5 years, but 22% were not diagnosed for
≥10 years7. In that study, 79% of patients initially received
an incorrect diagnosis, including migraine, sinusitis,
allergies or tooth-related issues7. Overlapping features
between cluster headache and migraine, such as the pres‑
ence of aura, photo­sensitivity, phonosensitivity and side-­
shifting of headache (that is, from one side of the head to
the other), probably c­ ontribute to misdiagnosis133,134,149.
Comorbidities
Individuals with cluster headache should be screened for
possible comorbidities or other lifestyle factors, includ‑
ing smoking, alcohol abuse, illicit drug use, depression
and sleep disorders9.
Smoking, alcohol and illicit drug use. As many as
70–90% of individuals with cluster headache smoke7,150.
Smoking is associated with more severe manifestations
of cluster headache (for example, longer cluster-bout
periods and more frequent attacks), although only 18%
of patients stopped smoking after cluster headache onset
based on results from a US survey 7. Smoking cessation
does not affect the course of the disorder 150,151. Different
studies have provided conflicting results regarding
whether the rates of alcohol use and abuse are higher
in individuals with cluster headache than the general
popu­lation151,152. However, alcohol can trigger cluster
attacks in 50–80% of patients, making its use problem‑
atic within this population and leading some individuals
with ­cluster headache to avoid alcohol137. Illicit drug use
is more common in individuals with cluster headache
than in the general population153, although this observa‑
tion might be true only in men154. In an Italian study of
210 patients (including 162 men) with cluster headache,
the rates of cannabis, opioids, cocaine, amphetamine and
ecstasy use were higher in those with cluster headache
than in the general population155. The use of illicit drugs,
such as psilocybin and forms of lysergic acid, as self-­
treatments is not uncommon for patients with cluster
headache156. However, some studies suggest that most
illicit drug users first used the drugs before the onset of
cluster headache155.
Depression and other psychological comorbidities.
Depression is frequent in patients with cluster headache.
Indeed, data from a population-based, cross-sectional
study of 462 patients showed the lifetime prevalence
of depression was 2.8‑fold higher in those with cluster
headache compared with healthy individuals157. In addi‑
tion, the 2.5‑year incidence of depression was 5.6‑fold
higher in patients with cluster headache than healthy
individuals in a population-based follow‑up study
using the Taiwan National Health Insurance database,
and more cluster-bout periods per year was a risk factor
for depression158. In the US Cluster Headache Survey,

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Table 1 | Characteristics of cluster headache and other headache types that can have overlapping features
Headache Attack duration Attack frequency Behaviour Sex ratio Complete response
(if untreated) during an attack (female:male) to indomethacin
Cluster headache 15–180 minutes Once every other day, up to 8 times per Agitated 1:4 No
(typically 100 minutes) day (typically 3–4 per day)
Hemicrania continua Continuous Continuous Nonspecific 2:1 Yes
Paroxysmal 2–30 minutes ≥5 per day (typically 10 per day) Agitated 2:1 Yes
hemicrania (typically 15 minutes)
SUNCT and SUNA 1–600 seconds ≥1 per day or more (typically 60 per day) Agitated 1:1.5 No
(typically 1 minute)
Side-locked At least 4 hours Variable Avoid physical 3:1 No
migraine (typically 24 hours) movement
SUNA, short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms; SUNCT, short-lasting unilateral neuralgiform headache attacks
with conjunctival injection and tearing.

55% of patients reported suicidal thoughts, and 2% had
attempted suicide7. Chronic cluster headache is associ‑
ated with a higher prevalence of lifetime depression than
episodic cluster headache157. Despite the high frequency,
the rates of diagnosis and treatment of depression are
low in patients with cluster headache, e­ mphasizing the
importance of screening for this condition157.
Whether anxiety and certain personality profiles are
more common in individuals with cluster headache is a
matter of debate. Although some studies have suggested
high rates of anxiety and obsessive-compulsive and
anti-social traits, other studies have found no differences
between those with cluster headache and comparator
groups, including healthy controls159–162. Further stud‑
ies are needed to define the psychological comorbidi­
ties of cluster headache and to assess how personality
traits might affect pain coping, quality of life and optimal
treatment recommendations.
Sleep disorders. As cluster headache attacks are fre‑
quently initiated during sleep, several studies have
evaluated patients with cluster headache for sleep dis­
orders28,133,163,164. Indeed, patients with cluster headache
had higher scores on the Pittsburgh Sleep Quality Index
than healthy individuals, which indicates a poorer self-­
assessment of sleep quality 28. Patients who reported sleep
as a trigger for their cluster attacks had higher scores
than patients who did not report sleep as a trigger 28. One
poly­somnography study showed a reduced percentage of
rapid eye movement (REM) sleep, longer REM latency
and fewer arousals in patients with cluster headache com‑
pared with healthy individuals164. No relationship was
observed between the occurrence of ­nocturnal attacks
and a specific sleep stage164.
Whether sleep-disordered breathing is more common
in patients with cluster headache is debated. In one study,
the rate of obstructive sleep apnoea was not higher in
patients with cluster headache compared with healthy
controls; however, sleep-disordered breathing was
present in 80% of patients (using an apnoea-hypopnea
index cut-off of ≥5)163,164 and in 44% of patients (using
an apnoea-hypopnea index cut-off of ≥10)163. A higher
rate of obstructive sleep apnoea has been reported dur‑
ing cluster-bout periods in patients with cluster headache
than in healthy controls (29% versus 7%, P = 0.018)165.
Although the existence and nature of the relation‑
ship between cluster headache and sleep disorders are
not clearly understood, screening patients with cluster
headache for sleep disorders is reasonable as sleep is a
trigger for attacks. Several studies suggest sleep disorders
in patients, and some evidence suggests treating sleep dis‑
orders can reduce cluster attack frequency for a subset
of patients.
Management
The treatment of cluster headache is based on empiri‑
cal data and only a few clinical trials. Pharmacological
treatment can be divided into acute attack abortion and
prophylaxis, and most patients receive both types of treat‑
ment. Several nonpharmacological treatments (excluding
neurostimulation) have been trialled but are ineffective
in nearly all patients. Pharmacological treatment has a
placebo rate that is similar to that for migraine treatment
(~25%)166. International treatment guidelines are avail­able
for cluster headache167,168, and the superiority of guide‑
line-adherent treatment compared with non-­guideline
treatment in cluster headache has been reported169.
During an attack
Oxygen. The inhalation of pure oxygen is effective at
aborting attacks170. Inhalation should start as soon as
possible but can commence at any point during the
attack and should last for 15 minutes while the patient
is in a sitting, upright position. The oxygen should be
delivered through a non-rebreather mask with reservoir
or, prefer­ably, with a demand valve oxygen mask171. Apart
from chronic obstructive pulmonary disease, there are
no ­common contraindications to oxygen therapy, as this
therapy is safe and without relevant adverse effects170.
More than 70% of all patients with cluster headache
respond to oxygen therapy with a substantial pain reduc‑
tion within 30 minutes170. Thus, oxygen is the first-choice
treatment for the abortion of cluster attacks, although
­little is known about its mechanism of action71.
Triptans. Subcutaneous injection of sumatriptan, a 5‑HT1B
and 5‑HT1D agonist, can render 75% of patients pain-free
within 20 minutes of injection and can be administered at
any point during the attack172,173. Sumatriptan injections
are safe and without adverse effects in most patients,

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even with frequent use (including daily use for several
years), and their effectiveness is not reduced over time174.
Contraindications are cardiovascular and cerebro­vascular
disorders and risk factors including untreated arterial
hypertension, hyperlipidaemia, diabetes mellitus, smok‑
ing and old age. The most specific and unpleasant adverse
effects are chest pains and distal paraesthesia, which can
occur in up to 10% of patients174. A zolmitriptan nasal
spray has been shown to reduce pain and accompany‑
ing symptoms during attacks in two placebo-controlled
­trials and has been approved by the European Medicines
Agency (EMA) for the acute treatment of cluster head‑
ache175,176. A sumatriptan nasal spray 177,178 and oral zol‑
mitriptan therapy 179 have also shown efficacy within
30  minutes in single, open-label and double-blind,
placebo-controlled trials.
Ergotamine. Oral ergotamine has been used for the
treatment of cluster headache attacks for >50 years and
is probably effective within 15 minutes if administered
early in the attack; however, placebo-controlled trials are
lacking. Short-term pro­phylaxis using ergotamine is not
recommended because of severe adverse effects, such as
vasoconstriction, soft tissue necrosis, distal paraesthe‑
sia and ulcers. Intranasal dihydro­ergotamine was not
superior to placebo in a single trial at aborting attacks180,
although intravenous administration was shown to abort
severe attacks in an o ­ pen-label ­retrospective181 and an
open-label ­prospective182 trial.
Others. The nasal installation of lidocaine — a local
anaesthetic that blocks neuronal voltage-gated sodium
channels — is probably effective in at least one-third of
patients when administered within 15 minutes of attack
onset, although this has only been reported in open-label
trials183–185. Intranasal lidocaine is safe but might cause
nasal discomfort; other adverse effects are unknown.
Subcutaneous octreotide is effective in the treatment
of acute attacks in a double-blind, placebo-­controlled
trial when given within 15 minutes of attack onset 186.
No adverse effects were reported in this trial. Further t­ rials
are not ongoing.
Preventive treatments
Verapamil. Verapamil — a voltage-dependent calcium
channel blocker — is the first drug of choice for the
prophylaxis of episodic and chronic cluster headache in
most countries. Although only a few sufficiently powered
double-blind, controlled trials have been conducted, they
demonstrate that ~70% of patients are responders9. In one
controlled trial, verapamil was shown to have a more rapid
action of onset than lithium, although both drugs showed
efficacy in attack prophylaxis compared with placebo187.
In another trial, verapamil was superior to placebo188.
Adverse effects of verapamil are bradycardia, oedema of
the legs, constipation, gastrointestinal dis­comfort, gingi­
val hyperplasia and dull headache. As verapamil can
increase cardiac conduction time, regu­lar electrocardio­
graphy (ECG) testing is necessary 189. Verapamil should
be administered for ~1.5 times of the assumed duration
of the cluster-bout period, starting at the beginning of the
period. The full effectiveness of verapamil can be expected
within 2–3 weeks after drug onset187. Slow-release formu‑
lations are available that enable fewer administrations per
day. When patients initially start verapamil, corticoster‑
oids are also administered by some clinicians for ~2 weeks
to bridge the time period of dose escalation of verapamil.
Corticosteroids. There are no sufficiently powered ran‑
domized, placebo-controlled trials for the use of oral
corticosteroids in cluster headache, although they are
regarded as highly effective and several open-label stud‑
ies and case series have been published and reviewed190.
All studies showed the efficacy of the different regimens.
Corticosteroids are recommended for short-term use,
such as for 2–3 weeks after onset of the cluster bout when
the rapid control of attacks is desired. Some patients are
attack-free only with steroid treatment, and continu‑
ous administration of steroids is rarely required by the
patient. Chronic use of corticosteroids is associated with
high morbidity and, accordingly, caution and short-
course therapy should be used; corticosteroids should
be avoided for chronic cluster headache. In particular,
the risk of opportunistic infections with corticosteroid
use should be carefully considered in medium to long-
term use. At high doses, ~70–80% of patients respond
to steroids. The injection of corticosteroids at the greater
occipital nerve has shown efficacy in placebo-controlled
trials for prevention191–193; this procedure is easy to per‑
form, has a very low rate of adverse effects compared with
other treatments, and the effect can last for days.
Lithium. More than 20 open-label trials have evaluated
the use of lithium carbonate for prophylaxis starting at
the beginning of a cluster-bout period194. An attack fre‑
quency reduction of >50% has been reported in up to
78% of patients with chronic cluster headache and 63%
of patients with episodic cluster headache194. However,
one placebo-controlled trial did not show any efficacy of
lithium in the prevention of episodic cluster headache195,
and one study showed a more rapid improvement in
headache frequency and better tolerability for verapamil
than lithium187. Liver, renal and thyroid function, in addi‑
tion to electrolyte levels, should be monitored regularly
in patients using lithium as the major adverse effects are
hypothyroidism, tremor and renal dysfunction194.
Anticonvulsants. Two open-label trials have suggested
a moderate efficacy of valproic acid for prevention196,197,
although one controlled study did not show a difference
compared with placebo198. The scientific evidence is that
valproic acid has no proven efficacy in either episodic or
chronic cluster headache because the controlled trial was
negative but can be tried as a third-line drug in patients
who do not respond to verapamil or lithium. On the basis
of results from open-label studies, other anti­convulsants,
such as topiramate199,200 and gabapentin201,202, have a
probable efficacy in the prophylaxis of episodic and
chronic cluster headache. The main adverse effects of
topiramate are cognitive disturbances, paraesthesia and
weight loss, and this drug is contraindicated in patients
with nephrolithiasis.

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Other therapies. The pre-emptive or prophylactic use of non­invasive vagus nerve stimulation (VNS) (FIG. 3)),
triptans in patients with cluster headache remains contro‑ which have given new hope to patients with refractory
versial. In one study, sumatriptan administered orally was cluster headache. However, large sham-controlled trials
not effective in preventing attacks in a placebo-­controlled are scarce, and data from some open-label studies have
trial203, although in open-label trials, eletriptan204 or nara­ to be confirmed.
triptan205 reduced the number of attacks in patients with
episodic cluster headache. SPG stimulation. Invasive techniques are g­ enerally con‑
The ipsilateral intranasal application of capsaicin sidered when patients fail to respond to usual pharmaco­
has been studied in two open-label trials206,207 and one logical therapies (and/or have intolerance to these
double-­blind, placebo-controlled208 trial, and showed treatments)221,222. The rationale for the use of SPG stimu‑
an efficacy in approximately two-thirds of patients with lation in cluster headache was based on the strong cranial
episodic cluster headache after repeated application in ipsilateral autonomic features that are frequently observed
all trials. Also, the intranasal application of civamide (cis-­during attacks (see Mechanisms/­pathophysiology, above)
capsaicin) showed moderate efficacy in a double-blind, and from data from pilot studies77. In the seminal ran‑
placebo-controlled study in patients with episodic cluster domized controlled trial (Pathway CH‑1)78, 28 patients
headache209. However, although these studies are categor­ with refractory chronic cluster headache received surgi‑
ized as blinded, the nasally applied treatments irritate the cal implantation of a stimulation device into the pterygo­
mucosa. No evidence suggests that a combination of palatine fossa (in which the SPG is located). The devices
prophylactic drugs is superior to single use; however, this could be remotely controlled by the patient and could ran‑
question has not yet been systematically studied. domly deliver one of three different stimulation patterns
when activated (no stimulation or sham, subthreshold
Third-line treatments. Several treatments can be con‑ stimu­lation, or full stimulation). Pain relief was reported
sidered for refractory cluster headache. Methysergide — in 67.1% of attacks treated with full-dose stimulation
a 5‑HT receptor antagonist — has been successfully used and in 7.4% of attacks with sham stimulation; pain free‑
as a prophylactic drug for episodic cluster headache but is dom within 15 minutes of stimulation was achieved in
no longer manufactured. However, this issue may change 34.1% of attacks with full-dose stimulation and in 1.5% of
as the licence for drug production is still valid. Oral mela­ attacks with sham stimulation. The acute responder rate
tonin was effective in reducing attack frequency in a was 32%, and 43% of patients reported a ≥50% reduction
­single double-blind, placebo-controlled study in patients in attack frequency compared with baseline78. Adverse
with episodic cluster headache210 but did not prov­ide any events related to maxillofacial surgery were frequent
additional efficacy when used as an adjunctive therapy to (such as pain, swelling and haematoma), but most of the
standard treatment in patients with refractory disease211. events were fully reversible. Furthermore, 81% of patients
Warfarin was reported to effectively reduce attack fre‑ had sensory disturbances in the region of the face inner‑
quency in a small controlled trial and in case reports of vated by the maxillary nerve (likely because this nerve is
patients with episodic cluster headache212,213 but should located near the SPG), but these were mostly reversible.
not be used as a treatment given its adverse effect pro‑ Six patients had to be re‑intervened.
file (including bleeding). Weak evidence from a small The Pathway CH‑1 study was followed by an open-­label
open-label study showed the efficacy of baclofen214 trial involving 33 patients with chronic cluster headache
in prophylaxis, and another open-label study showed no who had 5,956 cluster attacks over 24 months79. In this
evidence for transdermal clonidine215 in prophylaxis of trial, 30% of patients had ≥1 out-of-bout period(s) lasting
episodic cluster headache. ≥1 month (that is, they evolved to an episodic cluster head‑
ache form)223, 65% of attacks were success­fully relieved by
Unsuccessful treatments. Candesartan is effective in SPG stimulation and pain freedom was obtained in 50% of
migraine treatment but was not effective in a placebo-­ attacks. The 50% acute responder rate was 45%, and 35%
controlled trial in cluster headache prophylaxis216. Patients of evaluable patients had an attack frequency reduction of
with episodic cluster headache did not benefit from ≥50% compared with baseline after 24 months. Headache
botu­linum toxin type A injections for prophylactic treat‑ frequency increased in 35% of patients and remained
ment217,218, but there might be some prophylactic benefit stable in 29%. Because the study was designed to assess
following onabotulinumtoxinA administered to the SPG the efficacy of SPG stimulation in acute therapy in those
in patients with chronic cluster headache219. Hyperbaric with chronic cluster headache, a continuous monitor‑
oxygen inhalation is not effective in preventing attacks ing of attack frequency was not available in the Pathway
in episodic or chronic cluster headache220. Cannabis, CH‑1 study or the follow-up. Patients were asked to
other cannabinoids and similar psychotropic drugs are record their average attack frequency (in the past 4 weeks)
frequently used by patients with cluster ­headache153, every 3 months. Accordingly, further studies are needed
but self-reported effectiveness is very low 154. to determine the long-term effect of SPG ­stimulation
on attack frequency in chronic cluster headache.
Neuromodulation
Substantial progress has been achieved in the manage‑ Invasive ONS. Invasive ONS is being used for refrac‑
ment of cluster headache using invasive and noninvasive tory headache management and has been assessed for
neuromodulation techniques (such as SPG stimulation, cluster headache prevention in several open-label stud‑
invasive occipital nerve stimulation (ONS), DBS and ies224–229. Although most trials reported encouraging

NATURE REVIEWS | DISEASE PRIMERS VOLUME 4 | ARTICLE NUMBER 18006 | 11

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PRIMER

Hypothalamic DBS SPG stimulation

Hypothalamus

Greater occipital nerve SPG

Facial
Invasive ONS nerve Noninvasive VNS

Vagus
nerve

Figure 3 | Neuromodulation therapies for cluster headache. Neuromodulation methods that have been investigated
Nature Reviews
for the treatment of cluster headache. For example, postganglionic neurons of the sphenopalatine | Disease
ganglion (SPG) Primers
have
been implicated in cluster headache-associated pain and autonomic features, and SPG stimulation has been shown to
effectively abort cluster headache attacks and to reduce the frequency of attacks in some patients78,79. Invasive occipital
nerve stimulation (ONS) has been evaluated for the prevention of cluster headache owing to the anatomical overlap
between the trigeminal and cervical afferents, which is consequently termed the trigeminocervical complex, and
accordingly, ONS could modulate antinociceptive activity in the trigeminocervical complex and the pain network257.
The vagus nerve is a mixed motor and sensory nerve with projections to brain areas involved in pain modulation, including
the trigeminal nucleus caudalis. Accordingly, noninvasive vagus nerve stimulation (VNS) has been suggested to inhibit
nociceptive processing258 and has proved effective mainly in episodic cluster headache acute therapy. Hypothalamic deep
brain stimulation (DBS) has been investigated for the prevention of cluster attacks owing to clinical and neuroimaging
data, which proved the implications of hypothalamic function in the pathophysiology and the circadian and circannual
manifestations of this condition. Figure adapted from REF. 259, Macmillan Publishers Limited.

results with follow‑up ­periods of several years, sham-­
controlled ­trials of invasive ONS in cluster headache pre‑
vention have not been carried out. Overall, the open-label
trials have included 172 patients with chronic cluster
headache, usually those with drug-refractory forms224–229.
The attack frequency improved in ~58.1% of patients, but
most patients also required concomitant pharmacological
prophylaxis. Similar to SPG stimulation, evolution from
chronic to episodic cluster headache has been described
with invasive ONS in 10–40% of patients. Despite a reduc‑
tion in the attack frequency, invasive ONS had little or no
effect on the intensity of attacks or the duration of pain230.
Stimulator-related adverse events are quite common
with this treatment, mainly lead migration or device
infection, and battery depletion may require replace‑
ment surgeries in up to 100% of patients. Other adverse
events include paraesthesia induced by the stimulation,
which cannot be tolerated by some patients. In addition,
at least two long-term trials of up to 10 years in duration
have described a tolerance phenomenon with invasive
ONS228,231, which required the adjustment of the stimu‑
lation parameters and could be related to neuroplasticity
in the opioid system232. A large multi­centre randomized
controlled trial is currently underway to evaluate invasive
ONS for prevention of cluster headache (ICON study 233).
Hypothalamic DBS. DBS targeting the hypothalamus is
a neuromodulation technique that has been used to treat
drug-­refractory patients with cluster headache116 and is
based on the activation of the posterior hypothalamus
during attacks107. Several case series have been published
over the past 20 years with encouraging results, includ‑
ing a reduction in attack frequency and intensity 234, but
a significant risk of serious adverse events, including a
fatal haemorrhage, has been reported235. Only one hypo‑
thalamic DBS trial included a sham group117, and no
differences were observed between the active and sham
procedures in patients with chronic cluster headache,
although the duration of the sham period might have been
too short to detect a change. In the subsequent open-label
phase of this trial, the mean attack frequency improved in
6 out of 11 patients.
Some controversies regarding the accuracy of the
hypothalamic DBS stereotactic coordinates and the struc‑
tures that are modulated have led to new trials based on
different techniques236–238. The aim of these ­trials was also
to reduce the risk of serious adverse events. One study
used a modi­fied target in five patients239, and another
study evaluated DBS of the ventral tegmental area (VTA)
in 21 patients with chronic cluster headache114. The ration‑
ale of using the VTA for DBS was based on imaging studies

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 PRIMER

in patients previously treated with hypothalamic DBS that the standard of care group. An estimation of adherence
showed a maximal activation that was centred over the to therapy was 64% in the controlled phase (that is, 64%
VTA114. The median daily attack frequency decreased by of patients performed ≥80% of the recommended treat‑
60%, and 52% of patients had a 50% reduction in median ment sessions). Further evidence is needed to confirm the
frequency of attacks114. The feasibility and efficacy of endo­ ­usefulness of n
­ oninvasive VNS in attack prevention.
ventricular hypothalamic DBS using a floating electrode
that stimulates the floor of the third ventricle was reported Quality of life
in seven patients with chronic c­ luster headache240. Given the intense pain of cluster headaches, surprisingly
few studies have investigated the effect of the disorder on
Noninvasive VNS. Noninvasive VNS is the only non­ quality of life. Some studies suggest that patients have a
invasive neuromodulation technique that has been poorer quality of life during active cluster bouts than the
evalu­ated in cluster headache. In the ACT‑1 randomized general population and that the impairment is greater
controlled trial, 133 patients (of whom two-thirds had epi‑ in patients with an older age of onset 244. No difference
sodic cluster headache), were asked to use noninvasive was reported in the quality of life of patients during
VNS to treat five attacks each241. A trend to pain relief or cluster-­bout periods in those with episodic compared
pain freedom was reported in patients who received the with chronic cluster headache244. During the out-of-
active treatment compared with the sham, and a signifi­ bout period in patients with episodic cluster headache,
cant difference was observed in patients with episodic clus‑ quality-­of-life scores tended to improve and were similar
ter headache. In addition, exploratory efficacy end points to scores in those who are headache-free245,246, although
(such as pain freedom at 15 minutes and changes in attack other studies have reported high levels of disability in
duration) were significantly improved in the episodic clus‑ patients with episodic chronic headache during out-of-
ter headache subpopulation. The ACT‑2 study provided bout ­periods146,247. The degree of impairment that contin‑
similar results: noninvasive VNS was superior to sham ues beyond the cluster-bout period might be attributed to
in the episodic cluster headache subgroup only 242. The the unpredictability of the next cluster bout.
open-label controlled PREVA study evaluated the use of The consequences of cluster headache have been
noninvasive VNS add‑on therapy twice daily (to a total underlined by a recent US survey, which revealed that
of 12 minutes) for 1 month in 97 patients with chronic ~20% of patients had lost their job secondary to clus‑
cluster headache compared with patients who continued ter headache and 8% were unemployed7. One study in
their usual pharmacological prophylaxis (standard of Denmark reported that 16% of patients had lost their
care group)243. In the intention-to‑treat analysis, a mean job, and 8% needed early retirement; this occurred in
change in weekly attack frequency of −5.9 was reported episodic and chronic cluster headache146. Given that
in the noninvasive VNS group compared with −2.1 in most attacks occur during the night, a major problem in
patients is sleep deprivation. Generally, up to one-third of
patients found that the disorder limited their career 146,247.
Table 2 | Selected planned or ongoing trials in patients with cluster headache Compared with migraine, in which several question‑
Treatment Stage ClinicalTrials.gov naires that measure the impact or disability of headache
identifier have been validated, only one scale has been developed
Pharmacological for cluster headache248. This scale assesses the restriction
on activities of daily living, the impact on mood and
Psilocybin Phase 1 NCT02981173 inter­personal relationships, pain and anxiety, and lack of
Botulinum toxin type A Phase 1–2 NCT03066635 vitality 248. However, using the Headache Impact Test‑6
R‑Verapamil Phase 2 NCT02209155 (HIT‑6) scale, 74% of patients with cluster headache were
SOM230 Phase 2 NCT02619617
classified as severely affected (HIT‑6 grade IV disabil‑
ity)249, with 78% of patients reporting restrictions in daily
Sodium oxybate Phase 3 NCT02637648 ­living and 96% needing to make a lifestyle change146. Social
Fremanezumab Phase 3 NCT03107052 and leisure activities, family life and housework were dis‑
Civamide nasal solution Phase 3 NCT01341548 rupted. Agoraphobic symptoms have been reported in
33% of patients, depressive symptoms in 56% of patients
LY2951742 Phase 3 NCT02397473
and suicidal tendencies in 22% of patients247,249. In general,
LY2951742 (galcanezumab) Phase 3 NCT02797951 patients live in fear and uncertainty because of their con‑
TEV‑48125 Phase 3 NCT02945046 dition250, and patients have high levels of self-­aggression
TEV‑48125 (fremanezumab) Phase 3 NCT02964338 and depression, which correlates with greater emotional
and functional impairment251. Self-aggression and depres‑
Acetium Not provided NCT02310828
sion substantially impair the patient’s life and, accordingly,
Neuromodulation should be c­ onsidered as important therapeutic targets.
Occipital nerve stimulation Phase 3 NCT01151631
SPG stimulation Not provided NCT02510729 Outlook
In the past 20 years, great advances in our understanding
Deep brain stimulation V3 Not provided NCT02782533
of the pathophysiology of cluster headache have come
US‑guided greater occipital nerve injection Not provided NCT02031822 from findings in the central and peripheral nervous sys‑
SPG, sphenopalatine ganglion; US, ultrasound. tems. The vascular model, involving an inflammation of

NATURE REVIEWS | DISEASE PRIMERS VOLUME 4 | ARTICLE NUMBER 18006 | 13

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PRIMER

the walls of the cavernous sinus, has been rendered out‑
dated by the recognition that the neurovascular phenom­
ena and a hypothalamic impulse generator, or ‘oscillator,’
seem to be more important. However, at present, the
molecular and genetic background of cluster headache
remains largely unknown, possibly due to the low
­prevalence compared with migraine.
Hypothalamic DBS has been used for the treatment
of drug-refractory chronic cluster headache and can
decrease attack frequency in 60% of patients. However,
DBS is an invasive technique that is associated with seri‑
ous complications in some patients116; accordingly, other
minimally invasive or noninvasive neurostimulation tech‑
niques, such as SPG stimulation and noninvasive VNS,
have been evaluated in patients with cluster headache230.
Although these techniques have demonstrated efficacy in
several trials, most trials have been open-label studies or
have included only a limited number of patients in the
placebo (sham) group. Accordingly, double-blind, ran­
domized controlled studies with long-term outcomes are
needed to expand the repertoire of therapeutic options for
treating drug-­refractory disease. To this end, several new
therapies are under study, including neuromodulation
and ­pharmacological therapies (TABLE 2).
As previously mentioned, circulating levels of CGRP
are increased during attacks62, suggesting a key role for
this system in cluster headache. Several selective CGRP
receptor antagonists are under development and seem to
be effective in inhibiting nociceptive trigeminal process‑
ing in both animal models and patients252,253. However,
the development of some older CGRP receptor antago­
nists has been halted because of severe adverse effects,
such as hepatotoxicity 254. The more recent and prom‑
ising develop­ment of monoclonal antibodies targeting
free CGRP and CGRP receptors has enabled clinicians to
circumvent these adverse effects. These antibodies have
promising efficacy in patients with migraine255,256 and are
likely to be effective in cluster headache, although these
trials are still ongoing. Future development of monoclonal
antibodies and pharmacological agents targeting CGRP
and possibly PACAP might improve the clinical manage‑
ment of cluster headache. Further studies to identify new
bio­markers other than CGRP, accompanied by supportive
brain ­imaging data, are warranted.

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Author contributions
Introduction (A.M.); Epidemiology (P.P.‑R. and D.M.);
Mechanisms/pathophysiology (A.M. and S.‑J.W.); Diagnosis,
screening and prevention (T.J.S.); Management (S.E. and
D.M.); Quality of life (P.P.‑R.); Outlook (S.‑J.W. and A.M.);
Overview of the Primer (all authors).
Competing interests
A.M. has been a consultant or speaker for Allergan, Autonomic
Technologies, Desitin, Electrocore and Teva and is the Editor in
Chief for Cephalalgia. T.J.S. has acted as a consultant or has
served on the advisory boards of Allergan, Amgen, Autonomic
Technologies, Avanir, Dr. Reddy’s, Nocira, Novartis and Teva;
has stock options in Nocira and Second Opinion; and has
received royalties from UpToDate. D.M. has received research
and travel grants from ElectroCore LLC. P.P.‑R. has received
honoraria as a consultant or speaker from Allergan, Almirall,
Chiesi, Eli Lilly, Novartis and Teva. S.E. has received honoraria
as a speaker from or is a member of an advisory board for
Allergan, Johnson & Johnson, Novartis, Reckitt Benckiser and
TAD Pharma. S.-J.W. has served on the advisory boards of
Daiichi-Sankyo, Eli Lilly and Taiwan Pfizer and has received
honoraria as a moderator from the Taiwan branches of Bayer,
Eisai, Eli Lilly and Pfizer.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional
claims in published maps and institutional affiliations.
How to cite this article
May, A. et al. Cluster headache. Nat. Rev. Dis. Primers 4,
18006 (2018).

NATURE REVIEWS | DISEASE PRIMERS VOLUME 4 | ARTICLE NUMBER 18006 | 17

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