Clinical Review & Education

JAMA Neurology | Review

Management of Trigeminal Autonomic Cephalalgias

Including Chronic Cluster
A Review
Hans Christoph Diener, MD; Cristina Tassorelli, MD; David W. Dodick, MD

IMPORTANCE Trigeminal autonomic cephalalgias (TACs) comprise a unique collection

of primary headache disorders characterized by moderate or severe unilateral pain, localized
in in the area of distribution of the first branch of the trigeminal nerve, accompanied by
cranial autonomic symptoms and signs. Most TACs are rare diseases, which hampers the
possibility of performing randomized clinical trials and large studies. Therefore, knowledge
of treatment efficacy must be based only on observational studies, rare disease registries,
and case reports, where real-world data and evidence play an important role in health
care decisions.

OBSERVATIONS Chronic cluster headache is the most common of these disorders, and the Author Affiliations: Institute for
Medical Informatics, Biometry and
literature offers some evidence from randomized clinical trials to support the use of Epidemiology (IMIBE), Department
pharmacologic and neurostimulation treatments. Galcanezumab, a monoclonal antibody of Neuroepidemiology, University
targeting the calcitonin gene-related peptide, was not effective at 3 months in a randomized Duisburg-Essen, Essen, Germany
(Diener); Department of Brain and
clinical trial but showed efficacy at 12 months in a large case series. For the other TACs (ie,
Behavioral Sciences, University of
paroxysmal hemicrania, hemicrania continua, short-lasting unilateral neuralgiform headache Pavia, Pavia, Italy (Tassorelli);
attacks with conjunctival injection and tearing, and short-lasting unilateral neuralgiform Headache Science &
headache attacks with cranial autonomic symptoms), only case reports and case series are Neurorehabilitation Centre, IRCCS C.,
Mondino Foundation, Pavia, Italy
available to guide physicians in everyday management.
(Tassorelli); Department of
Neurology, Mayo Clinic, Phoenix,
CONCLUSIONS AND RELEVANCE The accumulation of epidemiologic, pathophysiologic, natural
Arizona (Dodick); Atria Institute,
history knowledge, and data from case series and small controlled trials, especially over the New York, New York (Dodick).
past 20 years from investigators around the world, has added to the previously limited Corresponding Author: Hans
evidence and has helped advance and inform the treatment approach to rare TACs, which Christoph Diener, MD, Institute for
can be extremely challenging for clinicians. Medical Informatics, Biometry and
Epidemiology (IMIBE), Department
of Neuroepidemiology, University
JAMA Neurol. 2023;80(3):308-319. doi:10.1001/jamaneurol.2022.4804 Duisburg-Essen, Hufelandstrasse 55,
Published online January 17, 2023. 45147 Essen, Germany (hans.diener
@uk-essen.de).

T
rigeminal autonomic cephalalgias (TACs) are characterized
by the presence of autonomic accompanying symptoms
during headache. The most frequently observed accom-
panying symptoms are rhinorrhoea, nasal congestion, conjunctival
injection, and lacrimation. In addition, patients may report edema
of the eyelid, miosis, ptosis, redness of the face, and sweating of
the forehead and face. TACs are strictly unilateral headaches. TACs
include cluster headache, paroxysmal hemicrania, hemicrania con-
tinua, short-lasting unilateral neuralgiform headache attacks with
conjunctival injection and tearing (SUNCT), and short-lasting unilat-
eral neuralgiform headache attacks with cranial autonomic symp-
toms (SUNA). Most TACs can occur in an episodic or chronic form.
The most important feature to differentiate between these entities
is the duration of the headache attack (Figure).
This review is dedicated to the management of rare TACs, and
we summarize the results from studies published in the last 20
years with a specific focus on research after 2018. Several thera-
peutic approaches have been tested and proposed, based on the
putative mechanism of action of the drugs (Figure) or on previous
isolated observations. Management recommendations are mostly
based on results from patient series or case reports. Aiming on rare
TACS, we decided to report data on chronic cluster headache for
2 reasons. First, episodic cluster headache was covered in several
recent reviews between 2018 and 2022.1-4 Second, data from the
literature show that episodic and chronic cluster headache respond
differently to treatments.5-7
Methods
A MEDLINE search in PubMed was performed from 2000 to 2022
for the terms cluster headache, paroxysmal hemicrania, hemicra-
nia continua, SUNCT, and SUNA. Search terms were epidemiology,
pathophysiology, clinical symptoms, management, and therapy.
For treatment and management, we selected articles reporting
results from at least 10 patients. For the tables, we selected results
from review articles when only case reports with small numbers
were available.

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 Management of Trigeminal Autonomic Cephalalgias Including Chronic Cluster Review Clinical Review & Education

Figure. Phenotypic Spectrum and Treatment Targets for Trigeminal Autonomic Cephalalgias

A Differentiation of trigeminal-autonomic cephalalgias B Therapeutic approaches based on target structure and mechanism of action

Hemicrania continua
Continuous pain with exacerbations
10
Somatosensory cortex
Pain intensity

Pain signal processing

5

Thalamocortical
0 sensory processing
0 6 12 18 24
Therapy options
Time, h
• Topiramate
EX • Carbamazepine
Cluster headache RT
CO • Lamotrigine
Duration: 15-180 min (usually 30-60 min) L
A UM
R OS
Frequency: 0.5-8 per day (mean, 4 per day) B LL
E
CA

R
10

CE
S
U
P
Thalamus
Pain intensity

R
O
C
Pain signal processing
5

Hypothalamus
0 IN
6 60 120 180 240 300 360 Therapy options

A
M

R
Time, min LU • CGRP pathway

DB
L blockers

MI
E
B
• Verapamil
RE

Paroxysmal hemicrania
CE

Duration: 2-30 min (mean, 26 min)

• Steroids
PONS
Frequency: 5-40 per day (mean, 15 per day)
10
Superior salivary nucleus
Pain intensity

Origin of cranial autonomic symptoms

LA Connection to sphenopalatine ganglion
DUL
5
Therapy options
ME

Trigeminal nucleus • Vagal nerve stimulation

0 Trigeminovascular • Sphenopalatine ganglion stimulation
0 60 120 180 240 300 360 system • Indomethacin
Time, min Therapy options
• Topiramate
Trigeminocervical nucleus
SUNCT/SUNA • Carbamazepine
Duration: 5-600 s (usually 10-120 s; mean, 60 s) • COX inhibitors Convergence of upper cervical nerves
Frequency: 3-200 per day (mean, 28 per day) • OnabotulinumtoxinA (eg, greater occipital nerve) with
10 trigeminal nucleus
• Lidocaine
• CGRP pathway Therapy options
Pain intensity

blockers • Greater occipital nerve neuromodulation

5 • Indomethacin • Greater occipital nerve block (lidocaine)

0
0 6 12 18 24 30 36
Time, min

CGRP indicates calcitonin gene-related peptide; SUNA, short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms; SUNCT, short-lasting
unilateral neuralgiform headache attacks with conjunctival injection and tearing.

as a disease. In a meta-analysis, pooled data showed a lifetime

Management of Chronic Cluster Headache
Clinical Presentation
Cluster headache can manifest in 2 forms: episodic and chronic.8
The definition of cluster headache as well as episodic and chronic
cluster were published by the International Headache Society.8
For chronic cluster headache, attacks occur for more than 1 year
without remission or with remission lasting less than 1 month. In
about 10% of patients with chronic cluster headache, the chronic
pattern is present ab initio.9 In terms of nomenclature, a distinc-
tion is made between a single cluster attack and cluster headache
prevalence of cluster headache of 124 per 100 000.10 Assuming
that about 10% of patients with cluster headache experience
chronic cluster headache, the prevalence is estimated to be 10 to
15 per 100 000.
Treatment
The management of cluster headache is divided into the immedi-
ate treatment of attacks and the preventive treatment for reducing/
stopping recurrence of attacks during the active periods. Most
therapy recommendations are based on the results of open obser-
vational studies.

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 Clinical Review & Education Review Management of Trigeminal Autonomic Cephalalgias Including Chronic Cluster

Table 1. Cluster Headache Attack Treatment

No. of Response No. of attacks
Treatment Dose Route Study patients rate, %a Placebo/sham, %b or end points

100% 7-12 Cohen et al15 76 78 20 150 Attacks

Oxygen Inhalation
L/min Dirkx et al16 55 68 NA 710 Attacks
Ekbom et al17 134 75 35 6 mg
Sumatriptan 3 or 6 mg Subcutaneous 80 12 mg
Hardebo and Dahlöf18 26 49 NA 62 Attacks
Hardebo and Dahlöf18 26 14 NA 52 Attacks
Schuh-Hofer et al19 10 50 NA 154 Attacks
Sumatriptan 20 mg Nasal spray
van Vliet et al14 118 47 18 Pain free at 15 min;
154 attacks
Cittadini et al20 92
5 mg 42 23 65 Attacks
10 mg 61 NA 63 Attacks
Rapoport et al21 52 151 Attacks
Zolmitriptan 5 or 10 mg Nasal spray 5 mg 50 30
10 mg 63 NA
Hedlund et al22 121 121 Attacks
5 mg 48 30
10 mg 63 NA
Three Silberstein et al23 133 27 15 NA
Transcutaneous
Vagus nerve consecutive
at the cervical Goadsby et al24 92 14 12 NA
stimulation 2-min
level
stimulations
Electrical Schoenen et al25 28 67 7 566 Attacks
stimulation
Electrode Goadsby et al26 93 62 39 992 Attacks
Stimulation of the parameters
implanted in the
sphenopalatine adjusted
pterygopalatine
ganglionc according to
fossa
provoked
paresthesias
b
Abbreviation: NA, not applicable. Placebo NA = no placebo group.
a c
Response rate for primary end point and number of attacks. No longer marketed.

Immediate Treatment of the Cluster Attack
Cluster attacks are quite short with a duration of 15 minutes to 180
minutes. Therefore, oral medications are not optimal because they
take too long to be effective. A very effective and adverse reaction–
free therapy is the inhalation of oxygen, 100%, through a mask
covering the mouth and nose in a sitting position. The efficacy of
this therapy was evaluated in a placebo-controlled trial.11
Drug therapy for cluster attacks involves subcutaneous admin-
istration of sumatriptan or administration of sumatriptan or zolmi-
triptan via the nasal spray modality. The efficacy of subcutaneous
sumatriptan has been demonstrated in several placebo-controlled
trials. A meta-analysis found a rate of pain relief after 15 minutes of
48% with sumatriptan and 17% with placebo.12 Sumatriptan is well
tolerated but is contraindicated in patients with clinically relevant
cardiovascular disease.13
Results of randomized placebo-controlled trials are also avail-
able for the administration of sumatriptan, 20 mg, as a nasal spray.
The rate of being pain free after 30 minutes was 47% for sumatrip-
tan and 18% for placebo.14 Intranasal administration of zolmitrip-
tan in doses of 5 and 10 mg was studied in 2 randomized placebo-
controlled trials. A meta-analysis of the studies with 121 patients
showed improvement of headache at 30 minutes after zolmitrip-
tan, 10 mg, in 63% of patients; after zolmitriptan, 5 mg, in 48% of
patients; and, after placebo in 30% of patients (Table 1).15-22
Noninvasive vagus nerve stimulation has been investigated both
for the immediate treatment and the prevention of cluster head-
ache. The 2 Acute Treatment of Cluster Headache (ACT1 and ACT2)
studies were prospective double-blind placebo-controlled random-
ized trials that investigated the gammaCore (electroCore) device.23,24
The ACT1 study showed a reduction in pain within 15 minutes in
26.7% of patients with active stimulation compared with 15.1% with
sham stimulation.23 Vagus nerve stimulation was more effective
than sham stimulation in the ACT2 study for the episodic cluster
headache group with 48% of responders vs 6% in the sham arm
(P = .003). Sphenopalatine ganglion stimulation was developed for
the treatment of acute cluster attacks and evaluated in 2 con-
trolled studies.25,26 In the first study, a reduction in pain intensity
within 15 minutes was achieved in 67% of attacks in the active stimu-
lation group compared with 7% in the sham stimulation group. In
the second study, the proportion of attacks with relief of pain within
15 minutes was 62.5% (95% CI, 49.1%-74.1%) in the group with ac-
tive stimulation vs 38.9% (95% CI, 28.6%-56.2%) in the sham group.
Three of 36 patients experienced a serious adverse event during im-
plantation (aspiration during intubation, nausea and vomiting, and
venous injury or compromise). A fourth serious adverse event was
an infection that was attributed to both the stimulation device and
the implantation procedure. There are additional open studies sug-
gesting efficacy of sphenopalatine ganglion stimulation for the

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 Management of Trigeminal Autonomic Cephalalgias Including Chronic Cluster Review Clinical Review & Education

Table 2. Preventive Treatment of CCH

No. of
cluster
patients No. of
in the patients Response Placebo,
Treatment Dose Modality Study study with CCH rate, % % Outcome
NA Gabai and 48 15 69 NA Improved >75%
Spierings32
Verapamil 200-480 mg Oral Blau and Engel33 70 18 55 NA Complete relief
< or >500 mg Petersen et al34 400 146 23 NA >50% Attack reduction
Lithium 600-900 mg Oral Ekbom35 304 304 78 NA Chronic cluster headache
review article
Mathew et al36 12 3 0 NA Improvement
Láinez et al37 26 14 80 NA Cluster remission
Topiramate 100-200 mg Oral
Leone et al38 33 10 10 NA >50% Attack reduction
Huang et al39 12 1 100 NA Remission of headache
Leandri et al40 12 4 100 NA Cluster remission
Gabapentin 900 mg Oral
Schuh-Hofer et al41 8 8 75 NA Cluster remission
10 mg Leone et al42 20 2 50 NA % Attack reduction
Melatonin Oral
2 mg Pringsheim et al43 9 6 0 0 Add-on therapy
300 mg Subcutaneous Dodick et al6 237 237 32 27 >50% Responders at
week 3
Galcanezumab 300 mg Subcutaneous Riesenberg et al44 164 111 40 NA Open label: 50% very
much better or 29% much
better at 12 mo
Wilbrink et al45 131 NA 4.08 6.50 Reduction in weekly attack
frequency week 21-24
Aibar-Durán et al46 17 17 21 NA Mean reduction in number
of weekly attacks at 6 mo
Occipital nerve 100% Intensity Implanted Miller et al47 51 51 46 NA % Reduction in attack
stimulation vs 30% intensity electrodes frequency at 39 mo
Leplus et al48 105 105 69 NA Percentage >50%
responders at 44 mo
Fontaine et al49 13 13 68 NA % Reduction in attack
frequency at month 12
Jürgens et al28 31 31 35 NA Percentage of >50%
responders at month 24
Implanted Schoenen et al25 28 28 41 NA Percentage of >50%
SPG stimulation NA
electrode responders
Barloese et al29 85 78 55 NA Reduction in attacks/week
Computed NA Transcutaneous Xin et al50 10 10 100 NA Numeric rating scale
tomography–
guided
radiofrequency
thermocoagu-
lation of SPG
Vagus nerve Three 2-min Transcutaneous Gaul et al51 93 NA 40 8a Percentage of >50%
stimulation stimulations stimulation responders
twice daily

Abbreviations: CCH, chronic cluster headache; NA, not applicable; SPG, sphenopalatine ganglion.
a
Comparison with standard of care.

immediate treatment of cluster attacks (Table 1).27-29 In conclu-
sion, sphenopalatine ganglion stimulation has been shown to be
effective, but due to its invasive nature, it should be restricted to
patients in whom all other prophylactic medications to treat clus-
ter attacks failed. Sphenopalatine ganglion stimulation can be pro-
posed only if the device and therapy receives regulatory approval
and there is certainty that the manufacturer will make the technol-
ogy available and ensure maintenance.30,31
In conclusion, the inhalation of oxygen, 100%, is a very effec-
tive treatment of cluster attacks, devoid of adverse events. The most
effective immediate therapy is the subcutaneous administration
of sumatriptan.
Prevention of Chronic Cluster Headache
All patients with chronic cluster headache should receive preven-
tive treatment. There are only very few randomized placebo-
controlled trials, mostly in episodic cluster headache. Most recom-
mendations for treatment of chronic cluster headache are based on
case reports, small placebo-controlled studies, or open-label stud-
ies (Table 2).32,33,36 A scoping review of the literature concluded that
the quality of treatment studies in chronic cluster headache did not
allow to perform a network meta-analysis.52 Several of the drugs
listed in Table 2 may induce adverse reactions, especially at the high-
est doses tested in the literature. This requires careful monitoring
of the patients to capture and address incident adverse events.

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 Clinical Review & Education Review
A meta-analysis of the 2 open-label studies investigating ver-
apamil showed that 87% of patients either had complete elimina-
tion of cluster attacks or a 50% or greater reduction in attack
frequency.53 The Danish Headache Center observed a 44% effi-
cacy for the end point of more than 50% attack reduction in 146
patients with chronic cluster headache.34 One underpowered study
compared lithium and placebo for the prevention of cluster at-
tacks. The trial was terminated due to futility.54 Open and small stud-
ies summarized by Ekbom35 observed a positive response to lithium
in about 75% of patients. A meta-analysis of 3 open studies with
a total of 103 patients found that lithium was effective in inducing
cluster remission or reducing attack frequency by at least 50% in
77% of patients.53 In patients treated with lithium, plasma levels
should be monitored on a regular basis due to the potential toxicity
of the drug.
There are only open studies on topiramate for the prevention
of cluster headache. Doses of topiramate ranged from 100 to 200
mg daily, and due to the small patient numbers, efficacy cannot
be evaluated (Table 2). Gabapentin showed efficacy in 2 small
studies.40,41 Given the circadian rhythm of cluster attacks, melato-
nin has also been studied for the prevention of cluster headache. In
a small randomized placebo-controlled trial of 20 patients, melato-
nin, 10 mg, was more effective than placebo over a 14-day period.42
The study had only 2 patients with chronic cluster headache. A study
with 6 patients showed no efficacy.43
Calcitonin gene-related peptide plays an important role not only
in the pathophysiology of migraine but also in cluster headache. Se-
rum levels of calcitonin gene-related peptide are elevated during
cluster attacks.55 Galcanezumab, a monoclonal antibody targeting
calcitonin gene-related peptide, was studied in episodic and chronic
cluster headache.7 When tested in a subgroup of patients with
chronic cluster headache, galcanezumab did not prove superior
to placebo.6 However, the study had a high placebo response. In
a long-term open-label safety study, 111 patients with chronic clus-
ter headache who participated in the placebo-controlled study
continued treatment with galcanezumab for 6 to 12 months. At
month 12, data from 79 patients were available, and 50% and 29%
of these patients reported to be very much better or much better,
respectively.44 The most common adverse reactions were naso-
pharyngitis and injection site pain.56 Galcanezumab was approved
only for episodic cluster headache prevention in the US. A clinical
trial evaluating the efficacy of fremanezumab for the prevention of
chronic cluster headache (NCT02964338) was terminated due to
futility. Clinical trials evaluating eptinezumab for chronic cluster
headache (NCT05064397) are ongoing.
Neurostimulation for the Preventive Treatment
of Chronic Cluster Headache
Noninvasive and invasive methods of neurostimulation are used for
patients with chronic cluster headache in whom drug therapy is not
sufficiently effective or is not tolerated.57
Bilateral stimulation of the occipital nerve acts through both pe-
ripheral and central mechanisms.1 For the procedure, stimulating
electrodes are placed subcutaneously over the occipital nerves. Elec-
trical stimulation is provided via an implantable pulse generator. The
only randomized double-blind multicenter study conducted to date
and to our knowledge to evaluate occipital nerve stimulation for clus-
ter headache prevention (ICON trial45) included 131 patients with
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Management of Trigeminal Autonomic Cephalalgias Including Chronic Cluster
chronic cluster headache who were randomized to receive either
100% stimulus intensity (n = 65) or 30% stimulus intensity (n = 66).
The median weekly attack frequency in the total population de-
creased from 15.75 attacks at baseline to 7.38 (2.50 to 18.50; P < .001)
in weeks 21 to 24. The most common adverse reactions were local
pain, wound healing disorders, local infections, neck stiffness, cable
breaks, and malfunction of the stimulator. The lack of a proper con-
trol group and the absence of difference in the efficacy observed with
the low- and high-intensity stimulations weakens the results.45
Several open studies investigated the efficacy of occipital nerve
stimulation in patients with chronic cluster headache (Table 2). The
success rate measured by a reduction more than 50% in the fre-
quency of cluster attacks per week or month ranged from 40% to
70%.46-49,58,59
A potential preventive effect has been suggested for spheno-
palatine ganglion stimulation in 2 long-term studies investigating
the efficacy of the procedure in the immediate treatment.25,28 One
study investigated the long-term effects.29 Between 35% and 55%
of patients had a reduction in cluster attack frequency. However,
sphenopalatine ganglion stimulation is no longer available because
the company left the market. A small open study performed com-
puted tomography–guided radiofrequency thermocoagulation of
the sphenopalatine ganglion in 10 patients with chronic cluster
hedache.50 The authors claimed a positive treatment response in
all patients. Another treatment option is gamma knife radiosur-
gery of the trigeminal nerve or the sphenopalatine ganglion. A sys-
tematic review from 5 open studies and 48 patients reported a
meaningful pain reduction in 77%.60
Noninvasive vagus nerve stimulation was examined as adjunc-
tive prophylactic treatment of chronic cluster headache in the PREVA
trial.51 PREVA was a prospective, open-label, randomized study
that compared adjunctive prophylactic noninvasive vagus nerve
stimulation (n = 48) with standard of care alone (n = 49). During
the randomization phase, patients treated with standard of care plus
noninvasive vagus nerve stimulation had a significantly greater re-
duction in the number of attacks per week vs controls (−5.9 vs −2.1)
for a mean therapeutic gain of 3.9 fewer attacks per week (95% CI,
0.5-7.2; P = .02).
The potential benefit of invasive stimulation of the posterior
hypothalamus has been suggested in relatively large case series of
patients with refractory chronic cluster headache, but the efficacy
was not confirmed in a randomized phase of a controlled study, al-
though a benefit was reported by 6 of 11 patients in the open-label
10-month phase.61 In this study, there were 3 serious adverse events,
including subcutaneous infection, transient loss of consciousness,
and micturition syncope. Of note, in a previous open-label study,
a fatal event occurred in 1 of the 6 patients who underwent the pro-
cedure. Because of the possible serious adverse events, invasive
stimulation of the posterior hypothalamus should only be consid-
ered in cases of failure of all pharmacological preventive treat-
ments, used also in combination, and the extracranial invasive or
noninvasive neurostimulation methods.62
Conclusions and Future Treatment Concepts
In conclusion, bilateral stimulation of the greater occipital nerve is
probably the most effective therapy in patients with chronic clus-
ter headache who do not tolerate treatment with verapamil or
lithium. However, the optimal parameters for stimulation have not
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 Management of Trigeminal Autonomic Cephalalgias Including Chronic Cluster
yet been definitively determined. The failure of galcanezumab to
show superiority over placebo for the preventive treatment of
chronic cluster headache, despite efficacy being demonstrated in
episodic cluster headache, has raised several questions about
differences in etiology, pathophysiology, and trial design.63,64 The
discrepancy between the results of the placebo-controlled study and
the open long-term study might be due to the high placebo re-
sponse. Further research elucidating the reasons for what may be
a differential response to preventive treatments, and careful trial
designs in both patient populations are needed.
Ketamine, a noncompetitive N-methyl-D-aspartic acid recep-
tor antagonist, has been increasingly used in pain management in
recent years. In a small study of 13 patients with chronic cluster head-
ache, low-dose intravenous ketamine was given every 2 weeks.65
Half of the patients had a reduction in the number of cluster at-
tacks. Pasireotide is a somatostatin analogue and was studied in a
double-blind placebo-controlled trial in patients with episodic or
chronic cluster headache. The study was terminated early due to lack
of efficacy (NCT02619617). OnabotulinumtoxinA has been evaluated
in a small open-label study involving 17 patients with chronic cluster
headache.66 The results obtained show that 59% of the study
patients achieved the primary outcome measure represented
by a more than 50% reduction in cumulative headache minutes.
Paroxysmal Hemicrania
Clinical Presentation
Paroxysmal hemicrania is characterized by severe short attacks of
head and facial pain with high frequency, averaging 10 attacks per
day with a range between 5 to 40 attacks in 24 hours. Pain is asso-
ciated with autonomic symptoms or signs including lacrimation,
conjunctival injection, nasal congestion, and/or rhinorrhea. The
pain is unilateral, very rarely bilateral, and the attacks last 2 to 30
minutes.67 The definition is provided by the International Head-
ache Society.8
Paroxysmal hemicrania occurs in 2 subtypes: episodic and
chronic.8 One of the clinical landmarks of paroxysmal hemicrania
is the complete efficacy of indomethacin when taken regularly.
Treatment
The attacks of paroxysmal hemicrania are too short for immediate
drug therapy to be effective. Therefore, preventive therapy is rec-
ommended (Table 3). The most effective treatment is indometha-
cin. The dose is slowly increased from 25 mg 3 times per day to 150
mg per day. Higher doses, up to 300 mg daily, have also been re-
ported in the literature. For most patients, the maintenance dose is
between 25 and 100 mg daily. After discontinuation of indometha-
cin, the symptoms of paroxysmal hemicrania usually return within
hours to days.68 Some patients are unable to take indomethacin
long term because of gastrointestinal adverse reactions despite
taking proton pump inhibitors.
Single-case reports suggest the efficacy of COX-2 inhibitors,
topiramate, verapamil, and carbamazepine (Table 3). The efficacy
of blockade of the sphenopalatine ganglion, occipital nerve
stimulation,86 and neuromodulation with noninvasive stimulation
of the vagus nerve with 2 consecutive 2-minute doses delivered
3 daily stimulations have been reported.74,75
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Review Clinical Review & Education
Conclusion
In conclusion, paroxysmal hemicrania is a TAC characterized by uni-
lateral and severe pain, predominantly located in the orbital region,
associated with cranial parasympathetic features. The attacks re-
spond completely to indomethacin. A few other treatment options
are available for patients who cannot tolerate indomethacin.
Hemicrania Continua
Clinical Presentation
Hemicrania continua is a unilateral continuous headache. Pain is usu-
ally described as dull and pressing, typically located in the tempo-
ral, orbital, or frontal region, although sometimes it may be re-
ported in the retro-orbital, occipital, and parietal regions.87 Typically,
the continuous headache has superimposed exacerbations with stab-
bing or pulling pain of moderate to severe intensity. The duration of
pain exacerbations varies markedly from a few seconds to days or
even weeks.76 Accompanying the headache are autonomic symp-
toms ipsilateral to the pain. The most important diagnostic feature
is the complete, although transient, response of the headache to
therapeutic doses of indomethacin.8
Treatment
Recent advancements in treatment options for hemicrania conti-
nua have prompted the possibility to use either invasive or nonin-
vasive approaches (Table 3). Indomethacin serves to confirm the
diagnosis,88 although cases of secondary hemicrania continua with
complete response to indomethacin have been reported.
Hemicrania continua does not necessarily respond immediately
to therapy. In one case series, only 10% of patients showed a re-
sponse within 24 hours, whereas 43% of patients reported a com-
plete response within 1 week and some patients might require up to
4 weeks.89,90 An interesting observation is that other nonsteroidal
anti-inflammatory drugs are much less effective than indomethacin.
In preclinical models, data implicated a nitric oxide–related signaling
mechanism underlying the unique response to indomethacin.91
In patients who cannot tolerate indomethacin or have contra-
indications to it, other drugs have been proposed in case reports
and open studies (Table 3). A positive treatment response has
been observed with the COX-2 inhibitor celecoxib, piroxicam, and
topiramate.76,92 Topiramate can also be used in association to in-
domethacin as a sparing agent of this latter.93 Melatonin (6-9 mg/d)
was effective in a few patients in combination with indomethacin,77
allowing the reduction of indomethacin in half the patients.77 Posi-
tive case reports were also published for corticosteroids, high-
dose ibuprofen, aspirin, gabapentin, amitriptyline, acemethacin,
verapamil, and onabotulinumtoxinA (Table 3).76
Nerve blocks can be effective in hemicrania continua with
a benefit that lasts up to 2 to 10 months. Blockade of the greater
occipital or supraorbital nerves, alone or in combination, may be
considered.94 A crossover study and an open study in 16 patients
also reported a positive response to occipital nerve stimulation.95,96
A small case series with botulinum toxin showed a reduction of 50%
or more in moderate to severe headache days in 5 of 9 patients.78
Noninvasive vagus nerve stimulation was used in 9 patients with
hemicrania continua who could not tolerate indomethacin and
induced a reduction in continuous pain.75
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 Clinical Review & Education Review Management of Trigeminal Autonomic Cephalalgias Including Chronic Cluster

Table 3. Preventive Treatment of Paroxysmal Hemicrania, Hemicrania Continua, and SUNCT and SUNA
No. of Response Outcomes or
Treatment Dose Modality Study patients rate, % Placebo No. of publications
Paroxysmal hemicrania
25-150 mg Pareja et al68 10 100 Relief of symptoms
50-300 mg Cittadini et al69 31 96 Absolute response
50-225 mg Prakash et al70 17 100 Complete response
Indomethacin Oral NA
50-200 mg Boes and Dodick71 40 75 Data for 40 of 74 patients
2.75 mg/kg of Mauritz et al72 8 75 Pediatric patients
Body weight
Verapamil 250 mg Oral Baraldi et al73 30 47 NA 11 Publications
Carbamazepine 800 mg Oral Baraldi et al73 15 20 NA 6 Publications
Topiramate 50-200 mg Oral Baraldi et al73 12 75 NA 7 Publications
Kamourieh et al74 8 75 >50% Improvement
Two 2-min
Vagus nerve Tso et al75 6 75 Complete cessation to
stimulations Transcutaneous NA
stimulation decreased severity; 2
3 times/d
patients had no response
Hemicrania continua
Indomethacin 25-200 mg Oral Baraldi et al73 159 99 NA 55 Publications
Topiramate 100-200 mg Oral Prakash and Patel76 16 100 NA 7 Publications
Gabapentin 1600 mg Oral Baraldi et al73 13 85 NA 6 Publications
Melatonin 10 mg Oral Rozen77 11 45 NA <20% Pain freedom
OnabotulinumtoxinA 155 Injection Miller et al78 9 55 NA >50% Reduction in
headache days
73
COX-2 inhibitors NA Oral Baraldi et al 18 83 NA Celecoxib, piroxicam
Nerve blocksa Local anesthetic NA Baraldi et al73 32 72 NA NA
Neurostimulationb NA NA Baraldi et al73 14 86 NA NA
Vagus nerve 2 min 3 Times/d NA Trimboli et al79 4 60 NA NA
stimulation
SUNCT and SUNA
Lidocaine 1.3-3.3 mg/kg of Intravenous Marmura80 34 95 NA Short-term treatment;
Body weight 4 publications
Lambru et al81
SUNCT, 50-700 mg SUNCT 74 77 NA Improvement
SUNA 60 77
Weng et al82 Percentage with reduction
Lamotrigine Oral
in frequency and severity
SUNCT 29 62 NA of attacks
SUNA, 150-600 mg SUNA 16 31
Baraldi et al73 84 81 NA Percentage of responders;
21 studies
81
Lambru et al
SUNCT 48 54 NA Improvement
SUNA 31 35
Weng et al82
Topiramate 50-400 mg Oral Percentage with reduction
SUNCT 27 48 NA in frequency and severity
of attacks
SUNA 9 11
Baraldi et al73 36 56 NA Percentage of responders;
11 studies
Lambru et al81
SUNCT 50 32 NA Improvement
SUNA 30 33
Weng et al82
Gabapentin 300-3600 mg Oral Percentage with reduction
SUNCT 29 38 NA in frequency and severity
of attacks
SUNA 18 39
Baraldi et al73 48 59 NA Percentage of responders;
11 studies
Lambru et al81
Pregabalin 25-600 mg Oral SUNCT 37 32 NA Improvement
SUNA 29 31

(continued)

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 Management of Trigeminal Autonomic Cephalalgias Including Chronic Cluster Review Clinical Review & Education

Table 3. Preventive Treatment of Paroxysmal Hemicrania, Hemicrania Continua, and SUNCT and SUNA (continued)
No. of Response Outcomes or
Treatment Dose Modality Study patients rate, % Placebo No. of publications
Lambru et al81
SUNCT 44 38 NA Improvement
SUNA 43 63
Weng et al82
Carbamazepine 100-2000 mg Oral Percentage with reduction
SUNCT 43 36 NA in frequency and severity
of attacks
SUNA 20 20
Baraldi et al73 78 49 NA Percentage of responders;
27 studies
Lambru et al81
SUNCT 29 69 NA Improvement
SUNA 34 73
Oxcarbazepine 600-3600 mg Oral
Weng et al82
Percentage with reduction
SUNCT 7 14 NA in frequency and severity
of attacks
SUNA 6 0
Lambru et al81
Duloxetine 30-120 mg Oral SUNCT 20 60 NA Improvement
SUNA 17 35
Deep brain 185 Hz; amplitude, Stimulation Miller et al83 11 82 NA Percentage >50% reduction
stimulation 4 mV in attack frequency; median
follow-up, 29 mo
Greater occipital Methylprednisolone Local injection Lambru et al81 58 37 NA Improvement
nerve block and lidocaine, 2%
Occipital nerve Amplitude, Stimulation Miller et al84 31 77 NA Percentage >50% reduction
stimulation 0.3-3.15 V; in daily attacks; median
frequency, follow-up, 45 mo
60-130 Hz
Trigeminal NA Surgery Lambru et al85 47 79 NA 75%-100% Reduction in
microvascular weekly attack frequency
decompression
a
Abbreviations: NA, not applicable; SUNA, short-lasting unilateral neuralgiform Nerve blocks: supraorbital nerve block and occipital nerve block.
headache attacks with cranial autonomic symptoms; SUNCT, short-lasting b
Neurostimulation: occipital nerve stimulation.
unilateral neuralgiform headache attacks with conjunctival injection and tearing.

Conclusions fication of Headache Disorders.8 SUNCT is characterized by the si-

In conclusion, hemicrania continua requires an absolute response
to indomethacin, which can take several weeks to occur. Indometha-
cin dose-sparing treatment options include melatonin and topira-
mate, while extracranial nerve blocks can provide a sustained re-
sponse lasting months in some patients.
Short-Lasting Unilateral Neuralgiform
Headache Attacks
Clinical Presentation
This group of trigeminal autonomic cephalalgias refers to head-
ache occurring with daily attacks of moderate or severe unilateral
head pain, with orbital, supraorbital, temporal, and/or other trigemi-
nal distribution, lasting for 1 to 600 seconds and manifesting as single
stabs, series of stabs, or in a sawtooth pattern. Typical accompany-
ing symptoms include conjunctival injection, lacrimation, rhinor-
rhoea, nasal congestion, ptosis, and eyelid edema. Two subtypes are
known: SUNCT and SUNA.
SUNCT and SUNA are rare primary headache syndromes. Af-
fected patients experience very frequent, brief attacks of head and
facial pain combined with autonomic symptoms. The diagnostic cri-
teria of SUNA and SUNCT are provided by the International Classi-
multaneous presence of conjunctival injection and lacrimation, while
in SUNA, either 1 of the 2 symptoms is present. The frequency of daily
pain attacks can be between 1 and 100 attacks, with the number vary-
ing extremely from patient to patient. Sixty percent of all patients
have episodic SUNCT or SUNA with periods of pain-free weeks or
months and 40% have the chronic form.97 A certain degree of over-
lap exists between the clinical features of SUNCT/SUNA and trigemi-
nal neuralgia98 when considering the very high frequency and short
duration of attacks, the neuralgiform quality of the pain, and the lack
of circadian rhythmicity. Furthermore, SUNCT and SUNA attacks may
be triggered by ipsilateral cutaneous or intraoral stimulations. This
partial overlap is also found in the therapeutic options (see below).
Treatment
Individual attacks of SUNCT and SUNA are so short that immediate
treatment is not useful. Preventive therapy is separated into short
term and long term (Table 3). In short-term prevention, a therapeu-
tic effect of intravenous lidocaine was observed over a period of up
to 12 weeks.82,99 Sumatriptan, 6 mg, subcutaneous and intrave-
nous dihydroergotamine, corticosteroids, indomethacin, and inha-
lation of oxygen were not effective.82
There are only observational studies on long-term prevention.
The only placebo-controlled trial found a beneficial effect of topi-

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 Clinical Review & Education Review Management of Trigeminal Autonomic Cephalalgias Including Chronic Cluster

Table 4. Priority of Treatments for Trigeminal Autonomic Cephalalgias

Chronic cluster headache Prevention

Priority Acute Paroxysmal Hemicrania
of treatment immediate Prevention hemicrania continua SUNCT/SUNA
First choice Oxygen Verapamil Indomethacin Indomethacin Lamotrigine
Second choice Sumatriptan Lithium Topiramate Topiramate Topiramate
(subcutaneous) Abbreviations: SUNA, short-lasting
Third choice Zolmitriptan Occipital nerve Verapamil Neurostimulation Carbamazepine unilateral neuralgiform headache
nasal spray stimulation, vagus attacks with cranial autonomic
nerve stimulation symptoms; SUNCT, short-lasting
Other possibly Vagus nerve Topiramate, Vagus nerve Gabapentin Occipital nerve unilateral neuralgiform headache
effective stimulation galcanezumab, stimulation stimulation attacks with conjunctival injection
options gabapentin and tearing.

ramate compared with placebo.82 Open-label studies found effi- Conclusions

cacy of lamotrigine (effectiveness, 62%) and topiramate (effective-
ness, 48%) (Table 3).82 Other positive treatment results have been
reported with gabapentin, carbamazepine, oxcarbazepine, du-
loxetine, and zonisamide.73,81 In clinical practice, a combination of
preventive medications is sometimes necessary.
Among procedural treatments, efficacy of occipital nerve ma-
jor blocks and infraorbital and supraorbital nerve blocks have been
described.100 There are also positive therapeutic effects of micro-
vascular decompression of the trigeminal nerve root101 that have
recently been confirmed in a larger population62 The largest study
so far was an uncontrolled open-label prospective single-center
study conducted between 2012 and 2020 to evaluate the efficacy
and safety of trigeminal microvascular decompression in refrac-
tory chronic SUNCT or SUNA in patients with magnetic resonance
imaging evidence of trigeminal neurovascular conflict ipsilateral to
the pain side.85 The study group consisted of 47 patients of whom
31 had SUNCT and 16 had SUNA. The mean postsurgery follow-up
was 57 months. Postoperatively, 78.7% of patients obtained either
an excellent or a good response.
Stimulation of the greater occipital nerves seems also to be
effective.84 Seven of 9 patients treated with sphenopalatine gan-
glion pulsed radiofrequency were considered responders.102 Miller
et al83 presented a case series of 11 patients treated with ventral teg-
mental area deep brain stimulation in an uncontrolled, open-label
prospective observational study. The responder rate (defined as
at least a 50% improvement in daily attack frequency) was 82%
and 4 patients became pain free for prolonged periods of time.
Initially, drug therapy should be proposed. If this is not effec-
tive or tolerated, neuromodulation procedures can be considered.
The best data are available for bilateral chronic stimulation of the oc-
cipital nerve. If microvascular compression of the trigeminal nerve
in the posterior fossa is demonstrated on magnetic resonance angi-
ography, microvascular decompression surgery may be considered.
In conclusion, SUNCT and SUNA are excruciating, unilateral, short-
lasting periorbital paroxysms of pain with cranial autonomic
features that occur between 1 to 100 times per day. Intravenous
lidocaine can provide sustained relief for months, while placebo-
controlled efficacy exists for topiramate only. Lamotrigine and other
anticonvulsants may be effective. When pharmacological treat-
ments fail, surgical options in selected patients include occipital nerve
stimulation, microvascular decompression of the trigeminal nerve,
gamma knife radiosurgery or pulsed radiofrequency of the spheno-
palatine ganglion, and deep brain stimulation.
Conclusions and Future Directions
Recent progress has been made in our understanding of the epi-
demiology, pathogenesis, prognosis, and treatment of TACs. The
extreme severity of pain and the rare nature for chronic cluster
headache, paroxysmal hemicranias, hemicrania continua, and
SUNCT/SUNA has made controlled clinical trials a challenge and as
such, there is a less than robust evidence base that identifies the
optimal first and second-line treatments for these disorders. Nev-
ertheless, the accumulation of data from clinical case series
around the world has advanced our knowledge and provided guid-
ance on appropriate treatments and management strategies
(Table 4). Further advances will require consortia of multiple cen-
ters participating in collaborative prospective patient registries
where standardized patient-level data are systematically collected
and sample sizes sufficient for proper controlled clinical treatment
trials are generated. However, the lack of a reliable biomarker of
disease, the difficulty in proper blinding, and ethical consider-
ations about stopping a potentially effective treatment in rare con-
ditions may represent important limitations and undermine the
solidity of results.

ARTICLE INFORMATION
Accepted for Publication: November 3, 2022.
Published Online: January 17, 2023.
doi:10.1001/jamaneurol.2022.4804
Conflict of Interest Disclosures: Dr Diener
reported personal fees from Eli Lilly and Company,
Lundbeck, Novartis, Pfizer, and Teva
Pharmaceuticals; other support from WebMD as
author; grants from the German Research Council,
German Ministry of Education and Research, and
the European Union during the conduct of the
study; serves on the editorial board of Cephalalgia,
Lancet Neurology, and Drugs; and is a member of
the clinical trials committee of the International
Headache Society. Dr Tassorelli reported personal
fees from AbbVie, Eli Lilly and Company, Novartis,
Teva Pharmaceuticals, Lundbeck, Dompé, and
WebMD; grants from AbbVie during the conduct
of the study; is principal investigator or collaborator
in clinical trials sponsored by Alder, Eli Lilly and
Company, IBSA, Novartis, and Teva
Pharmaceuticals; grants from the European
Commission, the Italian Ministry of Health, the
Italian Ministry of University, and the Migraine
Research Foundation; is president of and serves on
the clinical trials committee for the International
Headache Society; and serves on the editorial
boards of Cephalalgia and The Journal of Headache
and Pain. Dr Dodick reported personal fees from
AbbVie, Acorda, AEON, Alcobra, Alder, Allergan,
American Academy of Neurology, Amgen, Arteaus,
Atria Health, Autonomic Technologies, Axsome,
Biocentric, Biohaven, Boston Scientific, Bristol
Myers Squibb, CapiThera, CC Ford West Group,
Cerecin, Ceruvia, Charleston Laboratories, Colucid,

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 Management of Trigeminal Autonomic Cephalalgias Including Chronic Cluster
CoolTech Medical, CTRLM, Decision Resources,
Dr Reddy’s–Promius Pharma, electroCore, Eli Lilly
and Company, eNeura, Equinox, Ethicon, Foresight,
Genentech, GSK, Impax, Impel, Insys, IntraMed,
Ispen, Labrys, Linpharma, Lundbeck, Magellan,
MAP BioPharma, Medtronic, Merck, Neurolief,
Nocira, Novartis, NuPathe, Oxford University Press,
Perfood, Pfizer, Pieris, Praxis, Revance, SAGE
Publishing, Salvia, Satsuma, St Jude, Supernus,
Teva Pharmaceuticals, Theranica, Tonix, UpToDate,
Vedanta, Wiley Blackwell, WL Gore, Wolters Kluwer
Health, Xenon, Xoc Pharmaceuticals, Zogenix,
Zosano, and ZP Opco; grants and personal fees
from Cefaly, electroCore, Eli Lilly and Company,
Novartis, Merz Pharma, Teva Pharmaceuticals,
Specifar, Amgen, Biogen, and Genesis Pharma;
personal fees and nonfinancial support from West
Virginia University Foundation, Canadian Headache
Society, Healthlogix, Universal Meeting
Management, WebMD/Medscape, Oregon Health
Science Center, Albert Einstein University,
University of Toronto, Synergy, MedNet, Peer View
Institute for Medical Education, Medicom,
Medlogix, Chameleon Communications, Academy
for Continued Healthcare Learning, Haymarket
Medical Education, Global Scientific
Communications, Miller Medical, MeetingLogiX,
University of British Columbia, University of
Southern California, University of California
(Los Angeles), American Academy of Neurology,
and Canadian Headache Society outside the
submitted work; nonfinancial support from Starr
Clinical, International Headache Society, American
Headache Society, American Brain Foundation,
and American Migraine Foundation; a patent for
Wolters Kluwer with royalties paid, for Oxford
University Press with royalties paid, Cambridge
University Press with royalties paid, for botulinum
toxin dosage regimen for chronic migraine
prophylaxis (nonroyalty bearing) issued, and for
Synaquell (Precon Health) pending; research
support from Department of Defense, National
Institutes of Health, Henry Jackson Foundation,
Sperling Foundation, American Migraine
Foundation, and Patient-Centered Outcomes
Research Institute; leadership or fiduciary role in
other board, society, committee or advocacy group,
paid or unpaid from American Migraine Foundation,
American Brain Foundation, International
Headache Society Global Patient Advocacy
Coalition; stock options/shareholder/patents/board
of directors from Aural Analytics, Axon
Therapeutics, ExSano, Man and Science, Healint,
Theranica, Second Opinion/Mobile Health, Epien,
Nocira, Matterhorn, Ontologics, King-Devick
Technologies, Precon Health, AYYA Biosciences,
and Atria Health; payment or honoraria for lectures,
presentations, and educational events from
Amgen, Novartis, Eli Lilly and Company, Teva
Pharmaceuticals, Allergan, AbbVie, Lundbeck,
Biohaven, and Pfizer; and honoraria from Vector
Psychometric Group, Clinical Care Solutions,
CME Outfitters, Curry Rockefeller Group,
DeepBench, Global Access Meetings,
KLJ Associates, Academy for Continued
Healthcare Learning, Majallin LLC, Medlogix
Communications, MJH Lifesciences, Miller Medical
Communications, and WebMD Health/Medscape.
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