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
Behavioral Sciences, University of
(ie, paroxysmal hemicrania, hemicrania continua, short-lasting unilateral neuralgiform Pavia, Pavia, Italy (Tassorelli);
headache attacks with conjunctival injection and tearing, and short-lasting unilateral Headache Science &
neuralgiform headache attacks with cranial autonomic symptoms), only case reports Neurorehabilitation Centre,
IRCCS C., Mondino Foundation, Pavia,
and case series are available to guide physicians in everyday management.
Italy (Tassorelli); Department of
Neurology, Mayo Clinic, Phoenix,
CONCLUSIONS AND RELEVANCE The accumulation of epidemiologic, pathophysiologic,
Arizona (Dodick); Atria Institute,
natural history knowledge, and data from case series and small controlled trials, especially New York, New York (Dodick).
over the past 20 years from investigators around the world, has added to the previously Corresponding Author: Hans
limited evidence and has helped advance and inform the treatment approach to rare TACs, Christoph Diener, MD, Institute for
which can be extremely challenging for clinicians. Medical Informatics, Biometry and
Epidemiology (IMIBE), Department
of Neuroepidemiology, University
JAMA Neurol. 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 character-
ized by the presence of autonomic accompanying
symptoms during headache. The most frequently
observed accompanying symptoms are rhinorrhoea, nasal conges-
tion, 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 hemicra-
nia, hemicrania continua, short-lasting unilateral neuralgiform
headache attacks with conjunctival injection and tearing (SUNCT),
and short-lasting unilateral neuralgiform headache attacks with
cranial autonomic symptoms (SUNA). Most TACs can occur in an
episodic or chronic form. The most important feature to differenti-
ate 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 therapeutic approaches have been tested and proposed,
based on the putative mechanism of action of the drugs (Figure)
or on previous isolated observations. Management recommenda-
tions 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 clus-
ter 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 re-
sults from review articles when only case reports with small num-
bers were available.

jamaneurology.com (Reprinted) JAMA Neurology Published online January 17, 2023 E1

© 2023 American Medical Association. All rights reserved.

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

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 im-
mediate 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
observational studies.

E2 JAMA Neurology Published online January 17, 2023 (Reprinted) jamaneurology.com

© 2023 American Medical Association. All rights reserved.

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

Table 1. Cluster Headache Attack Treatment

No. of Response Placebo/ No. of attacks
Treatment Dose Route Study patients rate, %a sham, %b or end points
Cohen et al15 76 78 20 150 Attacks
Oxygen 100% 7-12 L/min Inhalation
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

Vagus nerve Three consecutive Transcutaneous at Silberstein et al23 133 27 15 NA

stimulation 2-min stimulations the cervical level Goadsby et al24 92 14 12 NA
Electrical stimulation Electrode Schoenen et al25 28 67 7 566 Attacks
Stimulation of the
parameters adjusted implanted in the
sphenopalatine
according to provoked pterygopalatine Goadsby et al26 93 62 39 992 Attacks
ganglionc
paresthesias fossa
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 re-
action–free therapy is the inhalation of oxygen, 100%, through a
mask covering the mouth and nose in a sitting position. The effi-
cacy 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
headache. The 2 Acute Treatment of Cluster Headache (ACT1
and ACT2) studies were prospective double-blind placebo-
controlled randomized trials that investigated the gammaCore (elec-
troCore) device.23,24 The ACT1 study showed a reduction in pain
within 15 minutes in 26.7% of patients with active stimulation com-
pared 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 controlled studies.25,26 In the first study, a reduction in pain in-
tensity within 15 minutes was achieved in 67% of attacks in the ac-
tive stimulation 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 active stimulation vs 38.9% (95% CI, 28.6%-56.2%) in the sham
group. Three of 36 patients experienced a serious adverse event
during implantation (aspiration during intubation, nausea and vom-
iting, 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 suggesting efficacy of sphenopalatine ganglion stimulation
for the immediate treatment of cluster attacks (Table 1).27-29 In con-
clusion, 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

jamaneurology.com (Reprinted) JAMA Neurology Published online January 17, 2023 E3

© 2023 American Medical Association. All rights reserved.

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

Table 2. Preventive Treatment of CCH

No. of cluster No. of
patients in patients Response Placebo,
Treatment Dose Modality Study the study with CCH rate, % % Outcome
NA Gabai and Spierings32 48 15 69 NA Improved >75%
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
48
Leplus et al 105 105 69 NA Percentage >50% responders
at 44 mo
Fontaine et al49 13 13 68 NA % Reduction in attack
frequency at month 12
28
Jürgens et al 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
29
Barloese et al 85 78 55 NA Reduction in attacks/week
Computed NA Transcutaneous Xin et al50 10 10 100 NA Numeric rating scale
tomography–guided
radiofrequency
thermocoagulation
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.

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
studies (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.
A meta-analysis of the 2 open-label studies investigating verap-
amil showed that 87% of patients either had complete elimination of
clusterattacksora50% orgreaterreductioninattackfrequency.53 The
Danish Headache Center observed a 44% efficacy 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 attacks. The trial was terminated due to
futility.54 Open and small studies summarized by Ekbom35 observed
apositiveresponsetolithiuminabout75%ofpatients.Ameta-analysis
of 3 open studies with a total of 103 patients found that lithium was ef-
fective 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 poten-
tial 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

E4 JAMA Neurology Published online January 17, 2023 (Reprinted) jamaneurology.com

© 2023 American Medical Association. All rights reserved.

Management of Trigeminal Autonomic Cephalalgias Including Chronic Cluster
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,
melatonin, 10 mg, was more effective than placebo over a 14-day
period.42 The study had only 2 patients with chronic cluster head-
ache. 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 cluster head-
ache 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 pa-
tients reported to be very much better or much better, respectively.44
The most common adverse reactions were nasopharyngitis and in-
jection 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
peripheral and central mechanisms.1 For the procedure, stimulat-
ing electrodes are placed subcutaneously over the occipital
nerves. Electrical 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 cluster headache prevention (ICON trial45)
included 131 patients with chronic cluster headache who were ran-
domized to receive either 100% stimulus intensity (n = 65) or
30% stimulus intensity (n = 66). The median weekly attack fre-
quency in the total population decreased 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 mal-
function of the stimulator. The lack of a proper control 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
stimulationinpatientswithchronicclusterheadache(Table2).Thesuc-
cess rate measured by a reduction more than 50% in the frequency of
clusterattacksperweekormonthrangedfrom40%to70%.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%
jamaneurology.com
© 2023 American Medical Association. All rights reserved.
Review Clinical Review & Education
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 systematic review from 5 open studies and 48 patients reported
a meaningful pain reduction in 77%.60
Noninvasive vagus nerve stimulation was examined as ad-
junctive prophylactic treatment of chronic cluster headache in the
PREVA trial.51 PREVA was a prospective, open-label, randomized study
thatcomparedadjunctiveprophylacticnoninvasivevagusnervestimu-
lation(n = 48)withstandardofcarealone(n = 49).Duringtherandom-
ization phase, patients treated with standard of care plus noninvasive
vagusnervestimulationhadasignificantlygreaterreductioninthenum-
ber of attacks per week vs controls (−5.9 vs −2.1) for a mean therapeu-
tic 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,
although 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 con-
sciousness, and micturition syncope. Of note, in a previous open-
label study, a fatal event occurred in 1 of the 6 patients who under-
went the procedure. Because of the possible serious adverse
events, invasive stimulation of the posterior hypothalamus should
only be considered in cases of failure of all pharmacological preven-
tive treatments, 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
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 dif-
ferences 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 pla-
cebo response. Further research elucidating the reasons for what
may be a differential response to preventive treatments, and care-
ful 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
(Reprinted) JAMA Neurology Published online January 17, 2023 E5
 Clinical Review & Education Review Management of Trigeminal Autonomic Cephalalgias Including Chronic Cluster

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, con-
junctival 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 Headache 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
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
stabbing or pulling pain of moderate to severe intensity. The dura-
tion of pain exacerbations varies markedly from a few seconds to
days or even weeks.76 Accompanying the headache are autonomic

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 Mauritz et al72 8 75 Pediatric patients
of 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 stimulation stimulations Transcutaneous Tso et al75 6 75 NA Complete cessation to
3 times/d decreased severity; 2
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
COX-2 inhibitors NA Oral Baraldi et al73 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 stimulation 2 min 3 Times/d NA Trimboli et al79 4 60 NA NA

(continued)

E6 JAMA Neurology Published online January 17, 2023 (Reprinted) jamaneurology.com

© 2023 American Medical Association. All rights reserved.

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
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
Lambru et al81
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
SUNA 9 11 of attacks

Baraldi et al73 36 56 NA Percentage of responders;

11 studies
81
Lambru et al
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
SUNA 18 39 of attacks

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
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
SUNA 20 20 of attacks

Baraldi et al73 78 49 NA Percentage of responders;

27 studies
81
Lambru et al
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
SUNA 6 0 of attacks

Lambru et al81
Duloxetine 30-120 mg Oral SUNCT 20 60 NA Improvement
SUNA 17 35
Deep brain stimulation 185 Hz; amplitude, 4 Stimulation Miller et al83 11 82 NA Percentage >50% reduction
mV in attack frequency; median
follow-up, 29 mo
Greater occipital nerve Methylprednisolone Local injection Lambru et al81 58 37 NA Improvement
block and lidocaine, 2%
84
Occipital nerve stimulation Amplitude, 0.3-3.15 Stimulation Miller et al 31 77 NA Percentage >50% reduction
V; frequency, 60-130 in daily attacks; median
Hz follow-up, 45 mo
Trigeminal microvascular NA Surgery Lambru et al85 47 79 NA 75%-100% Reduction in
decompression weekly attack frequency
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.

jamaneurology.com (Reprinted) JAMA Neurology Published online January 17, 2023 E7

© 2023 American Medical Association. All rights reserved.

 Clinical Review & Education Review
symptoms ipsilateral to the pain. The most important diagnostic
feature is the complete, although transient, response of the head-
ache 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 response
within 24 hours, whereas 43% of patients reported a complete re-
sponse 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
Positive case reports were also published for corticosteroids,
high-dose ibuprofen, aspirin, gabapentin, amitriptyline, acemetha-
cin, verapamil, and onabotulinumtoxinA (Table 3).76
Nerve blocks can be effective in hemicrania continua with a ben-
efit that lasts up to 2 to 10 months. Blockade of the greater occipi-
tal 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 in-
duced a reduction in continuous pain.75
Conclusions
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 ac-
companying symptoms include conjunctival injection, lacrimation,
E8 JAMA Neurology Published online January 17, 2023 (Reprinted)
© 2023 American Medical Association. All rights reserved.
Management of Trigeminal Autonomic Cephalalgias Including Chronic Cluster
rhinorrhoea, nasal congestion, ptosis, and eyelid edema. Two sub-
types 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-
fication of Headache Disorders.8 SUNCT is characterized by the si-
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 num-
ber varying 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 de-
gree of overlap exists between the clinical features of SUNCT/
SUNA and trigeminal neuralgia98 when considering the very high fre-
quency 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 in-
traoral stimulations. This partial overlap is also found in the thera-
peutic 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
inhalation 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-
ramate compared with placebo.82 Open-label studies found effi-
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
major blocks and infraorbital and supraorbital nerve blocks have
been described.100 There are also positive therapeutic effects
of microvascular decompression of the trigeminal nerve root101
that have recently been confirmed in a larger population 62
The largest study so far was an uncontrolled open-label prospec-
tive single-center study conducted between 2012 and 2020 to
evaluate the efficacy and safety of trigeminal microvascular
decompression in refractory chronic SUNCT or SUNA in patients
with magnetic resonance imaging evidence of trigeminal neuro-
vascular 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. Postop-
eratively, 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
jamaneurology.com
Management of Trigeminal Autonomic Cephalalgias Including Chronic Cluster Review Clinical Review & Education

Table 4. Priority of Treatments for Trigeminal Autonomic Cephalalgias

Chronic cluster headache Prevention

Priority of Paroxysmal Hemicrania
treatment Acute 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 options stimulation galcanezumab, stimulation stimulation attacks with conjunctival injection
gabapentin and tearing.

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
occipital nerve. If microvascular compression of the trigeminal
nerve in the posterior fossa is demonstrated on magnetic reso-
nance angiography, microvascular decompression surgery may be
considered.
Conclusions
In conclusion, SUNCT and SUNA are excruciating, unilateral, short-
lasting periorbital paroxysms of pain with cranial autonomic fea-
tures 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 epide-
miology, pathogenesis, prognosis, and treatment of TACs. The ex-
treme severity of pain and the rare nature for chronic cluster head-
ache, 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. Nevertheless, the
accumulation of data from clinical case series around the world has
advanced our knowledge and provided guidance on appropriate
treatments and management strategies (Table 4). Further ad-
vances will require consortia of multiple centers participating in col-
laborative 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 considerations about stopping a potentially ef-
fective treatment in rare conditions may represent important limi-
tations 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,
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

jamaneurology.com (Reprinted) JAMA Neurology Published online January 17, 2023 E9

© 2023 American Medical Association. All rights reserved.

 Clinical Review & Education Review
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.
REFERENCES
1. Hoffmann J, May A. Diagnosis, pathophysiology,
and management of cluster headache. Lancet Neurol.
2018;17(1):75-83. doi:10.1016/S1474-4422(17)
30405-2
2. Diener HC, May A. Drug treatment of cluster
headache. Drugs. 2022;82(1):33-42. doi:10.1007/
s40265-021-01658-z
3. Burish MJ, Rozen TD. Trigeminal autonomic
cephalalgias. Neurol Clin. 2019;37(4):847-869.
doi:10.1016/j.ncl.2019.07.001
4. Schindler EAD, Burish MJ. Recent advances in
the diagnosis and management of cluster
headache. BMJ. 2022;376:e059577. doi:10.1136/
bmj-2020-059577
5. de Coo IF, Marin JC, Silberstein SD, et al.
Differential efficacy of non-invasive vagus nerve
stimulation for the acute treatment of episodic
and chronic cluster headache: a meta-analysis.
Cephalalgia. 2019;39(8):967-977. doi:10.1177/
0333102419856607
6. Dodick DW, Goadsby PJ, Lucas C, et al. Phase 3
randomized, placebo-controlled study of
galcanezumab in patients with chronic cluster
headache: results from 3-month double-blind
treatment. Cephalalgia. 2020;40(9):935-948.
doi:10.1177/0333102420905321
7. Goadsby PJ, Dodick DW, Leone M, et al. Trial of
galcanezumab in prevention of episodic cluster
headache. N Engl J Med. 2019;381(2):132-141.
doi:10.1056/NEJMoa1813440
8. Headache Classification Committee of the
International Headache Society (IHS) The
International Classification of Headache Disorders,
3rd edition. Cephalalgia. 2018;38(1):1-211.
doi:10.1177/0333102417738202
9. Giani L, Proietti Cecchini A, Leone M. Cluster
headache and risk of chronic transformation. Neurol
Sci. 2020;41(suppl 2):497-498. doi:10.1007/
s10072-020-04674-1
10. Fischera M, Marziniak M, Gralow I, Evers S.
The incidence and prevalence of cluster headache:
a meta-analysis of population-based studies.
Cephalalgia. 2008;28(6):614-618. doi:10.1111/j.1468-
2982.2008.01592.x
11. Cohen AS, Mathura MS, Burns B, Goadsby PJ.
Randomized, double-blind placebo-controlled trial
of high-flow inhaled oxygen in acute cluster
headache. Cephalalgia. 2007;27:1188.
12. Law S, Derry S, Moore RA. Triptans for acute
cluster headache. Cochrane Database Syst Rev.
E10 JAMA Neurology Published online January 17, 2023 (Reprinted)
© 2023 American Medical Association. All rights reserved.
Management of Trigeminal Autonomic Cephalalgias Including Chronic Cluster
2013;2013(7):CD008042. doi:10.1002/14651858.
CD008042.pub3
13. Dodick D, Lipton RB, Martin V, et al; Triptan
Cardiovascular Safety Expert Panel. Consensus
statement: cardiovascular safety profile of triptans
(5-HT agonists) in the acute treatment of migraine.
Headache. 2004;44(5):414-425. doi:10.1111/j.1526-
4610.2004.04078.x
14. van Vliet JA, Bahra A, Martin V, et al. Intranasal
sumatriptan in cluster headache: randomized
placebo-controlled double-blind study. Neurology.
2003;60(4):630-633. doi:10.1212/01.WNL.
0000046589.45855.30
15. Cohen AS, Burns B, Goadsby PJ. High-flow
oxygen for treatment of cluster headache:
a randomized trial. JAMA. 2009;302(22):2451-2457.
doi:10.1001/jama.2009.1855
16. Dirkx THT, Haane DYP, Koehler PJ. Oxygen
treatment for cluster headache attacks at different
flow rates: a double-blind, randomized, crossover
study. J Headache Pain. 2018;19(1):94. doi:10.1186/
s10194-018-0917-4
17. Ekbom K, Monstad I, Prusinski A, Cole JA,
Pilgrim AJ, Noronha D; The Sumatriptan Cluster
Headache Study Group. Subcutaneous sumatriptan
in the acute treatment of cluster headache: a dose
comparison study. Acta Neurol Scand. 1993;88(1):
63-69. doi:10.1111/j.1600-0404.1993.tb04189.x
18. Hardebo JE, Dahlöf C. Sumatriptan nasal spray
(20 mg/dose) in the acute treatment of cluster
headache. Cephalalgia. 1998;18(7):487-489. doi:10.
1046/j.1468-2982.1998.1807487.x
19. Schuh-Hofer S, Reuter U, Kinze S, Einhäupl KM,
Arnold G. Treatment of acute cluster headache with
20 mg sumatriptan nasal spray: an open pilot study.
J Neurol. 2002;249(1):94-99. doi:10.1007/
PL00007854
20. Cittadini E, May A, Straube A, Evers S,
Bussone G, Goadsby PJ. Effectiveness of intranasal
zolmitriptan in acute cluster headache:
a randomized, placebo-controlled, double-blind
crossover study. Arch Neurol. 2006;63(11):1537-1542.
doi:10.1001/archneur.63.11.nct60002
21. Rapoport AM, Mathew NT, Silberstein SD, et al.
Zolmitriptan nasal spray in the acute treatment of
cluster headache: a double-blind study. Neurology.
2007;69(9):821-826. doi:10.1212/01.wnl.
0000267886.85210.37
22. Hedlund C, Rapoport AM, Dodick DW,
Goadsby PJ. Zolmitriptan nasal spray in the acute
treatment of cluster headache: a meta-analysis of
two studies. Headache. 2009;49(9):1315-1323.
doi:10.1111/j.1526-4610.2009.01518.x
23. Silberstein SD, Mechtler LL, Kudrow DB, et al;
ACT1 Study Group. Non-invasive vagus nerve
stimulation for the acute treatment of cluster
headache: findings from the randomized,
double-blind, sham-controlled ACT1 study. Headache.
2016;56(8):1317-1332. doi:10.1111/head.12896
24. Goadsby PJ, de Coo IF, Silver N, et al; ACT2
Study Group. Non-invasive vagus nerve stimulation
for the acute treatment of episodic and chronic
cluster headache: a randomized, double-blind,
sham-controlled ACT2 study. Cephalalgia. 2018;38
(5):959-969. doi:10.1177/0333102417744362
25. Schoenen J, Jensen RH, Lantéri-Minet M, et al.
Stimulation of the sphenopalatine ganglion (SPG)
for cluster headache treatment: pathway CH-1:
a randomized, sham-controlled study. Cephalalgia.
2013;33(10):816-830. doi:10.1177/0333102412473667
26. Goadsby PJ, Sahai-Srivastava S, Kezirian EJ,
et al. Safety and efficacy of sphenopalatine
ganglion stimulation for chronic cluster headache:
a double-blind, randomised controlled trial. Lancet
Neurol. 2019;18(12):1081-1090. doi:10.1016/
S1474-4422(19)30322-9
27. Ansarinia M, Rezai A, Tepper SJ, et al. Electrical
stimulation of sphenopalatine ganglion for acute
treatment of cluster headaches. Headache. 2010;
50(7):1164-1174. doi:10.1111/j.1526-4610.2010.01661.x
28. Jürgens TP, Barloese M, May A, et al. Long-term
effectiveness of sphenopalatine ganglion
stimulation for cluster headache. Cephalalgia. 2017;
37(5):423-434. doi:10.1177/0333102416649092
29. Barloese M, Petersen A, Stude P, Jürgens T,
Jensen RH, May A. Sphenopalatine ganglion
stimulation for cluster headache, results from a
large, open-label European registry. J Headache Pain.
2018;19(1):6. doi:10.1186/s10194-017-0828-9
30. Jürgens TP, Schoenen J, Rostgaard J, et al.
Stimulation of the sphenopalatine ganglion in
intractable cluster headache: expert consensus on
patient selection and standards of care. Cephalalgia.
2014;34(13):1100-1110. doi:10.1177/
0333102414530524
31. May A. The need for continued care after
sponsor closure. Lancet Neurol. 2020;19(3):205.
doi:10.1016/S1474-4422(20)30023-5
32. Gabai IJ, Spierings EL. Prophylactic treatment
of cluster headache with verapamil. Headache.
1989;29(3):167-168. doi:10.1111/j.1526-4610.1989.
hed2903167.x
33. Blau JN, Engel HO. Individualizing treatment
with verapamil for cluster headache patients.
Headache. 2004;44(10):1013-1018. doi:10.1111/j.1526-
4610.2004.04196.x
34. Petersen AS, Lund N, Jensen RH, Barloese M.
Real-life treatment of cluster headache in a tertiary
headache center: results from the Danish Cluster
Headache Survey. Cephalalgia. 2021;41(5):525-534.
doi:10.1177/0333102420970455
35. Ekbom K. Treatment of cluster headache:
clinical trials, design and results. Cephalalgia. 1995;
15(suppl 15):33-36.
36. Mathew NT, Kailasam J, Meadors L. Prophylaxis
of migraine, transformed migraine, and cluster
headache with topiramate. Headache. 2002;42(8):
796-803. doi:10.1046/j.1526-4610.2002.02183.x
37. Láinez MJ, Pascual J, Pascual AM, Santonja JM,
Ponz A, Salvador A. Topiramate in the prophylactic
treatment of cluster headache. Headache. 2003;43
(7):784-789. doi:10.1046/j.1526-4610.2003.03137.x
38. Leone M, Dodick D, Rigamonti A, et al.
Topiramate in cluster headache prophylaxis: an
open trial. Cephalalgia. 2003;23(10):1001-1002.
doi:10.1046/j.1468-2982.2003.00665.x
39. Huang WY, Lo MC, Wang SJ, Tsai JJ, Wu HM.
Topiramate in prevention of cluster headache in the
Taiwanese. Neurol India. 2010;58(2):284-287.
doi:10.4103/0028-3886.63784
40. Leandri M, Luzzani M, Cruccu G, Gottlieb A.
Drug-resistant cluster headache responding to
gabapentin: a pilot study. Cephalalgia. 2001;21(7):
744-746. doi:10.1046/j.1468-2982.2001.00260.x
41. Schuh-Hofer S, Israel H, Neeb L, Reuter U,
Arnold G. The use of gabapentin in chronic cluster
jamaneurology.com
Management of Trigeminal Autonomic Cephalalgias Including Chronic Cluster
headache patients refractory to first-line therapy.
Eur J Neurol. 2007;14(6):694-696. doi:10.1111/j.
1468-1331.2007.01738.x
42. Leone M, D’Amico D, Moschiano F, Fraschini F,
Bussone G. Melatonin versus placebo in the
prophylaxis of cluster headache: a double-blind
pilot study with parallel groups. Cephalalgia. 1996;
16(7):494-496. doi:10.1046/j.1468-2982.1996.
1607494.x
43. Pringsheim T, Magnoux E, Dobson CF, Hamel E,
Aubé M. Melatonin as adjunctive therapy in the
prophylaxis of cluster headache: a pilot study.
Headache. 2002;42(8):787-792. doi:10.1046/j.1526-
4610.2002.02181.x
44. Riesenberg R, Gaul C, Stroud CE, et al.
Long-term open-label safety study of
galcanezumab in patients with episodic or chronic
cluster headache. Cephalalgia. 2022;42(11-12):
1225-1235. doi:10.1177/03331024221103509
45. Wilbrink LA, de Coo IF, Doesborg PGG, et al;
ICON study group. Safety and efficacy of occipital
nerve stimulation for attack prevention in medically
intractable chronic cluster headache (ICON):
a randomised, double-blind, multicentre, phase 3,
electrical dose-controlled trial. Lancet Neurol. 2021;
20(7):515-525. doi:10.1016/S1474-4422(21)00101-0
46. Aibar-Durán JA, Álvarez Holzapfel MJ,
Rodríguez R, Belvis Nieto R, Roig Arnall C, Molet
Teixido J. Occipital nerve stimulation and deep
brain stimulation for refractory cluster headache:
a prospective analysis of efficacy over time.
J Neurosurg. Published online January 17, 2020.
doi:10.3171/2019.11.JNS192042
47. Miller S, Watkins L, Matharu M. Treatment of
intractable chronic cluster headache by occipital
nerve stimulation: a cohort of 51 patients. Eur J
Neurol. 2017;24(2):381-390. doi:10.1111/ene.13215
48. Leplus A, Fontaine D, Donnet A, et al; French
ONS registry group. Long-term efficacy of occipital
nerve stimulation for medically intractable cluster
headache. Neurosurgery. 2021;88(2):375-383.
doi:10.1093/neuros/nyaa373
49. Fontaine D, Christophe Sol J, Raoul S, et al.
Treatment of refractory chronic cluster headache
by chronic occipital nerve stimulation. Cephalalgia.
2011;31(10):1101-1105. doi:10.1177/0333102411412086
50. Xin B, Xie K, Luo G, Yao M. Long-term
follow-up safety and effectiveness of CT-guided
radiofrequency thermocoagulation of
sphenopalatine ganglion in refractory headache
treatment. Pain Ther. 2022;11(3):1011-1023. doi:10.
1007/s40122-022-00401-0
51. Gaul C, Diener HC, Silver N, et al; PREVA Study
Group. Non-invasive vagus nerve stimulation for
PREVention and Acute treatment of chronic cluster
headache (PREVA): a randomised controlled study.
Cephalalgia. 2016;36(6):534-546. doi:10.1177/
0333102415607070
52. Medrea I, Christie S, Tepper SJ, Thavorn K,
Hutton B. Effects of acute and preventive therapies
for episodic and chronic cluster headache:
a scoping review of the literature. Headache. 2022;
62(3):329-362. doi:10.1111/head.14284
53. Pompilio G, Migliore A, Integlia D. Systematic
literature review and Bayesian network
meta-analysis of episodic cluster headache drugs.
Eur Rev Med Pharmacol Sci. 2021;25(3):1631-1640.
doi:10.26355/eurrev_202102_24874
jamaneurology.com
© 2023 American Medical Association. All rights reserved.
54. Steiner TJ, Hering R, Couturier EG, Davies PT,
Whitmarsh TE. Double-blind placebo-controlled
trial of lithium in episodic cluster headache.
Cephalalgia. 1997;17(6):673-675. doi:10.1046/j.1468-
2982.1997.1706673.x
55. Goadsby PJ, Edvinsson L. Human in vivo
evidence for trigeminovascular activation in cluster
headache: neuropeptide changes and effects of
acute attacks therapies. Brain. 1994;117(Pt 3):
427-434. doi:10.1093/brain/117.3.427
56. Láinez MJA, Schoenen J, Stroud C, et al.
Tolerability and safety of galcanezumab in patients
with chronic cluster headache with up to 15 months
of galcanezumab treatment. Headache. 2022;62(1):
65-77. doi:10.1111/head.14234
57. Vukovic Cvetkovic V, Jensen RH.
Neurostimulation for the treatment of chronic
migraine and cluster headache. Acta Neurol Scand.
2019;139(1):4-17. doi:10.1111/ane.13034
58. Magis D, Gerardy PY, Remacle JM, Schoenen J.
Sustained effectiveness of occipital nerve
stimulation in drug-resistant chronic cluster
headache. Headache. 2011;51(8):1191-1201. doi:10.
1111/j.1526-4610.2011.01973.x
59. Mueller O, Diener HC, Dammann P, et al.
Occipital nerve stimulation for intractable chronic
cluster headache or migraine: a critical analysis of
direct treatment costs and complications.
Cephalalgia. 2013;33(16):1283-1291. doi:10.1177/
0333102413493193
60. Franzini A, Clerici E, Navarria P, Picozzi P.
Gamma knife radiosurgery for the treatment of
cluster headache: a systematic review. Neurosurg Rev.
2022;45(3):1923-1931. doi:10.1007/s10143-021-
01725-9
61. Leone M. Deep brain stimulation in headache.
Lancet Neurol. 2006;5(10):873-877. doi:10.1016/
S1474-4422(06)70575-0
62. Coppola G, Magis D, Casillo F, et al.
Neuromodulation for chronic daily headache. Curr
Pain Headache Rep. 2022;26(3):267-278. doi:10.
1007/s11916-022-01025-x
63. Dodick DW, Goadsby PJ, Ashina M, et al.
Challenges and complexities in designing cluster
headache prevention clinical trials: a narrative
review. Headache. 2022;62(4):453-472. doi:10.1111/
head.14292
64. Barloese MCJ, Beske RP, Petersen AS,
Haddock B, Lund N, Jensen RH. Episodic and
chronic cluster headache: differences in family
history, traumatic head injury, and chronorisk.
Headache. 2020;60(3):515-525. doi:10.1111/head.
13730
65. Moisset X, Giraud P, Meunier E, et al.
Ketamine-magnesium for refractory chronic cluster
headache: a case series. Headache. 2020;60(10):
2537-2543. doi:10.1111/head.14005
66. Lampl C, Rudolph M, Bräutigam E.
OnabotulinumtoxinA in the treatment of refractory
chronic cluster headache. J Headache Pain. 2018;
19(1):45. doi:10.1186/s10194-018-0874-y
67. Degirmenci Y, Kececi H. Can paroxysmal
hemicrania be bilateral? a case report. Neurol Sci.
2016;37(8):1377-1378.
doi:10.1007/s10072-016-2560-7
68. Pareja JA, Caminero AB, Franco E, Casado JL,
Pascual J, Sánchez del Río M. Dose, efficacy and
tolerability of long-term indomethacin treatment of
chronic paroxysmal hemicrania and hemicrania
(Reprinted) JAMA Neurology Published online January 17, 2023
Review Clinical Review & Education
continua. Cephalalgia. 2001;21(9):906-910. doi:10.
1046/j.1468-2982.2001.00287.x
69. Cittadini E, Matharu MS, Goadsby PJ.
Paroxysmal hemicrania: a prospective clinical study
of 31 cases. Brain. 2008;131(pt 4):1142-1155. doi:10.
1093/brain/awn010
70. Prakash S, Belani P, Susvirkar A, Trivedi A,
Ahuja S, Patel A. Paroxysmal hemicrania:
a retrospective study of a consecutive series of 22
patients and a critical analysis of the diagnostic
criteria. J Headache Pain. 2013;14(1):26. doi:10.
1186/1129-2377-14-26
71. Boes CJ, Dodick DW. Refining the clinical
spectrum of chronic paroxysmal hemicrania:
a review of 74 patients. Headache. 2002;42(8):
699-708. doi:10.1046/j.1526-4610.2002.02171.x
72. Mauritz MD, Enninger A, Wamsler C, Wager J,
Zernikow B. Long-term outcome of indomethacin
treatment in pediatric patients with paroxysmal
hemicrania: a case series. Children (Basel). 2021;8
(2):101. doi:10.3390/children8020101
73. Baraldi C, Pellesi L, Guerzoni S, Cainazzo MM,
Pini LA. Therapeutical approaches to paroxysmal
hemicrania, hemicrania continua and short lasting
unilateral neuralgiform headache attacks: a critical
appraisal. J Headache Pain. 2017;18(1):71. doi:10.
1186/s10194-017-0777-3
74. Kamourieh S, Lagrata S, Matharu MS.
Non-invasive vagus nerve stimulation is beneficial
in chronic paroxysmal hemicrania. J Neurol
Neurosurg Psychiatry. 2019;90(9):1072-1074.
doi:10.1136/jnnp-2018-319538
75. Tso AR, Marin J, Goadsby PJ. Noninvasive
vagus nerve stimulation for treatment of
indomethacin-sensitive headaches. JAMA Neurol.
2017;74(10):1266-1267. doi:10.1001/jamaneurol.
2017.2122
76. Prakash S, Patel P. Hemicrania continua: clinical
review, diagnosis and management. J Pain Res.
2017;10:1493-1509. doi:10.2147/JPR.S128472
77. Rozen TD. How effective is melatonin as a
preventive treatment for hemicrania continua? a
clinic-based study. Headache. 2015;55(3):430-436.
doi:10.1111/head.12489
78. Miller S, Correia F, Lagrata S, Matharu MS.
OnabotulinumtoxinA for hemicrania continua: open
label experience in 9 patients. J Headache Pain.
2015;16:19. doi:10.1186/s10194-015-0502-z
79. Trimboli M, Al-Kaisy A, Andreou AP, Murphy M,
Lambru G. Non-invasive vagus nerve stimulation for
the management of refractory primary chronic
headaches: a real-world experience. Cephalalgia.
2017;333102417731349. doi:10.1177/
0333102417731349
80. Marmura MJ. Intravenous lidocaine and
mexiletine in the management of trigeminal
autonomic cephalalgias. Curr Pain Headache Rep.
2010;14(2):145-150. doi:10.1007/s11916-010-0098-6
81. Lambru G, Stubberud A, Rantell K, Lagrata S,
Tronvik E, Matharu MS. Medical treatment of
SUNCT and SUNA: a prospective open-label study
including single-arm meta-analysis. J Neurol
Neurosurg Psychiatry. 2021;92(3):233-241. doi:10.
1136/jnnp-2020-323999
82. Weng HY, Cohen AS, Schankin C, Goadsby PJ.
Phenotypic and treatment outcome data on SUNCT
and SUNA, including a randomised
placebo-controlled trial. Cephalalgia. 2018;38(9):
1554-1563. doi:10.1177/0333102417739304
E11
 Clinical Review & Education Review
83. Miller S, Akram H, Lagrata S, Hariz M, Zrinzo L,
Matharu M. Ventral tegmental area deep brain
stimulation in refractory short-lasting unilateral
neuralgiform headache attacks. Brain. 2016;139
(Pt 10):2631-2640. doi:10.1093/brain/aww204
84. Miller S, Watkins L, Matharu M. Long-term
follow up of intractable chronic short lasting
unilateral neuralgiform headache disorders treated
with occipital nerve stimulation. Cephalalgia.
2018;38(5):933-942. doi:10.1177/0333102417721716
85. Lambru G, Lagrata S, Levy A, et al. Trigeminal
microvascular decompression for short-lasting
unilateral neuralgiform headache attacks. Brain.
2022;145(8):2882-2893. doi:10.1093/brain/awac109
86. Miller S, Lagrata S, Watkins L, Matharu M.
Occipital nerve stimulation for medically refractory
chronic paroxysmal hemicrania. Headache. 2017;57
(10):1610-1613. doi:10.1111/head.13187
87. Cittadini E, Goadsby PJ. Hemicrania continua:
a clinical study of 39 patients with diagnostic
implications. Brain. 2010;133(Pt 7):1973-1986.
doi:10.1093/brain/awq137
88. Mehta A, Chilakamarri P, Zubair A, Kuruvilla DE.
Hemicrania continua: a clinical perspective on
diagnosis and management. Curr Neurol Neurosci Rep.
2018;18(12):95. doi:10.1007/s11910-018-0899-2
89. Prakash S, Golwala P. A proposal for revision of
hemicrania continua diagnostic criteria based on
critical analysis of 62 patients. Cephalalgia. 2012;32
(11):860-868. doi:10.1177/0333102412452043
90. Prakash S, Shah ND. Delayed response of
indomethacin in patients with hemicrania continua:
E12 JAMA Neurology Published online January 17, 2023 (Reprinted)
© 2023 American Medical Association. All rights reserved.
Management of Trigeminal Autonomic Cephalalgias Including Chronic Cluster
real or phantom headache? Cephalalgia. 2010;30
(3):375-379. doi:10.1111/j.1468-2982.2009.01910.x
91. Summ O, Andreou AP, Akerman S, Holland PR,
Hoffmann J, Goadsby PJ. Differential actions of
indomethacin: clinical relevance in headache. Pain.
2021;162(2):591-599. doi:10.1097/j.pain.
0000000000002032
92. Fantini J, Koscica N, Zorzon M, Belluzzo M,
Granato A. Hemicrania continua with visual aura
successfully treated with a combination of
indomethacin and topiramate. Neurol Sci. 2015;36
(4):643-644. doi:10.1007/s10072-014-2036-6
93. Prakash S, Rana K. Topiramate as an
indomethacin-sparing agent in hemicrania
continua: a report of 2 cases. Headache. 2019;59
(3):444-445. doi:10.1111/head.13490
94. Guerrero AL, Herrero-Velázquez S, Peñas ML,
et al. Peripheral nerve blocks: a therapeutic
alternative for hemicrania continua. Cephalalgia.
2012;32(6):505-508. doi:10.1177/
0333102412439800
95. Miller S, Watkins L, Matharu MS. Treatment of
intractable hemicrania continua by occipital nerve
stimulation. J Neurol Neurosurg Psychiatry. 2017;88
(9):805-806. doi:10.1136/jnnp-2017-315747
96. Burns B, Watkins L, Goadsby PJ. Treatment of
hemicrania continua by occipital nerve stimulation
with a bion device: long-term follow-up of a
crossover study. Lancet Neurol. 2008;7(11):1001-1012.
doi:10.1016/S1474-4422(08)70217-5
97. Cohen AS, Matharu MS, Goadsby PJ.
Short-lasting unilateral neuralgiform headache
attacks with conjunctival injection and tearing
(SUNCT) or cranial autonomic features (SUNA)--
a prospective clinical study of SUNCT and SUNA.
Brain. 2006;129(Pt 10):2746-2760. doi:10.1093/
brain/awl202
98. Lambru G, Matharu MS. SUNCT, SUNA and
trigeminal neuralgia: different disorders or variants
of the same disorder? Curr Opin Neurol. 2014;27(3):
325-331. doi:10.1097/WCO.0000000000000090
99. Williams MH, Broadley SA. SUNCT and SUNA:
clinical features and medical treatment. J Clin
Neurosci. 2008;15(5):526-534. doi:10.1016/j.jocn.
2006.09.006
100. Yalın OO, Uludüz D, Özge A. Peripheral nerve
blocks for the treatment of short-lasting unilateral
neuralgiform headache with conjunctival injection
and tearing (SUNCT) during pregnancy. Agri. 2018;
30(1):28-30. doi:10.5505/agri.2016.25991
101. Hassan S, Lagrata S, Levy A, Matharu M,
Zrinzo L. Microvascular decompression or
neuromodulation in patients with SUNCT and
trigeminal neurovascular conflict? Cephalalgia.
2018;38(2):393-398. doi:10.1177/0333102417735847
102. Ornello R, Palmisani S, Murphy M, Sacco S,
Al-Kaisy A, Lambru G. Sphenopalatine ganglion
pulsed radiofrequency for the treatment of
refractory chronic SUNCT and SUNA: a prospective
case series. Headache. 2020;60(5):938-945.
doi:10.1111/head.13788
jamaneurology.com