-
7/29/2019 Acute and Preventive Pharmacologic Treatment of Cluster Headache
1/13
DOI 10.1212/WNL.0b013e3181eb58c82010;75;463Neurology
George J. Francis, Werner J. Becker and Tamara M. Pringsheimheadache
Acute and preventive pharmacologic treatment of cluster
September 25, 2011This information is current as of
http://www.neurology.org/content/75/5/463.full.html
located on the World Wide Web at:The online version of this article, along with updated information and services, is
rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.Allsince 1951, it is now a weekly with 48 issues per year. Copyright 2010 by AAN Enterprises, Inc.
is the official journal of the American Academy of Neurology. Published continuouslyNeurology
by guest on September 25, 2011www.neurology.orgDownloaded from
http://www.neurology.org/content/75/5/463.full.htmlhttp://www.neurology.org/content/75/5/463.full.htmlhttp://www.neurology.org/content/75/5/463.full.htmlhttp://www.neurology.org/http://www.neurology.org/http://www.neurology.org/http://www.neurology.org/content/75/5/463.full.html -
7/29/2019 Acute and Preventive Pharmacologic Treatment of Cluster Headache
2/13
Acute and preventive pharmacologictreatment of cluster headache
George J. Francis, BSc
Werner J. Becker, MD
Tamara M. Pringsheim,
MD
ABSTRACT
Cluster headache (CH) is a rare and disabling primary headache disorder. CH attacks are unilateral,
short, severe headaches associated with ipsilateral autonomic symptoms that occur in a periodic
fashion. We provide a systematic review and meta-analysis of existing trials of pharmacotherapy for
CH and evidence-based suggestions for acute abortive treatment and preventive therapy for cluster
headache. Prospective, double-blind, randomized controlled trials of any pharmacologic agent for the
symptomatic relief or prevention of CH were included in this evidence-based review. The main out-
comes considered were headache response and pain-free response at 15 and 30 minutes for acute
treatment trials, and the cessation of CH attacks within a specific time period or the number of days
on which CH attacks occurred for preventive trials. Twenty-seven trials were included in the analysis.
The American Academy of Neurology quality criteria were used to assess trial quality and to grade
advisements. Based on the evidence, for acute treatment of CH, Level A advice can be given forsubcutaneous sumatriptan 6 mg, zolmitriptan nasal spray 5 mg and 10 mg, and 100% oxygen 612
L/min. Level B advice can be given for sumatriptan nasal spray 20 mg and oral zolmitriptan 5 mg and
10 mg. For the prevention of CH, Level B advice can be given for intranasal civamide 100 g daily and
suboccipital steroid injections, andLevel C advicecan be given forverapamil 360mg, lithium 900mg,
and melatonin 10 mg.Neurology 2010;75:463473
GLOSSARYAAN American Academy of Neurology; AE adverse event; CH cluster headache; CI confidence interval; NS nasalspray; OR odds ratio; RCT randomized controlled trial; SC subcutaneous; SCHSG Sumatriptan Cluster HeadacheStudy Group.
The International Classification of Headache Disorders, 2nd edition,1 defines CH as at least 5
severe to very severe unilateral headache attacks, lasting 15 to180 minutes untreated. Attacksare accompanied by ipsilateral autonomic symptoms, restlessness, or agitation. Attack fre-quency ranges from 1 every other day to 8 per day. There are 2 types of CH: episodic CH and
chronic CH. Patients with episodic CH have attacks that occur in series lasting weeks ormonths separated by remission periods usually lasting months or years. Patients with chronicCH have attacks occurring for more than 1 year without remission or with remissions lastingless than 1 month. A total of 10% to 15% of patients with CH have chronic CH.1
The pathogenesis of CH is incompletely understood, although hypothalamic dysfunction issuspected.2 There is clinical evidence for altered biologic rhythms in patients with CH, and thetiming of attacks relates to the sleep-wake cycle in many patients.3 The uncertainty regarding
the pathogenesis of CH renders it difficult to aim treatments toward a specific target.Treatment of CH has 2 strategies: symptomatic therapy taken at the time of an attack, and
preventive therapy taken when the cluster bout begins to prevent further attacks. As CH causessignificant disability, the investigation of evidence-based medical treatments is warranted. We
present a systematic review and meta-analysis of treatment trials for CH and evidence-basedadvice for acute and preventive treatments of CH.
Editors Note: This article reflects the opinions of the authors and, unlike AAN evidence-based reviews, has not been endorsed by the AAN.
From the Department of Clinical Neurosciences, University of Calgary, Canada.
Disclosure: Author disclosures are provided at the end of the editorial.
Address correspondence and
reprint requests to Dr. Tamara
Pringsheim, Department of
Clinical Neurosciences, 2888
Shaganappi Trail NW, Calgary,
Alberta, T3B 6A8, Canada
Supplemental dataatwww.neurology.org
VIEWS & REVIEWS
Copyright 2010 by AAN Enterprises, Inc. 463by guest on September 25, 2011www.neurology.orgDownloaded from
http://www.neurology.org/http://www.neurology.org/http://www.neurology.org/http://www.neurology.org/ -
7/29/2019 Acute and Preventive Pharmacologic Treatment of Cluster Headache
3/13
OBJECTIVES/CLINICAL QUESTIONS
Which acute treatments for CH are effective in
reducing headache severity?
Which preventive treatments are effective in re-
ducing CH attacks?
CRITERIA FOR CONSIDERING STUDIES Stud-
ies were required to be prospective, double-blind,
parallel-group or crossover, randomized controlledtrials (RCTs) of any medication vs placebo or an-
other drug, for the symptomatic relief or prevention
of CH. Study participants were 18 or older with ei-
ther episodic CH or chronic CH.
For efficacy analysis, the following main out-
comes were considered:
1. Headache response at 15 or 30 minutes, defined
as a reduction in headache from moderate, severe,
or very severe to mild or no pain (symptomatic
trials)
2. Pain-free response at 15 or 30 minutes (symp-tomatic trials)
3. Cessation of CH attacks within a specific time
period (preventive trials)
4. Number of days on which a CH attack occurred
(preventive trials)
For the analysis of data on adverse events (AEs),
we considered the overall number of patients report-
ing AEs.
SEARCH METHODS FOR IDENTIFICATION OF
STUDIES MEDLINE (1950 to June 2009) andEMBASE (1980 to June 2009) databases were
searched for double-blind RCTs (see appendix e-1
on the Neurology Web site at www.neurology.org
for detailed search strategy).
METHODS OF REVIEW Two reviewers (T.P. and
G.J.F.) independently screened titles and abstracts
for trials fulfilling inclusion criteria. Data were ab-
stracted independently by the reviewers and con-
firmed for accuracy. Discrepancies between reviewers
were resolved by discussion.
The studies were evaluated using quality criteriadeveloped by the American Academy of Neurology
(AAN)4 (see appendix e-2). Suggestions were made
according to the AAN grades for classification of rec-
ommendations (see appendix e-3).
SUMMARIZING THE RESULTS Meta-analysis was
performed by treatment type. Odds ratios (OR) were
calculated with 95% confidence intervals (CI). ORs
from multiple studies were tested for homogeneity
using the 2 test and by calculating the I2 statistic. If
study estimates were homogenous, they were com-
bined using a fixed-effects model. When studies with
heterogeneous results were clinically similar, the
study estimates were combined using a random-
effects model. Clinical heterogeneity was assessed by
looking at trial and patient characteristics, and out-
come measures. Clinically heterogeneous studies
were not statistically combined.
DESCRIPTION OF STUDIES A total of 1,547 ab-
stracts were found by the combined searches (see the
figure for flow diagram). A total of 1,499 abstracts
did not meet inclusion criteria. Forty-nine full-text
articles were reviewed. Twenty-three did not meet
inclusion criteria (see appendix e-4). The remaining
26 studies were included in the analysis: 11 on acute
treatment of CH,5-15 14 on prevention of CH,16-29
and 1 on both acute treatment and prevention of
CH.30 The MEDLINE search was re-executed prior
to final revision of the manuscript (February 1,
2010). This revealed 22 more abstracts published
since the original search. One abstract met inclusioncriteria and was included in the study,31 giving a total
of 27 studies in the analysis.
RCTs for acute treatment of CH had similar inclu-
sion criteria. Studies included patients 18 to 65 years of
age, with a history of episodic CH or chronic CH, and
attacks of 45 minutes minimum duration untreated.
Trials using triptans excluded patients with heart dis-
ease, uncontrolled hypertension, or concomitant use of
ergotamine or monoamine oxidase inhibitors. The
most common endpoints used were the headache re-
sponse or pain-free response at 30 minutes. A summary
of the trial characteristics, methodologic flaws, and re-
sults can be seen in table 1.
Inclusion criteria for RCTs studying prevention of
CH included patients with at least 1 cluster period last-
ing at least 1 month prior to the study. Patients were in
a cluster period for no more than 10 days, with an ex-
pected remainder of cluster period of no less than 20
days. Specifically excluded were patients with cardiovas-
cular, pulmonary, hepatic, or renal disease, as well as
patients who were pregnant or currently taking prophy-
lactic CH medication. The primary endpoint for stud-
ies was a reduction in the number of headaches duringthe period of study medication use, in comparison to a
run-in period with no CH prophylaxis. A summary of
the trial characteristics, methodologic flaws, and results
can be seen in table 2.
RESULTS Acute treatment. Which acute treatments
for CH are effective in reducing pain? (See table 3 for
an advice summary.)
Sumatriptan. Three RCTs compare sumatriptan
to placebo, all meeting AAN Class I criteria.5-7 Ek-
bom et al.5 and The Sumatriptan Cluster Head-
464 Neurology 75 August 3, 2010 by guest on September 25, 2011www.neurology.orgDownloaded from
http://www.neurology.org/http://www.neurology.org/http://www.neurology.org/http://www.neurology.org/http://www.neurology.org/ -
7/29/2019 Acute and Preventive Pharmacologic Treatment of Cluster Headache
4/13
ache Study Group6 (SCHSG) performed crossover
studies of sumatriptan 6 mg subcutaneous injec-
tion (SC) vs placebo for 2 attacks. The study by
Ekbom et al. also assessed sumatriptan 12 mg. van
Vliet et al.7 performed a 2-group crossover study
of sumatriptan 20 mg nasal spray (NS) vs placebo
for 2 CH attacks. Only the Ekbom et al. and the
SCHSG studies were combined statistically, as
both these trials used sumatriptan SC.
Sumatriptan SC 6 mg or 12 mg. Headache response at15 minutes: the 2 studies included 258 CH at-
tacks.5,6 Meta-analysis using a random effects model
gave a summary OR of 6.22 in favor of sumatriptan
(95% CI 3.6110.72, p 0.00001). No difference
was found between the 2 sumatriptan doses. The
most common AEs reported were injection site reac-
tions, nausea and vomiting, dizziness, fatigue, and
paraesthesias.
Sumatriptan NS 20 mg. Headache response at 30 min-
utes: this crossover study included 83 patients. Two at-
tacks were treated with sumatriptan 20 mg NS or
placebo.7 Sumatriptan was superior to placebo, as 57%
of patients reported headache relief with sumatriptan
compared to 26% with placebo (p 0.002). The most
frequent AE reported was a bitter taste following use of
the nasal spray in 21% of patients.
Sumatriptan SC should be offered to patients for
acute treatment of CH (Level A). Sumatriptan NS
should be considered for acute treatment of CH
(Level B).
Zolmitriptan. Three RCTs compare zolmitriptanto placebo, all meeting AAN Class I criteria.8-10
Two are crossover studies8,9 comparing zolmi-
triptan NS 5 mg and 10 mg to placebo. The
other10 compares oral zolmitriptan 5 mg and 10
mg to placebo.
Zolmitriptan NS, 5 and 10 mg. Headache response at
30 minutes: Both studies used a primary efficacy
analysis of headache response at 30 minutes, includ-
ing 451 CH attacks.8,9 Meta-analysis using a random
effects model found a summary OR of 5.03 (95% CI
2.819.01, p 0.00001) for zolmitriptan 10 mg
Figure PRISMA flow diagram
Neurology 75 August 3, 2010 465by guest on September 25, 2011www.neurology.orgDownloaded from
http://www.neurology.org/http://www.neurology.org/http://www.neurology.org/http://www.neurology.org/ -
7/29/2019 Acute and Preventive Pharmacologic Treatment of Cluster Headache
5/13
http://www.neurology.org/ -
7/29/2019 Acute and Preventive Pharmacologic Treatment of Cluster Headache
6/13
http://www.neurology.org/ -
7/29/2019 Acute and Preventive Pharmacologic Treatment of Cluster Headache
7/13
and 2.61 (95% CI 1.474.61, p 0.001) for zolmi-
triptan 5 mg. The most common AEs reported were
bad taste (22%), nasal cavity discomfort (12%), and
somnolence (8%).Zolmitriptan oral, 5 and 10 mg. Headache response at
30 minutes: a single crossover study investigated
oral zolmitriptan 10 mg and 5 mg vs placebo for 3
attacks in 102 patients.10 Both doses of zolmi-
triptan doses were superior to placebo in patients
with episodic CH (p 0.05), but not those with
chronic CH. The most common AEs reported
were paraesthesia, heaviness, asthenia, nausea, diz-
ziness, and nonchest tightness.
Zolmitriptan NS should be offered to patients for
acute treatment of CH (Level A). Oral zolmitriptan
should be considered for acute treatment of episodic
CH (Level B).
Oxygen. Two Class I crossover studies have investi-
gated 100% oxygen vs placebo for the acute treat-ment of CH. Fogans study11 evaluated 100%
oxygen vs placebo (regular air), at a rate of 6 L/min
for up to 15 minutes during an acute attack. Nine-
teen patients treated up to 6 attacks. The primary
endpoint was headache relief following treatment. A
total of 56% of patients breathing oxygen perceived
substantial headache relief, compared with 7% of
those treated with placebo (p 0.01). AEs were not
reported.
A more recent study by Cohen et al.31 assessed
100% oxygen at 12 L/min for 15 minutes vs regular
Table 3 Summary of advisements for acute abortive treatment of cluster headache
Maneuver Effectiveness Levels of evidence Advice
Sumatriptan(subcutaneous)
Directevidencethat sumatriptan6mg iseffectivein improving headacheresponse in CH.Nonseriousadverseevents: injection site reactions,nauseaandvomiting, dizziness, fatigue,paresthesias.
Two randomized, controlledclinical trials; 2 AANClassI
LevelA: shouldbe offered foracute treatmentof CH
Zolmitriptan (nasalspray)
Directevidencethat zolmitriptan5mgand10 mgareeffective in improving
headache response in CH.Nonseriousadverse events: unpleasant taste, nasalcavity discomfort, somnolence,dizziness, nausea, throat/neck tightness.
Two randomized, controlledclinical trials; 2 AANClassI
LevelA: shouldbe offered foracute treatmentof CH
Sumatriptan (nasalspray)
Direct evidence thatsumatriptan 20mgis effectivein improvingheadacheresponse in CH.Nonseriousadverseevent: bittertaste.
One randomized, controlledclinical trial;AANClass I
LevelB: shouldbe consideredforacutetreatment ofCH
Zolmitriptan (oral) Directevidencethat zolmitriptan5mgand10 mgareeffective in improvingheadache response in CH.Nonseriousadverse events: paresthesias, heaviness,asthenia, nausea, dizziness,nonchesttightness.
One randomized, controlledclinical trial;AANClass I
LevelB: shouldbe consideredforacutetreatment ofCH
Oxygen Directevidencethat100%oxygen612L/min is effectivein improvingheadache response in CH.Adverseevents not reported.
Two randomized, controlledclinical trials; AANClassI
LevelA: shouldbe offered foracute treatmentof CH
Cocaine/lidocaine Evidence that10%cocainehydrochloride and10%lidocaineareeffectivein improving headacheresponse in CH.Nonseriousadverseevents: nasal congestion,unpleasantlidocaine taste.
One randomized, controlledclinical trial;AANClass II
LevelC:maybe consideredforacutetreatment ofCH
Octreotide Evidence thatoctreotide100g iseffectivein improving headacheresponse in CH.Nonseriousadverseevents: injection site reactions,diarrhea,abdominal bloating, nausea, dullbackgroundheadache,lethargy.
One randomized, controlledclinical trial;AANClass II
LevelC:maybe consideredforacutetreatment ofCH
Dihydroergotamine(nasal spray)
Insufficient evidence thatdihydroergotamine1 mg intranasally iseffectivein improving headacheresponse inCH.Adverseevents notreported.
One randomized, controlledclinical trial;AANClass III
LevelU: insufficient evidenceto advisefor theacutetreatmentof CH
Somatostatin Insufficient evidence thatsomatostatin25g is effectivein improvingheadacheresponse in CH.Nonseriousadverseevent: nausea without vomiting.
One randomized, controlledclinical trial;AANClass III
LevelU: insufficient evidenceto advisefor theacutetreatmentof CH
Prednisone Insufficient evidence thatprednisone30mg is effective in improvingheadacheresponse inCH.
One randomized, controlledclinical trial;AANClass III
LevelU: insufficient evidenceto advisefor theacutetreatmentof CH
Abbreviations:AANAmericanAcademy ofNeurology; CH cluster headache.
468 Neurology 75 August 3, 2010 by guest on September 25, 2011www.neurology.orgDownloaded from
http://www.neurology.org/http://www.neurology.org/http://www.neurology.org/http://www.neurology.org/http://www.neurology.org/ -
7/29/2019 Acute and Preventive Pharmacologic Treatment of Cluster Headache
8/13
air for the acute treatment of CH. Patients treated 4
attacks, 2 with each treatment, in a crossover fashion.
The primary endpoint was pain-free response at 15
minutes. Patients were pain-free at 15 minutes in
78% of attacks treated with oxygen, compared to
20% of attacks treated with air (p 0.001). No
serious adverse events occurred.
One hundred percent oxygen should be offered
for acute treatment of CH (Level A).
Cocaine/lidocaine. One Class II RCT assessed cocaine
intranasal vs lidocaine intranasal and placebo.12 The
study was a parallel-group design with 9 patients re-
ceiving 4050 mg of either10% cocaine hydrochlo-
ride, 10% lidocaine, or placebo intranasally for 1
nitroglycerin-induced headache. The primary endpoint
was the time elapsed until obtaining pain relief. On av-
erage, complete cessation of pain occurred after 31.3
minutes for cocaine, 37.0 minutes for lidocaine, and
59.3 minutes for saline (p 0.01 for both study medi-
cations). The most common side effects were nasal con-
gestion following study medication administration aswell as unpleasant taste of lidocaine.
Intranasal cocaine and lidocaine may be consid-
ered for acute treatment of CH (Level C).
Octreotide. One Class II crossover study evaluated
subcutaneous octreotide in 57 patients for the treat-
ment of 2 CH attacks.13 The primary endpoint was
headache response at 30 minutes. A total of 52% of
patients treated with octreotide reported headache relief
in 30 minutes, compared to 36% of patients treated
with placebo (p 0.007). Eight patients taking oct-
reotide reported diarrhea, abdominal bloating, or nau-
sea. Other AEs included a dull background headache,lethargy, and injection-site reactions.
Octreotide may be considered for acute treatment
of CH (Level C).Dihydroergotamine, ergotamine, somatostatin, and
prednisone. There are single Class III RCTs investigat-
ing dihydroergotamine NS,14 IM ergotamine,15 IV
somatostatin,15 and prednisone30 for the acute treat-
ment of CH. While all of these trials reported symp-
tomatic benefit, these studies had important
methodologic limitations, preventing evidence-based
advice to be given.
There is insufficient evidence to advise the use of
dihydroergotamine, ergotamine, somatostatin, and
prednisone for the acute treatment of CH (Level U).
Preventive treatment. Which preventive treatments
for CH are effective in reducing headache frequency,
duration, and pain? See table 4 for a summary of
suggestions.
Civamide. One Class I RCT investigated civamide
intranasal vs placebo16 for cluster prophylaxis. A total
of 28 patients received either 100 L of 0.025% civ-
amide into each nostril daily or placebo for 7 days.
Patients were observed for 20 days posttreatment.
The primary endpoint was change in frequency of
CH attacks per week during the observation period.
For the first 7 days of observation, patients taking
civamide had a greater decrease in the number of
headaches compared to the placebo group (55.5%
vs 25.9%; p 0.03) and a greater decrease for the
entire posttreatment period that approached signifi-
cance (61.4% vs 30.9%; p 0.054). The most
common reported AEs were nasal burning (78%),
lacrimation (50%), pharyngitis (44%), and
rhinorrhea (33%).
Intranasal civamide should be considered for the
prevention of CH (Level B).
Suboccipital steroid injection. There is 1 Class I RCT
investigating suboccipital steroid injections vs plac-
ebo.17 The study medication consisted of 12.46 mg
betamethasone dipropionate and 5.26 mg beta-
methasone disodium phosphate mixed with 0.5 mL
Xylocaine 2%. A total of 23 patients participated in
the study. The primary endpoint was the disappear-ance of CH attacks within 72 hours. A total of 85%
of patients in the study group had relief of attacks by
72 hours, compared to 0% of patients in the placebo
group (p 0.0001). Two patients reported transient
pain at the injection site.
Suboccipital steroid injection should be consid-
ered for the prevention of CH (Level B).
Sumatriptan, sodium valproate. There are single
Class I RCTs on the use of oral sumatriptan 100 mg
3 times18 daily and sodium valproate 500 mg19 vs
placebo for the prevention of CH. Neither of these
treatments resulted in a significant decrease in CH
attacks.
Sumatriptan and sodium valproate are not ad-
vised for the prevention of CH (Level B).
Lithium. There is 1 Class II RCT comparing lith-
ium 800 mg daily to placebo20 in patients with epi-
sodic CH, and one Class II RCT comparing lithium
900 mg daily to verapamil24 in patients with chronic
CH. The parallel-group study comparing lithium to
placebo assessed the percentage of patients in whom
attacks ceased within 1 week as the primary outcome.
A secondary endpoint was the percentage of patientswho were substantially better subjectively within 1
week. There was no difference in the percentage of
patients having cessation of attacks in the lithium
group (15%) compared to the placebo group (14%).
More patients, however, felt substantially better in
the lithium group (70%) than in the placebo group
(43%), though significance was not calculated. The
common AE reported by patients was polyuria.
Bussone et al.24 compared verapamil 360 mg
daily for 8 weeks to lithium 900 mg daily in a
Class II study. Thirty patients with chronic CH
Neurology 75 August 3, 2010 469by guest on September 25, 2011www.neurology.orgDownloaded from
http://www.neurology.org/http://www.neurology.org/http://www.neurology.org/http://www.neurology.org/ -
7/29/2019 Acute and Preventive Pharmacologic Treatment of Cluster Headache
9/13
participated in this crossover study, and outcomesincluded the intensity, frequency, and duration of
attacks during the trial period. A total of 50% of
patients in the verapamil group and 37% of those
in the lithium group experienced an improvement
in the headache index, compared to the run-in pe-
riod (p 0.01).
Lithium may be considered for the prevention of
CH (Level C).
Melatonin. There is 1 Class II RCT on melatonin
for cluster prevention.21 This placebo-controlled,
parallel-group trial of 20 patients investigated mela-
tonin 10 mg daily vs placebo for 2 weeks. In compar-ison to the run-in period, there was a reduction in
daily headache frequency in the melatonin group
(p 0.03), but not the placebo group. Adverse
events were not reported.
Melatonin may be considered for the prevention
of CH (Level C).
Misoprostol, 100% hyperbaric oxygen. There are single
Class II RCTs evaluating misoprostol22 and 100%
hyperbaric oxygen23 for the prevention of CH. Nei-
ther treatment resulted in a significant decrease in
CH attacks.
Table 4 Summary of advisements for preventivetreatment of cluster headache
Maneuver Effectiveness Levels of evidence Advice
Civamide Direct evidence thatcivamide100L iseffectivein improvingheadache responsein CH.Nonseriousadverseevents: nasalburning, lacrimation, pharyngitis,rhinorrhea.
One randomized,controlledclinical trial;AANClass I
Level B:shouldbe consideredforthe prevention ofCH
Suboccipitalsteroid injection
Direct evidence that long-and rapid-actingsteroids2.5mL areeffective in improvingheadache response in CH.Nonserious
adverse event: transient injection sitepain.
One randomized,controlledclinical trial;AANClass I
Level B:shouldbe consideredforthe prevention ofCH
Sodium valproate Direct evidence thatsodiumvalproate500mg is noteffective in improvingheadacheresponse inCH.Adverseevents notreported.
One randomized,controlledclinical trial;AANClass I
Level B:not advised forthepreventionof CH
Sumatriptan Direct evidence thatsumatriptan 100mgis noteffective in improvingheadacheresponse in CH.Nonseriousadverseevents: nausea, vomiting, headache,malaise.
One randomized,controlledclinical trial;AANClass I
Level B:not advised forthepreventionof CH
Melatonin Evidence that melatonin10 mg is effectivein improvingheadacheresponsein CH.Nonseriousadverseevents: nonereported.
One randomized,controlledclinical trial;AANClass II
Level C:maybe consideredforthe prevention ofCH
Verapamil Evidence that verapamil360mg iseffectivein improvingheadache responsein CH.Nonseriousadverseevents:constipation, reducedbloodpressure,
reduced heartrate.
Two randomized, controlledclinical trials; 1 AANClassII,1 AANClass III
Level C:maybe consideredforthe prevention ofCH
Cimetidine/chlorpheniramine
Evidence thatcimetidine2,000mg andchlorpheniramine20 mg arenot effectivein improvingheadacheresponsein CH.Nonseriousadverseevents: transient,erythematous skin rash. Otheradverseevents not reported.
Two randomized, controlledclinical trials; 2 AANClassII
Level C: notadvised forthepreventionof CH
Lithium Evidence that lithium900mg is effectivein improvingheadacheresponsein CH.Nonseriousadverseevent: polyuria.
Two randomized, controlledclinical trials; 2 AANClassII
Level C:maybe consideredforthe prevention ofCH
Misoprostol Evidence thatmisoprostol300g isnoteffectivein improvingheadache responseinCH.Adverseevents notreported.
One randomized,controlledclinical trial;AANClass II
Level C: notadvised forthepreventionof CH
Oxygen Evidence that100%hyperbaric oxygen isnot effectivein improving headacheresponse inCH.Adverseevents not
reported.
One randomized,controlledclinical trial;AANClass II
Level C: notadvised forthepreventionof CH
Capsaicin Insufficient evidence thatcapsaicin iseffectivein improvingheadache responseinCH.Adverseevents notreported.
One randomized,controlledclinical trial;AANClass III
LevelU: insufficient evidenceto advisefor thepreventionofCH
Nitrate tolerance Insufficient evidence thatnitrate tolerancevia5-ISMN 30mg is effectivein improvingheadache response in CH.Adverse eventsnot reported.
One randomized,controlledclinical trial;AANClass III
LevelU: insufficient evidenceto advisefor thepreventionofCH
Prednisone Insufficient evidence thatprednisone20mgeveryother dayis effectiveinimprovingheadache response in CH.Adverseevents not reported.
One randomized,controlledclinical trial;AANClass III
LevelU: insufficient evidenceto advisefor thepreventionofCH
Abbreviations:AANAmericanAcademy ofNeurology; CH cluster headache.
470 Neurology 75 August 3, 2010 by guest on September 25, 2011www.neurology.orgDownloaded from
http://www.neurology.org/http://www.neurology.org/http://www.neurology.org/http://www.neurology.org/http://www.neurology.org/ -
7/29/2019 Acute and Preventive Pharmacologic Treatment of Cluster Headache
10/13
Misoprostol and 100% hyperbaric oxygen are not
advised for the prevention of CH (Level C).
Verapamil. There are 2 RCTs investigating the use
of verapamil as a preventive medication for CH.24,25
Bussone et al.24 compared verapamil 360 mg daily for
8 weeks to lithium 900 mg daily in an AAN Class II
study (results reported in Lithium section). Leone et
al.25 studied verapamil 360 mg daily vs placebo for 2
weeks in 30 patients in an AAN Class III study. The
primary endpoint was the reduction in attack fre-
quency per week. Verapamil was found to be supe-
rior to placebo, with patients taking verapamil
experiencing 0.6 attacks per day, compared to 1.65
per day in the placebo group (p 0.001). Reported
AEs included constipation, reduced blood pressure,
and reduced heart rate.
Verapamil may be considered for the prevention
of CH (Level C).
Cimetidine/chlorpheniramine. Two Class III RCTs
have investigated the effect of cimetidine, an H2 an-
tagonist, vs placebo.26,27
One of these studies addi-tionally looked at chlorpheniramine, an H1
antagonist, vs placebo. Neither of these studies found
any benefit from the use of these treatments for the
prevention of cluster attacks.
Cimetidine and chlorpheniramine are not advised
for the prevention of CH (Level C).
Capsaicin, nitrate tolerance, prednisone. There are sin-
gle Class III RCTs on the use of capsaicin intranasal
cream,28 nitrate tolerance,29 and oral prednisone30 for
the prevention of CH. While the capsaicin study re-
ported less severe headaches in the treatment group
and the prednisone study reported more frequent at-
tacks in the placebo group, all studies had important
methodologic limitations.
There is insufficient evidence to advise the use of
intranasal capsaicin, nitrate tolerance, and pred-
nisone for the prevention of CH (Level U).
DISCUSSION The treatment of CH is largely phar-
macologic, although behavioral modification can
play a role in some patients, and surgical treatment
options are available for patients who do not respond
satisfactorily to drug treatment. Not all medicationswhich are used widely for CH based on clinical expe-
rience have been adequately studied using modern
clinical trial methodology. This review focused ex-
clusively on double-blind RCTs as such trials provide
the best evidence for therapeutic efficacy. Based on
the quality of published trials, verapamil receives a
Grade C rating. It is important to note, however,
that verapamil is generally considered to be the main-
stay of CH preventive therapy.32 Clinical experience
with both verapamil and lithium as preventive treat-
ments for CH is extensive. While both agents only
received Grade C ratings due to trial quality, they are
used much more routinely in clinical practice than
civamide, which, as a newer treatment, has only been
evaluated in 1 trial.
The evidence for the efficacy of lithium for the
prevention of CH is stronger for patients with
chronic CH than those with episodic CH. While
side effects reported in both trials were minimal,20,24
long-term use of lithium has been associated with
tremor, hypothyroidism, and nephrogenic diabetic
insipidus. Monitoring of serum lithium levels and
thyroid and renal function is recommended in pa-
tients on long-term therapy.33
The serotonin inhibitor methysergide has been
recommended for the prevention of CH in previous
guidelines,34 although no placebo-controlled,
double-blind studies of this treatment have been
completed. We have not advised methysergide for
several reasons in addition to the lack of controlled
studies. Methysergide is not available in the United
States, and has been associated with the developmentof pulmonary and retroperitoneal fibrosis, and there-
fore treatment must be limited to 6 months.35,36 In
addition, methysergide should not be coadminis-
tered with triptans or ergots,37 and sumatriptan and
zolmitriptan are standard symptomatic treatments
for CH. We recognize that there may be special clin-
ical scenarios in which the use of methysergide may
be appropriate but believe that general endorsements
for use of this drug should be avoided.
The use of a short course of steroids to stop a
cluster bout is common and, based upon clinical ex-
perience, effective. It is recommended in previous
guidelines.34 However, aside from the trial that ex-
amined the efficacy of suboccipital steroid injec-
tion,17 only 1 Class III RCT of steroids in CH has
been performed.30
Conceptually, one can consider some of the med-
ications used in CH as transitional preventive treat-
ments. Transitional treatments are medications that
are started with longer-term preventive drugs. Their
function is to stop the CH attacks almost immedi-
ately, and to maintain this pain relief until the dose
of the longer-term preventive drug can be increasedand becomes effective.38 Most transitional therapies
have not been subjected to rigorous clinical trials, but
are commonly used in clinical practice. They include
oral steroids (prednisone 60 mg daily for 3 days, then
decreased by 10 mg every 3 days for a total of 18 days
of therapy)39 and dihydroergotamine (1 mg SC/IM
twice a day for several days).39 Ergotamine tartrate 1
or 2 mg given once daily or in divided doses has also
been used for transitional therapy.39 Suboccipital ste-
roid injections might also be considered transitional
therapy.38,39 Transitional therapies are especially ap-
Neurology 75 August 3, 2010 471by guest on September 25, 2011www.neurology.orgDownloaded from
http://www.neurology.org/http://www.neurology.org/http://www.neurology.org/http://www.neurology.org/ -
7/29/2019 Acute and Preventive Pharmacologic Treatment of Cluster Headache
11/13
propriate for patients who present with a high fre-
quency of attacks.
Finally, in refractory patients prophylactics are of-
ten used in combination. For example, verapamil
prophylaxis may be combined with lithium in an at-
tempt to control intractable cluster headaches32 even
though there is no evidence base for this practice.
CONCLUSION For the acute treatment of CH at-
tacks, Level A advice can be given for the use ofsumatriptan SC 6 mg, intranasal zolmitriptan 5 and
10 mg, and 100% oxygen. Level B advice can be
given for the use of intranasal sumatriptan 20 mg and
oral zolmitriptan 5 and 10 mg. Level C advice can be
given for intranasal 10% cocaine, intranasal 10% li-
docaine, and subcutaneous octreotide 100 g.
For the prevention of CH attacks during a cluster
bout, Level B advice can be given for intranasal civ-
amide 100 L and suboccipital steroid injection.
Level C advice can be given for melatonin 10 mg,
verapamil 360 mg, and lithium 900 mg.Several new treatments are emerging for the pre-
vention of CH. Open-label and pilot studies have
been conducted with topiramate40 and gabapentin.41
Deep brain stimulation42-44 and occipital nerve stim-
ulation45 have also been assessed with small trials in
medically refractory patients. In the future, there
may be a greater number of evidence-based treat-
ment options for the prevention of CH.
When patients present with a new cluster bout, it is
appropriate to initiate both acute symptomatic therapy
and preventive therapy. Choosing between recom-
mended treatments should be based on headache fre-quency, patient comorbidities, and side effects.
AUTHOR CONTRIBUTIONS
Statistical analysis was conducted by Dr. Tamara Pringsheim.
DISCLOSURE
Dr. Francis reports no disclosures. Dr. Becker has served on medical advi-
sory boards for Merck Serono, Pfizer Inc., Allergan, Inc., AGA Medical
Corporation, and Teva Pharmaceutical Industries Ltd.; has been a local PI
for clinical trials for Merck Serono, Allergan, Inc., Medtronic, Inc., and
AGA Medical Corporation; and has received speaker honoraria from
Merck Serono, AGA Medical Corporation, and Pfizer Inc. Dr. Pring-
sheim has served on a scientific advisory board for Pfizer Inc. and has
received speaker honoraria from Shire Canada, Pfizer Inc., and Teva Phar-
maceutical Industries Ltd.
Received December 29, 2009. Accepted in final form April 22, 2010.
REFERENCES
1. Headache Classification Subcommittee of the Interna-
tional Headache Society. The International Classification
of Headache Disorders, 2nd edition. Cephalalgia 2004;
24(suppl 1):1160.
2. Bussone G. Cluster headache: from treatment to patho-
physiology. Neurol Sci 2008;29(suppl 1):S1S6.
3. Pringsheim T. Cluster headache: evidence for a disorder of
circadian rhythm and hypothalamic function. Can J Neu-
rol Sci 2002;29:3340.
4. Edlund W, Gronseth G, So Y, Franklin G. Clinical Prac-
tice Guideline Process Manual. St. Paul: American Acad-
emy of Neurology; 2004:157.
5. Ekbom K, Monstad I, Prusinski A, Cole JA, Pilgrim AJ,
Noronha D. Subcutaneous sumatriptan in the acute treat-
ment of cluster headache: a dose comparison study. Acta
Neurol Scand 1993;88:6369.
6. The Sumatriptan Cluster Headache Study Group. Treat-ment of acute cluster headache with sumatriptan. N Engl
J Med 1991;325:322326.
7. van Vliet JA, Bahra A, Martin V, et al. Intranasal sumatriptan
in cluster headache. Neurology 2003;60:630633.
8. Rapoport AM, Mathew NT, Silberstein SD, et al. Zolmi-
triptan nasal spray in the acute treatment of cluster head-
ache. Neurology 2007;69:821826.
9. Cittadini E, May A, Straube A, Evers S, Bussone G,
Goadsby PJ. Effectiveness of intranasal zolmitriptan in
acute cluster headache. Arch Neurol 2006;63:15371542.
10. Bahra A, Gawel MJ, Hardebo JE, Millson D, Breen SA,
Goadsby PJ. Oral zolmitriptan is effective in the acute
treatment of cluster headache. Neurology 2000;54:18321839.
11. Fogan L. Treatment of cluster headache: a double blind
comparison of oxygen v. air inhalation. Arch Neurol 1985;
42:362363.
12. Costa A, Pucci E, Antonaci F, et al. The effect of intranasal
cocaine and lidocaine on nitroglycerin-induced attacks in
cluster headache. Cephalalgia 2000;20:8591.
13. Matharu MS, Levy MJ, Meeran K, Goadsby PJ. Subcuta-
neous octreotide in cluster headache: randomized placebo-
controlled double-blind crossover study. Ann Neurol
2004;56:488494.
14. Andersson PG, Jespersen LT. Dihydroergotamine nasal
spray in the treatment of attacks of cluster headache.Cephalalgia 1986;6:5154.
15. Sicuteri F, Geppetti P, Marabini S, Lembeck F. Pain relief
by somatostatin in attacks of cluster headache. Pain 1984;
18:359365.
16. Saper JR, Klapper J, Mathew NT, Rapoport A, Phillips
SB, Bernstein JE. Intranasal civamide for the treatment of
episodic cluster headaches. Arch Neurol 2002;59:990
994.
17. Ambrosini A, Vandenheede M, Rossi P, et al. Suboccipital
injection with a mixture of rapid- and long-acting steroids
in cluster headache: a double-blind placebo-controlled
study. Pain 2005;118:9296.
18. Monstad I, Krabbe A, Micieli G, et al. Preemptive oral
treatment with sumatriptan during a cluster period. Head-
ache 1995;35:607613.
19. El Amrani M, Massiou H, Bousser MG. A negative trial of
sodium valproate in cluster headache: methodological is-
sues. Cephalalgia 2002;22:205208.
20. Steiner TJ, Hering R, Couturier EGM, Davies PTG,
Whitmarsh TE. Double-blind placebo-controlled trial of
lithium in episodic cluster headache. Cephalalgia 1997;17:
673675.
21. Leone M, DAmico 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;16:494 496.
472 Neurology 75 August 3, 2010 by guest on September 25, 2011www.neurology.orgDownloaded from
http://www.neurology.org/http://www.neurology.org/http://www.neurology.org/http://www.neurology.org/http://www.neurology.org/ -
7/29/2019 Acute and Preventive Pharmacologic Treatment of Cluster Headache
12/13
22. Evers S, Masur H, Soros P, Brilla R, Husstedt IW. Prosta-
glandin analog mechanisms are not effective in refractory
chronic cluster headache. Headache 1998;38:618 620.
23. Nilsson Remahl AIM, Ansjon R, Lind F, Waldenlind E.
Hyperbaric oxygen treatment of active cluster headache: a
double-blind placebo-controlled cross-over study. Cepha-
lalgia 2002;22:730 739.
24. Bussone G, Leone M, Peccarisi C, et al. Double blind
comparison of lithium and verapamil in cluster headache
prophylaxis. Headache 1990;30:411417.
25. Leone M, DAmico D, Frediani F, Moschiano F, Grazzi L,Attanasio A. Verapamil in the prophylaxis of episodic clus-
ter headache: a double-blind study versus placebo. Neurol-
ogy 2000;54:13821385.
26. Russell D. Cluster headache: trial of a combined histamine
H1 and H2 antagonist treatment. J Neurol Neurosurg
Psychiatry 1979;42:668 669.
27. Veger T, Russell D, Sjaastad O. Histamine H2 antagonists
and cluster headache. BMJ 1976;4:585.
28. Marks DR, Rapoport A, Padla D, et al. A double-blind
placebo-controlled trial of intranasal capsaicin for cluster
headache. Cephalalgia 1993;13:114116.
29. Christiansen I, Iversen HK, Olesen J. Induction of nitrate
tolerance is not a useful treatment in cluster headache.
Cephalalgia 2000;20:445454.
30. Jammes JL. The treatment of cluster headaches with pred-
nisone. Dis Nerv Syst 1975;36:375376.
31. Cohen A, Burns B, Goadsby P. High flow oxygen for treat-
ment of cluster headache. JAMA 2009;302:24512457.
32. Tfelt-Hansen P, Tfelt-Hansen J. Verapamil for cluster
headache: clinical pharmacology and possible mode of ac-
tion. Headache 2009;49:117125.
33. Thomson Reuters. Lithium. In: Micromedex 2.0. Avail-
able at: www.thomsonhc.com/micromedex2. Accessed
March 2, 2010.
34. May A, Leone M, Afra J, et al. EFNS guidelines on the
treatment of cluster headache and other trigeminal-
autonomic cephalalgias. Eur J Neurol 2006;13:1066
1077.
35. Graham J, Suby H, LeCompte P, Sadowsky N. Fibrotic
disorders associated with methysergide therapy for head-
ache. N Engl J Med 1966;270:6772.
36. Muller R, Weller P, Chemaissani A. Pleural fibrosis as a
side effect of years long methysergide therapy. Dtsch Med
Wochenschr 1991;116:14331436.
37. Thomson Reuters. Methysergide. In: Micromedex 2.0.
Availab le at: www.thomsonhc.com/mi cromed ex2. Ac-
cessed March 2, 2010.38. Peres MFP, Stiles MA, Siow HC, Rozen TD, Young WB,
Silberstein SD. Greater occipital nerve block for cluster
headache. Cephalalgia 2002;22:520522.
39. Gladstone JP, Dodick DW. Chronic daily Headache. In:
Johnson RT, Griffin JW, McArthur JC, eds. Current
Therapy in Neurologic Disease, 7th edition. Philadelphia:
Mosby Elsevier; 2006.
40. Wheeler SD, Carrazana EJ. Topiramate-treated cluster
headache. Neurology 1999;53:234236.
41. Schuh-Hofer S, Israel H, Neeb L, Reuter U, Arnold G.
The use of gabapentin in chronic cluster headache patients
refractory to first-line therapy. Eur J Neurol 2007;14:694
696.
42. Schoenen J, Di Clemente L, Vandenheede M, et al. Hypo-
thalamic stimulation in chronic cluster headache: a pilot
study of efficacy and mode of action. Brain 2005;128:
940947.
43. Leone M, Franzini A, Broggi G, Bussone G. Hypotha-
lamic stimulation for intractable cluster headache: long
term experience. Neurology 2006;67:150152.
44. Leone M, Proiette Cecchini A, Franzini A, et al. Lessons
from 8 years experience of hypothalamic stimulation in
cluster headache. Cephalalgia 2008;28:789797.
45. Burns B, Watkins L, Goadsby PJ. Treatment of intractable
cluster headache by occipital nerve stimulation in 14 pa-
tients. Neurology 2009;72:341345.
Neurology 75 August 3, 2010 473by guest on September 25, 2011www.neurology.orgDownloaded from
http://www.neurology.org/http://www.neurology.org/http://www.neurology.org/http://www.neurology.org/ -
7/29/2019 Acute and Preventive Pharmacologic Treatment of Cluster Headache
13/13
DOI 10.1212/WNL.0b013e3181eb58c82010;75;463Neurology
George J. Francis, Werner J. Becker and Tamara M. PringsheimAcute and preventive pharmacologic treatment of cluster headache
September 25, 2011This information is current as of
ServicesUpdated Information &
http://www.neurology.org/content/75/5/463.full.htmlincluding high resolution figures, can be found at:
Supplementary Material
C2.htmlhttp://www.neurology.org/content/suppl/2010/12/19/75.5.463.D
C1.htmlhttp://www.neurology.org/content/suppl/2010/07/31/75.5.463.DSupplementary material can be found at:
References
http://www.neurology.org/content/75/5/463.full.html#ref-list-1at:This article cites 41 articles, 23 of which can be accessed free
Citations
lshttp://www.neurology.org/content/75/5/463.full.html#related-urThis article has been cited by 1 HighWire-hosted articles:
Subspecialty Collections
http://www.neurology.org/cgi/collection/cluster_headacheCluster headache
tic_review_meta_analysis_http://www.neurology.org/cgi/collection/clinical_trials_systemaClinical trials Systematic review/meta analysisfollowing collection(s):This article, along with others on similar topics, appears in the
Permissions & Licensing
http://www.neurology.org/misc/about.xhtml#permissionstables) or in its entirety can be found online at:Information about reproducing this article in parts (figures,
Reprintshttp://www.neurology.org/misc/addir.xhtml#reprintsus
Information about ordering reprints can be found online:
b S b 25 2011lD l d d f
http://www.neurology.org/content/75/5/463.full.htmlhttp://www.neurology.org/content/75/5/463.full.htmlhttp://www.neurology.org/content/75/5/463.full.htmlhttp://www.neurology.org/content/suppl/2010/12/19/75.5.463.DC2.htmlhttp://www.neurology.org/content/suppl/2010/12/19/75.5.463.DC2.htmlhttp://www.neurology.org/content/suppl/2010/12/19/75.5.463.DC2.htmlhttp://www.neurology.org/content/suppl/2010/07/31/75.5.463.DC1.htmlhttp://www.neurology.org/content/suppl/2010/07/31/75.5.463.DC1.htmlhttp://www.neurology.org/content/suppl/2010/07/31/75.5.463.DC1.htmlhttp://www.neurology.org/content/75/5/463.full.html#ref-list-1http://www.neurology.org/content/75/5/463.full.html#ref-list-1http://www.neurology.org/content/75/5/463.full.html#ref-list-1http://www.neurology.org/content/75/5/463.full.html#related-urlshttp://www.neurology.org/content/75/5/463.full.html#related-urlshttp://www.neurology.org/content/75/5/463.full.html#related-urlshttp://www.neurology.org/cgi/collection/cluster_headachehttp://www.neurology.org/cgi/collection/cluster_headachehttp://www.neurology.org/cgi/collection/cluster_headachehttp://www.neurology.org/cgi/collection/clinical_trials_systematic_review_meta_analysis_http://www.neurology.org/cgi/collection/clinical_trials_systematic_review_meta_analysis_http://www.neurology.org/misc/about.xhtml#permissionshttp://www.neurology.org/misc/about.xhtml#permissionshttp://www.neurology.org/misc/about.xhtml#permissionshttp://www.neurology.org/misc/addir.xhtml#reprintsushttp://www.neurology.org/misc/addir.xhtml#reprintsushttp://www.neurology.org/misc/addir.xhtml#reprintsushttp://www.neurology.org/http://www.neurology.org/http://www.neurology.org/http://www.neurology.org/http://www.neurology.org/misc/addir.xhtml#reprintsushttp://www.neurology.org/misc/about.xhtml#permissionshttp://www.neurology.org/cgi/collection/cluster_headachehttp://www.neurology.org/cgi/collection/clinical_trials_systematic_review_meta_analysis_http://www.neurology.org/content/75/5/463.full.html#related-urlshttp://www.neurology.org/content/75/5/463.full.html#ref-list-1http://www.neurology.org/content/suppl/2010/12/19/75.5.463.DC2.htmlhttp://www.neurology.org/content/suppl/2010/07/31/75.5.463.DC1.htmlhttp://www.neurology.org/content/75/5/463.full.html