acute and preventive pharmacologic treatment of cluster headache

7/29/2019 Acute and Preventive Pharmacologic Treatment of Cluster Headache

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DOI 10.1212/WNL.0b013e3181eb58c82010;75;463Neurology

George J. Francis, Werner J. Becker and Tamara M. Pringsheimheadache

Acute and preventive pharmacologic treatment of cluster

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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

[email protected]

Supplemental dataatwww.neurology.org

VIEWS & REVIEWS

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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-

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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

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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


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


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.



Prednisone Insufficient evidence thatprednisone30mg is effective in improvingheadacheresponse inCH.



Abbreviations:AANAmericanAcademy ofNeurology; CH cluster headache.



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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



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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.


Level B:shouldbe consideredforthe prevention ofCH

Sodium valproate Direct evidence thatsodiumvalproate500mg is noteffective in improvingheadacheresponse inCH.Adverseevents notreported.


Level B:not advised forthepreventionof CH

Sumatriptan Direct evidence thatsumatriptan 100mgis noteffective in improvingheadacheresponse in CH.Nonseriousadverseevents: nausea, vomiting, headache,malaise.


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


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


Misoprostol Evidence thatmisoprostol300g isnoteffectivein improvingheadache responseinCH.Adverseevents notreported.



Oxygen Evidence that100%hyperbaric oxygen isnot effectivein improving headacheresponse inCH.Adverseevents not

reported.



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.



Prednisone Insufficient evidence thatprednisone20mgeveryother dayis effectiveinimprovingheadache response in CH.Adverseevents not reported.



Abbreviations:AANAmericanAcademy ofNeurology; CH cluster headache.



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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-



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.

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DOI 10.1212/WNL.0b013e3181eb58c82010;75;463Neurology

George J. Francis, Werner J. Becker and Tamara M. PringsheimAcute and preventive pharmacologic treatment of cluster headache

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