Acute and preventive pharmacologic treatment of cluster headache

George J. Francis, Werner J. Becker and Tamara M. Pringsheim Neurology 2010;75;463 DOI 10.1212/WNL.0b013e3181eb58c8 This information is current as of September 25, 2011

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://www.neurology.org/content/75/5/463.full.html

Neurology is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright 2010 by AAN Enterprises, Inc. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.

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VIEWS & REVIEWS

Acute and preventive pharmacologic treatment of cluster headache

George J. Francis, BSc Werner J. Becker, MD Tamara M. Pringsheim, MD

ABSTRACT

Address correspondence and reprint requests to Dr. Tamara Pringsheim, Department of Clinical Neurosciences, 2888 Shaganappi Trail NW, Calgary, Alberta, T3B 6A8, Canada tmprings@ucalgary.ca

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 outcomes 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 for subcutaneous sumatriptan 6 mg, zolmitriptan nasal spray 5 mg and 10 mg, and 100% oxygen 6 12 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, and Level C advice can be given for verapamil 360 mg, lithium 900 mg, and melatonin 10 mg. Neurology 2010;75:463473
GLOSSARY
AAN American Academy of Neurology; AE adverse event; CH cluster headache; CI spray; OR odds ratio; RCT randomized controlled trial; SC subcutaneous; SCHSG Study Group. confidence interval; NS nasal Sumatriptan Cluster Headache

Supplemental data at www.neurology.org

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. Attacks are accompanied by ipsilateral autonomic symptoms, restlessness, or agitation. Attack frequency 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 or months separated by remission periods usually lasting months or years. Patients with chronic CH have attacks occurring for more than 1 year without remission or with remissions lasting less 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 is suspected.2 There is clinical evidence for altered biologic rhythms in patients with CH, and the timing 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 causes significant 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-based advice 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. Copyright 25, 2011 Downloaded from www.neurology.org by guest on September 2010 by AAN Enterprises, Inc. 463

OBJECTIVES/CLINICAL QUESTIONS

Which acute treatments for CH are effective in reducing headache severity? Which preventive treatments are effective in reducing CH attacks?
CRITERIA FOR CONSIDERING STUDIES Studies were required to be prospective, double-blind, parallel-group or crossover, randomized controlled trials (RCTs) of any medication vs placebo or another drug, for the symptomatic relief or prevention of CH. Study participants were 18 or older with either episodic CH or chronic CH. For efficacy analysis, the following main outcomes were considered:

bined using a fixed-effects model. When studies with heterogeneous results were clinically similar, the study estimates were combined using a randomeffects model. Clinical heterogeneity was assessed by looking at trial and patient characteristics, and outcome measures. Clinically heterogeneous studies were not statistically combined. A total of 1,547 abstracts 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 inclusion criteria and was included in the study,31 giving a total of 27 studies in the analysis. RCTs for acute treatment of CH had similar inclusion 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 disease, uncontrolled hypertension, or concomitant use of ergotamine or monoamine oxidase inhibitors. The most common endpoints used were the headache response or pain-free response at 30 minutes. A summary of the trial characteristics, methodologic flaws, and results can be seen in table 1. Inclusion criteria for RCTs studying prevention of CH included patients with at least 1 cluster period lasting at least 1 month prior to the study. Patients were in a cluster period for no more than 10 days, with an expected remainder of cluster period of no less than 20 days. Specifically excluded were patients with cardiovascular, pulmonary, hepatic, or renal disease, as well as patients who were pregnant or currently taking prophylactic CH medication. The primary endpoint for studies was a reduction in the number of headaches during the 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.
DESCRIPTION OF STUDIES

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 (symptomatic 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 reporting AEs.
SEARCH METHODS FOR IDENTIFICATION OF STUDIES MEDLINE (1950 to June 2009) and

EMBASE (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 abstracted independently by the reviewers and confirmed for accuracy. Discrepancies between reviewers were resolved by discussion. The studies were evaluated using quality criteria developed by the American Academy of Neurology (AAN)4 (see appendix e-2). Suggestions were made according to the AAN grades for classification of recommendations (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 com464 Neurology 75 August 3, 2010 Downloaded from www.neurology.org

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 Ekbom et al.5 and The Sumatriptan Cluster HeadRESULTS Acute treatment.

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Figure

PRISMA flow diagram

ache Study Group6 (SCHSG) performed crossover studies of sumatriptan 6 mg subcutaneous injection (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 at 15 minutes: the 2 studies included 258 CH attacks.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 reactions, nausea and vomiting, dizziness, fatigue, and paraesthesias. Sumatriptan NS 20 mg. Headache response at 30 minutes: this crossover study included 83 patients. Two attacks 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 zolmitriptan to placebo, all meeting AAN Class I criteria.8-10 Two are crossover studies 8,9 comparing zolmitriptan 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, including 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
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466
Primary outcome Headache response at 10 min Headache response at 15 min Headache response at 30 min Headache response at 30 min Headache response at 30 min Headache response at 30 min Headache relief during attack Complete cessation of pain All patients treated attacks 9 patients had nitroglycerin induced attacks and were treated 48 patients treated attack 22 treated attacks 124 patients took trial med,123 evaluated 69 patients treated attack 52 patients treated attack 85 patients treated 2 attacks 39 patients evaluated 134 patients treated 2 attacks Dropouts Results Headache response: sumatriptan 12 mg 63%; sumatriptan 6 mg 49%; placebo 25% Headache response: sumatriptan 74%; placebo 26% Headache response: sumatriptan 57%; placebo 26% Headache response: zolmitriptan 10 mg 63.3%; zolmitriptan 5 mg 50%; placebo 30% Headache response: zolmitriptan 10 mg 61%; zolmitriptan 5 mg 42%; placebo 23% Headache response: zolmitriptan 10 mg 47%; zolmitriptan 5 mg 40%; placebo 29% Headache relief: oxygen 56%; room air 7% Complete cessation of pain: cocaine 31.3 min; lidocaine 37.0 min; placebo 59.3 min Headache response: octreotide 52%; placebo 36% Number of attacks strongly reduced: dihydroergotamine 41; placebo 12 Not stated Maximal pain reduction: somatostatin 18%; ergotamine 14%; placebo 0% All patients treated attacks 17/19 patients improved p Value 0.05 0.001 0.002 0.01; 0.002 0.02 0.01 0.01 No statement on allocation concealment 0.01 0.05 No statement on allocation concealment No statement on allocation concealment; no primary outcome stated 0.016 No statement on allocation concealment; no primary outcome stated 0.03 No statement on allocation concealment; no primary outcome stated 76 received treatment Pain-free at 15 minutes: 78% oxygen; 20% air 0.001 0.05 Quality criteria unfulfilled Headache response at 30 min Reduction in headache severity during the attack (not welldefined) Reduction of maximal pain intensity (not well-defined) Pain relief (not well-defined) Pain-free at 15 min

Table 1

Summary of results: The effect of acute treatment of cluster headache

Reference no.

No.

Quality assessment

Intervention

157

AAN Class I

Sumatriptan 6 or 12 mg SC vs placebo; 2 attacks

49

AAN Class I

Sumatriptan 6 mg SC vs placebo; 2 attacks

118

AAN Class I

Sumatriptan 20 mg nasal spray vs placebo; 2 attacks

78

AAN Class I

Zolmitriptan 5 or 10 mg nasal spray vs placebo; 3 attacks

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92

AAN Class I

Zolmitriptan 5 or 10 mg nasal spray vs placebo; 3 attacks

10

153

AAN Class I

Zolmitriptan 5 or 10 mg tab vs placebo; 3 attacks

11

19

AAN Class I

100% oxygen 6 L/min vs room air; 1 attack

12

15

AAN Class II

Cocaine 1 mL intranasal vs lidocaine 1 mL intranasal vs placebo; 1 attack

13

57

AAN Class II

Octreotide SC 100 g vs placebo; 1 attack

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14

25

AAN Class III

Dihydroergotamine 1 mg nasal spray vs placebo; maximum 8 attacks

15

AAN Class III

Somatostatin 25 g IV vs ergotamine 250 g IM vs placebo IV; 1 attack

30

19

AAN Class III

Prednisone 30 mg tablet vs placebo

31

109

AAN Class I

100% oxygen 12 L/min vs room air; 4 attacks

Abbreviations: AAN

American Academy of Neurology; SC

Table 2

Summary of results: The effect of short-term prevention on cluster headache

Reference no. Primary outcome Change in attack frequency per wk 4 did not complete All completed 1 did not complete All completed All completed All completed All completed All completed 6 did not complete All completed 3 did not complete 1 did not complete 3 excluded Reduction in attack frequency: sumatriptan 23%; placebo 22% Cessation of attacks: lithium 15%; placebo 14% Reduction in headache frequency: melatonin 1.79; placebo 0.12 Attack frequency: misoprostol 25.1; placebo 26.1 Patients with 50% reduction in headache index: hyperbaric oxygen 35.7%; sham 37.5% Reduction in headache index: verapamil 50%; lithium 37% Attack frequency: verapamil 0.6; placebo 1.65 Mean number of attacks at wk 12: cimetidine chlorpheniramine 8.7; placebo 10.7 Incidence improvement: cimetidine 4; placebo 0 Headache severity ratings: capsaicin 2.46; placebo 5.15 % patient improvement: sodium valproate 50%; placebo 62% NS NS NS 0.03 NS NS Headache-free: Verum 85%; placebo 0% 0.0001 Change in attack frequency at 1 wk posttreatment: civamide 55.5%; placebo 25.9% 0.03 Dropouts Results p Value

No.

Quality assessment

Intervention

Quality criteria unfulfilled

16

28

AAN Class I

Civamide 100 L intranasal vs placebo; 3 wk assessed Disappearance of attacks at 72 h1 wk % of patient improvement ( 50% reduction in attacks/wk) 50% reduction in attack frequency Cessation of attacks within 1 wk Reduction in daily headache frequency compared to run-in period Attack frequency 2 wk posttreatment 50% reduction in headache index following 1 wk of treatment Headache index relative to placebo period Daily attack frequency per wk

17

23

AAN Class I

Rapid- and long-acting steroids (Verum) 2.5 mL vs placebo SC; 2 wk assessed

19

96

AAN Class I

Sodium valproate 500 mg tab vs placebo; 2 wk assessed

18

168

AAN Class I

Sumatriptan 100 mg tab tid vs placebo; 1 wk assessed

20

27

AAN Class II

Lithium 800 mg tab vs placebo; 1 wk assessed

No statement on allocation concealment No statement on allocation concealment No statement on allocation concealment No statement on allocation concealment 0.01 0.001 No statement on allocation concealment No statement on allocation concealment, primary outcome not clearly stated NS No statement on allocation concealment, intervention not clearly stated NS No detailed results; no statement on allocation concealment 0.05 Assembly of incomparable groups; intervention not clearly stated; no statement on allocation concealment

21

20

AAN Class II

Melatonin 10 mg tab vs placebo; 2 wk assessed

22

AAN Class II

Misoprostol (prostaglandin E analogue) 300 g tab bid vs placebo; 2 wk assessed

23

16

AAN Class II

100% oxygen (hyperbaric) vs sham; 2 attacks

24

30

AAN Class II

Verapamil 120 mg tab tid vs lithium 300 mg tab tid; 8 wk assessed

25

30

AAN Class III

Verapamil 120 mg tab tid vs placebo; 2 wk assessed Mean number of attacks per wk

26

15

AAN Class III

Cimetidine 400 mg tid chlorpheniramine 4 mg tid vs placebo; 6 wk assessed

27

10

AAN Class III

Cimetidine 400 mg qid vs placebo; 6 wk assessed

Headache incidence and duration

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Headache severity rating over 2 wk Summed maximal interval headache score Attack frequency (not defined) 4 did not complete All completed Median summed maximal headache score: nitrate tolerance 42; placebo 0 Greater attack frequency in placebo group, data not given

28

17

AAN Class III

Capsaicin intranasal cream vs placebo; 2 wk assessed

29

AAN Class III

Nitrate tolerance 5-ISMN 30 mg tab tid vs placebo; 4 wk assessed

NS

No statement on allocation concealment, inadequate accounting for dropouts 0.03 No statement on allocation concealment; no primary outcome stated

30

19

AAN Class III

Prednisone 20 mg every other day for 1 wk vs placebo

Abbreviations: AAN

American Academy of Neurology; NS

not significant; SC

subcutaneous.

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Table 3
Maneuver

Summary of advisements for acute abortive treatment of cluster headache

Effectiveness Direct evidence that sumatriptan 6 mg is effective in improving headache response in CH. Nonserious adverse events: injection site reactions, nausea and vomiting, dizziness, fatigue, paresthesias. Direct evidence that zolmitriptan 5 mg and 10 mg are effective in improving headache response in CH. Nonserious adverse events: unpleasant taste, nasal cavity discomfort, somnolence, dizziness, nausea, throat/neck tightness. Direct evidence that sumatriptan 20 mg is effective in improving headache response in CH. Nonserious adverse event: bitter taste. Direct evidence that zolmitriptan 5 mg and 10 mg are effective in improving headache response in CH. Nonserious adverse events: paresthesias, heaviness, asthenia, nausea, dizziness, nonchest tightness. Direct evidence that 100% oxygen 6 12 L/min is effective in improving headache response in CH. Adverse events not reported. Evidence that 10% cocaine hydrochloride and 10% lidocaine are effective in improving headache response in CH. Nonserious adverse events: nasal congestion, unpleasant lidocaine taste. Evidence that octreotide 100 g is effective in improving headache response in CH. Nonserious adverse events: injection site reactions, diarrhea, abdominal bloating, nausea, dull background headache, lethargy. Insufficient evidence that dihydroergotamine 1 mg intranasally is effective in improving headache response in CH. Adverse events not reported. Insufficient evidence that somatostatin 25 g is effective in improving headache response in CH. Nonserious adverse event: nausea without vomiting. Insufficient evidence that prednisone 30 mg is effective in improving headache response in CH. Levels of evidence Two randomized, controlled clinical trials; 2 AAN Class I Advice Level A: should be offered for acute treatment of CH

Sumatriptan (subcutaneous)

Zolmitriptan (nasal spray)

Two randomized, controlled clinical trials; 2 AAN Class I

Level A: should be offered for acute treatment of CH

Sumatriptan (nasal spray)

One randomized, controlled clinical trial; AAN Class I

Level B: should be considered for acute treatment of CH

Zolmitriptan (oral)

One randomized, controlled clinical trial; AAN Class I

Level B: should be considered for acute treatment of CH

Oxygen

Two randomized, controlled clinical trials; AAN Class I

Level A: should be offered for acute treatment of CH

Cocaine/lidocaine

One randomized, controlled clinical trial; AAN Class II

Level C: may be considered for acute treatment of CH

Octreotide

One randomized, controlled clinical trial; AAN Class II

Level C: may be considered for acute treatment of CH

Dihydroergotamine (nasal spray)

One randomized, controlled clinical trial; AAN Class III

Level U: insufficient evidence to advise for the acute treatment of CH

Somatostatin

One randomized, controlled clinical trial; AAN Class III

Level U: insufficient evidence to advise for the acute treatment of CH Level U: insufficient evidence to advise for the acute treatment of CH

Prednisone

One randomized, controlled clinical trial; AAN Class III

Abbreviations: AAN

American Academy of Neurology; CH

cluster headache.

and 2.61 (95% CI 1.47 4.61, p 0.001) for zolmitriptan 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 zolmitriptan 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, dizziness, and nonchest tightness. Zolmitriptan NS should be offered to patients for acute treatment of CH (Level A). Oral zolmitriptan
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should be considered for acute treatment of episodic CH (Level B). Oxygen. Two Class I crossover studies have investigated 100% oxygen vs placebo for the acute treatment 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. Nineteen 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

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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 receiving 40 50 mg of either10% cocaine hydrochloride, 10% lidocaine, or placebo intranasally for 1 nitroglycerin-induced headache. The primary endpoint was the time elapsed until obtaining pain relief. On average, 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 medications). The most common side effects were nasal congestion following study medication administration as well as unpleasant taste of lidocaine. Intranasal cocaine and lidocaine may be considered for acute treatment of CH (Level C). Octreotide. One Class II crossover study evaluated subcutaneous octreotide in 57 patients for the treatment 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 octreotide reported diarrhea, abdominal bloating, or nausea. 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 treatment of CH. While all of these trials reported symptomatic 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% civamide 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 significance ( 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 placebo.17 The study medication consisted of 12.46 mg betamethasone dipropionate and 5.26 mg betamethasone disodium phosphate mixed with 0.5 mL Xylocaine 2%. A total of 23 patients participated in the study. The primary endpoint was the disappearance 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 considered 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 advised for the prevention of CH (Level B). Lithium. There is 1 Class II RCT comparing lithium 800 mg daily to placebo20 in patients with episodic 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 patients who 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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Table 4
Maneuver Civamide

Summary of advisements for preventive treatment of cluster headache

Effectiveness Direct evidence that civamide 100 L is effective in improving headache response in CH. Nonserious adverse events: nasal burning, lacrimation, pharyngitis, rhinorrhea. Direct evidence that long- and rapid-acting steroids 2.5 mL are effective in improving headache response in CH. Nonserious adverse event: transient injection site pain. Direct evidence that sodium valproate 500 mg is not effective in improving headache response in CH. Adverse events not reported. Direct evidence that sumatriptan 100 mg is not effective in improving headache response in CH. Nonserious adverse events: nausea, vomiting, headache, malaise. Evidence that melatonin 10 mg is effective in improving headache response in CH. Nonserious adverse events: none reported. Evidence that verapamil 360 mg is effective in improving headache response in CH. Nonserious adverse events: constipation, reduced blood pressure, reduced heart rate. Evidence that cimetidine 2,000 mg and chlorpheniramine 20 mg are not effective in improving headache response in CH. Nonserious adverse events: transient, erythematous skin rash. Other adverse events not reported. Evidence that lithium 900 mg is effective in improving headache response in CH. Nonserious adverse event: polyuria. Evidence that misoprostol 300 g is not effective in improving headache response in CH. Adverse events not reported. Evidence that 100% hyperbaric oxygen is not effective in improving headache response in CH. Adverse events not reported. Insufficient evidence that capsaicin is effective in improving headache response in CH. Adverse events not reported. Insufficient evidence that nitrate tolerance via 5-ISMN 30 mg is effective in improving headache response in CH. Adverse events not reported. Insufficient evidence that prednisone 20 mg every other day is effective in improving headache response in CH. Adverse events not reported. Levels of evidence One randomized, controlled clinical trial; AAN Class I Advice Level B: should be considered for the prevention of CH

Suboccipital steroid injection

One randomized, controlled clinical trial; AAN Class I

Level B: should be considered for the prevention of CH

Sodium valproate

One randomized, controlled clinical trial; AAN Class I

Level B: not advised for the prevention of CH

Sumatriptan

One randomized, controlled clinical trial; AAN Class I

Level B: not advised for the prevention of CH

Melatonin

One randomized, controlled clinical trial; AAN Class II Two randomized, controlled clinical trials; 1 AAN Class II, 1 AAN Class III

Level C: may be considered for the prevention of CH Level C: may be considered for the prevention of CH

Verapamil

Cimetidine/ chlorpheniramine

Two randomized, controlled clinical trials; 2 AAN Class II

Level C: not advised for the prevention of CH

Lithium

Two randomized, controlled clinical trials; 2 AAN Class II One randomized, controlled clinical trial; AAN Class II One randomized, controlled clinical trial; AAN Class II

Level C: may be considered for the prevention of CH Level C: not advised for the prevention of CH Level C: not advised for the prevention of CH

Misoprostol

Oxygen

Capsaicin

One randomized, controlled clinical trial; AAN Class III One randomized, controlled clinical trial; AAN Class III

Level U: insufficient evidence to advise for the prevention of CH Level U: insufficient evidence to advise for the prevention of CH Level U: insufficient evidence to advise for the prevention of CH

Nitrate tolerance

Prednisone

One randomized, controlled clinical trial; AAN Class III

Abbreviations: AAN

American Academy of Neurology; CH

cluster headache.

participated in this crossover study, and outcomes included 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 period ( 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 mela470 Neurology 75 August 3, 2010 Downloaded from www.neurology.org

tonin 10 mg daily vs placebo for 2 weeks. In comparison 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. Neither treatment resulted in a significant decrease in CH attacks.

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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 frequency per week. Verapamil was found to be superior 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 antagonist, vs placebo.26,27 One of these studies additionally 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 single 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 reported less severe headaches in the treatment group and the prednisone study reported more frequent attacks in the placebo group, all studies had important methodologic limitations. There is insufficient evidence to advise the use of intranasal capsaicin, nitrate tolerance, and prednisone for the prevention of CH (Level U).
DISCUSSION

The treatment of CH is largely pharmacologic, 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 medications which are used widely for CH based on clinical experience have been adequately studied using modern clinical trial methodology. This review focused exclusively 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 mainstay of CH preventive therapy.32 Clinical experience with both verapamil and lithium as preventive treatments 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 patients 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 development of pulmonary and retroperitoneal fibrosis, and therefore treatment must be limited to 6 months.35,36 In addition, methysergide should not be coadministered with triptans or ergots,37 and sumatriptan and zolmitriptan are standard symptomatic treatments for CH. We recognize that there may be special clinical 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 experience, effective. It is recommended in previous guidelines.34 However, aside from the trial that examined the efficacy of suboccipital steroid injection,17 only 1 Class III RCT of steroids in CH has been performed.30 Conceptually, one can consider some of the medications used in CH as transitional preventive treatments. Transitional treatments are medications that are started with longer-term preventive drugs. Their function is to stop the CH attacks almost immediately, and to maintain this pain relief until the dose of the longer-term preventive drug can be increased and 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 steroid injections might also be considered transitional therapy.38,39 Transitional therapies are especially ap471

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propriate for patients who present with a high frequency of attacks. Finally, in refractory patients prophylactics are often used in combination. For example, verapamil prophylaxis may be combined with lithium in an attempt to control intractable cluster headaches32 even though there is no evidence base for this practice.
CONCLUSION For the acute treatment of CH attacks, Level A advice can be given for the use of sumatriptan 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% lidocaine, and subcutaneous octreotide 100 g. For the prevention of CH attacks during a cluster bout, Level B advice can be given for intranasal civamide 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 prevention of CH. Open-label and pilot studies have been conducted with topiramate40 and gabapentin.41 Deep brain stimulation42-44 and occipital nerve stimulation45 have also been assessed with small trials in medically refractory patients. In the future, there may be a greater number of evidence-based treatment 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 recommended treatments should be based on headache frequency, patient comorbidities, and side effects.

3.

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7. 8.

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10.

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AUTHOR CONTRIBUTIONS
Statistical analysis was conducted by Dr. Tamara Pringsheim.

16.

DISCLOSURE
Dr. Francis reports no disclosures. Dr. Becker has served on medical advisory 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. Pringsheim has served on a scientific advisory board for Pfizer Inc. and has received speaker honoraria from Shire Canada, Pfizer Inc., and Teva Pharmaceutical Industries Ltd.

17.

18.

19.

Received December 29, 2009. Accepted in final form April 22, 2010. 20. REFERENCES 1. Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders, 2nd edition. Cephalalgia 2004; 24(suppl 1):1160. 2. Bussone G. Cluster headache: from treatment to pathophysiology. Neurol Sci 2008;29(suppl 1):S1S6.
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Acute and preventive pharmacologic treatment of cluster headache George J. Francis, Werner J. Becker and Tamara M. Pringsheim Neurology 2010;75;463 DOI 10.1212/WNL.0b013e3181eb58c8 This information is current as of September 25, 2011
Updated Information & Services Supplementary Material including high resolution figures, can be found at: http://www.neurology.org/content/75/5/463.full.html Supplementary material can be found at: http://www.neurology.org/content/suppl/2010/07/31/75.5.463.D C1.html http://www.neurology.org/content/suppl/2010/12/19/75.5.463.D C2.html This article cites 41 articles, 23 of which can be accessed free at: http://www.neurology.org/content/75/5/463.full.html#ref-list-1 This article has been cited by 1 HighWire-hosted articles: http://www.neurology.org/content/75/5/463.full.html#related-ur ls This article, along with others on similar topics, appears in the following collection(s): Clinical trials Systematic review/meta analysis http://www.neurology.org/cgi/collection/clinical_trials_systema tic_review_meta_analysis_ Cluster headache http://www.neurology.org/cgi/collection/cluster_headache Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus

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