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Clin Evid (Online). 2010; 2010: 1212.
Published online Feb 9, 2010.
PMCID: PMC2907610
Cluster headache
Manjit Matharu, Senior lecturer and Consultant Neurologist
Manjit Matharu, The Headache Group, Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK;
MSM is the co-author of one RCT referenced in this review.
We would like to acknowledge the previous contributors of this review, including Nicholas Silver.
Introduction
The revised International Headache Society (IHS) criteria for cluster headache are: attacks of severe or very severe, strictly unilateral pain, which is orbital, supraorbital, or temporal pain, lasting 15 to 180 minutes and occurring from once every other day to eight times daily.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions to abort cluster headache? What are the effects of interventions to prevent cluster headache? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2009 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations, such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 23 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review, we present information relating to the effectiveness and safety of the following interventions: baclofen (oral); botulinum toxin (intramuscular); capsaicin (intranasal); chlorpromazine; civamide (intranasal); clonidine (transdermal); corticosteroids; ergotamine and dihydroergotamine (oral or intranasal); gabapentin (oral); greater occipital nerve injections (betamethasone plus xylocaine); high-dose and high-flow-rate oxygen; hyperbaric oxygen; leuprolide; lidocaine (intranasal); lithium (oral); melatonin; methysergide (oral); octreotide (subcutaneous); pizotifen (oral); sodium valproate (oral); sumatriptan (oral, subcutaneous, and intranasal); topiramate (oral); tricyclic antidepressants (TCAs); verapamil; and zolmitriptan (oral and intranasal).
The revised International Headache Society (IHS) criteria for cluster headache are: attacks of severe or very severe, strictly unilateral pain, which is orbital, supraorbital, or temporal pain, lasting 15 to 180 minutes and occurring from once every other day to eight times daily. The attacks are associated with one or more of the following, all of which are ipsilateral: conjunctival injection, lacrimation, nasal congestion, rhinorrhoea, forehead and facial sweating, miosis, ptosis, and eyelid oedema. Most people are restless or agitated during an attack. Cluster headache may be episodic or chronic.
  • Cluster headache is rare, but the exact prevalence remains a matter of debate.
The main focus of intervention is to abort attacks once they have begun and to prevent future attacks.
Sumatriptan, used subcutaneously or intranasally, and zolmitriptan used intranasally reduce the severity and duration of cluster headache attacks once they have begun.
  • Oral zolmitriptan reduces severity of attacks in people with episodic cluster headache, but we don't know how effective it is in people with chronic cluster headache.
  • We don't know whether oral sumatriptan is effective.
There is consensus that high-dose and high-flow-rate oxygen is effective for abortive treatment of episodic or chronic cluster headache. We don't know whether this consensus can be applied to hyperbaric oxygen, as little research has been conducted.
There is also consensus that subcutaneous octreotide is effective for abortive treatment of cluster headache.
We don't know whether intranasal lidocaine is effective for abortive treatment of cluster headache.
There is consensus that both verapamil and lithium prevent cluster headache, but that verapamil is more effective than lithium, and causes fewer adverse effects.
We don't know whether baclofen, botulinum toxin, capsaicin, chlorpromazine, civamide, clonidine, ergotamine or dihydroergotamine, gabapentin, leuprolide, melatonin, methysergide, pizotifen, sodium valproate, oral sumatriptan, topiramate, or tricyclic antidepressants are effective for prevention of cluster headache. Some of these interventions are not routinely used in clinical practice.
Definition
The revised International Headache Society (IHS) criteria for cluster headache are: attacks of severe or very severe, strictly unilateral pain, which is orbital, supraorbital, or temporal pain, lasting 15 to 180 minutes, and occurring from once every other day to eight times daily (see table 1 for full details).[1] The attacks are associated with at least one of the following cranial autonomic features, all of which are ipsilateral: conjunctival injection, lacrimation, nasal congestion, rhinorrhoea, forehead and facial sweating, miosis, ptosis, and eyelid oedema. The revised IHS criteria allow the diagnosis of cluster headache to be made in the absence of ipsilateral cranial autonomic features, provided the person reports a sense of restlessness or agitation. Attacks usually occur in series (cluster periods) lasting for weeks or months, separated by remission periods usually lasting months or years. However, about 10% to 15% of people have chronic symptoms without remissions. Cluster headache is further subclassified according to the duration of the bout. Episodic cluster headache is diagnosed when cluster headache attacks occur in periods lasting 7 days to 1 year, separated by remissions lasting 1 month or longer. Chronic cluster headache is diagnosed when cluster headache attacks occur for more than 1 year without remission, or with remissions lasting less than 1 month. The term cluster headache is now widely accepted, although historically the condition has been known by several different names, including: migrainous neuralgia, Horton's headache, histaminic cephalalgia, sphenopalatine neuralgia, Sluder's neuralgia, petrosal neuralgia, red migraine, erythroprosopalgia of Bing, ciliary neuralgia, erythromelalgia of the head, Vidian neuralgia, hemicrania angioparalytica, hemicrania periodic neuralgiforms, syndrome of hemicephalic vasodilation of sympathetic origin, and autonomic faciocephalalgia.
Table 1
Table 1
The International Classification of Headache Disorders II (ICHD-II) diagnostic criteria for cluster headache.[1]
Incidence/ Prevalence
Cluster headache is rare, but the exact prevalence remains a matter of debate because of the remarkable variation of the estimated prevalence — between 56 and 401 per 100,000 population — in the various studies.[2] [3] [4] [5] [6] [7] Recent studies suggest that the prevalence of cluster headache is likely to be at least one person per 500.[8] Cluster headache is more prevalent in men. The gender ratio in the various case series varies between 2.5:1 and 7.2:1.[9] [10] [11] [12] [13] [14] [15] [16] [17]
Aetiology/ Risk factors
There is a small increased familial risk of cluster headache, suggesting a genetic role in causation.[18] People with cluster headache may over indulge in non-essential consumption habits[11] [19] [20] including smoking,[16] [17] intake of alcohol,[21] [22] and consumption of coffee.[23] There is an increased incidence of previous head trauma in cluster headache, ranging between 5% and 37%, although there is often a long interval between the head trauma and the onset of the headaches.[11] [23] [24] [25]
Prognosis
Onset of symptoms most commonly occurs between the second and fourth decades of life,[14] [16] [18] although cluster headache has been reported in all age groups. Although there is a paucity of literature on the long-term prognosis of cluster headache, the available evidence suggests that it is a lifelong disorder in most people. In one study, episodic cluster headache (ECH) evolved into chronic cluster headache (CCH) in about 10% of people, whereas CCH transformed into ECH in one third of people.[26] Furthermore, a substantial proportion of people with cluster headache can expect to develop longer remission periods with increasing age.[27]
Aims of intervention
To reduce frequency, severity, and duration of headache once attacks have begun (abortive treatment) and to prevent attacks (preventive treatment), with minimal adverse effects from treatment; to improve quality of life.
Outcomes
Headache relief (measured by headache frequency, headache severity, and headache duration).
Methods
Clinical Evidence search and appraisal June 2009. The following databases were used to identify studies for this systematic review: Medline 1966 to June 2009, Embase 1980 to June 2009, and The Cochrane Database of Systematic Reviews, Issue 2, 2009 (1966 to date of issue). An additional search within The Cochrane Library was carried out for the Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA). We also searched for retractions of studies included in the review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the contributor for additional assessment, using predetermined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews of RCTs and RCTs in any language, at least single blinded, and containing any number of individuals of whom more than 60% were followed up. There was no minimum length of follow-up required to include studies. We excluded all studies described as "open", "open label", or not blinded, unless blinding was impossible. We included systematic reviews of RCTs and RCTs where harms of an included intervention were studied applying the same study design criteria for inclusion as we did for benefits. In addition, we did an observational harms search for specific harms as highlighted by the contributor, peer reviewer, and editor. We searched for observational studies assessing cerebrovascular adverse effects of triptans, cardiovascular adverse effects of verapamil, and visceral fibrosis/scleroderma as an adverse effect of methysergide. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).
Table
Table
GRADE Evaluation of interventions for Cluster headache.
Glossary
Low-quality evidenceFurther research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Moderate-quality evidenceFurther research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Very low-quality evidenceAny estimate of effect is very uncertain.

Notes
Disclaimer
The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.
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Sumatriptan (subcutaneous and intranasal) for aborting cluster headache
Summary
Sumatriptan, used subcutaneously or intranasally, reduces the severity and duration of cluster headache attacks once they have begun.
We found no direct information from RCTs about oral sumatriptan for the abortive treatment of episodic or chronic cluster headaches.
Benefits and harms
Subcutaneous sumatriptan versus placebo:
We found one systematic review (search date 1998),[28] which identified two RCTs.[29] [30] The review did not carry out a meta-analysis. The searches in the systematic review were restricted to English language studies.
Headache relief
Subcutaneous sumatriptan compared with placebo Subcutaneous sumatriptan may be more effective at reducing the severity and duration of headache at 15 minutes in people with episodic or chronic cluster headaches (very low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Headache relief
[29]
RCT
Crossover design
49 people with episodic or chronic cluster headache
In review [28]
Headache relief 15 minutes
29/39 (74%) attacks with subcutaneous sumatriptan (6 mg)
10/39 (26%) attacks with placebo

P <0.001
Effect size not calculatedsubcutaneous sumatriptan
[30]
RCT
Crossover design
3-armed trial
157 people with episodic or chronic cluster headache admitted to hospital for treatment
In review [28]
Headache relief 10 minutes
63% with subcutaneous sumatriptan 12 mg
25% with placebo
Absolute numbers not reported

P <0.01 for sumatriptan 12 mg v placebo
Effect size not calculatedsubcutaneous sumatriptan
[30]
RCT
Crossover design
3-armed trial
157 people with episodic or chronic cluster headache admitted to hospital for treatment
In review [28]
Headache relief 10 minutes
49% with subcutaneous sumatriptan 6 mg
25% with placebo
Absolute numbers not reported

P <0.01 for sumatriptan 6 mg v placebo
Effect size not calculatedsubcutaneous sumatriptan
[30]
RCT
Crossover design
3-armed trial
157 people with episodic or chronic cluster headache admitted to hospital for treatment
In review [28]
Headache relief 15 minutes
80% with subcutaneous sumatriptan 12 mg
35% with placebo
Absolute numbers not reported

P <0.01 for sumatriptan 12 mg v placebo
Effect size not calculatedsubcutaneous sumatriptan
[30]
RCT
Crossover design
3-armed trial
157 people with episodic or chronic cluster headache admitted to hospital for treatment
In review [28]
Headache relief 15 minutes
75% with subcutaneous sumatriptan 6 mg
35% with placebo
Absolute numbers not reported

P <0.01 for sumatriptan 6 mg v placebo
Effect size not calculatedsubcutaneous sumatriptan
Resolution of attacks
[29]
RCT
Crossover design
49 people with episodic or chronic cluster headache
In review [28]
Attacks resolved 30 minutes
77% with subcutaneous sumatriptan (6 mg)
49% with placebo
Absolute numbers not reported

P = 0.004
Effect size not calculatedsubcutaneous sumatriptan
Adverse effects
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects
[29]
RCT
Crossover design
49 people with episodic or chronic cluster headache
In review [28]
Adverse effects
17/49 (35%) with subcutaneous sumatriptan (6 mg)
12/47 (26%) with placebo

Significance not assessed
[29]
RCT
Crossover design
49 people with episodic or chronic cluster headache
In review [28]
Injection-site reactions
11/49 (22%) with subcutaneous sumatriptan (6 mg)
7/47 (15%) with placebo

Significance not assessed
[29]
RCT
Crossover design
49 people with episodic or chronic cluster headache
In review [28]
Neurological symptoms
12/49 (24%) with subcutaneous sumatriptan (6 mg)
8/47 (17%) with placebo

Significance not assessed
[30]
RCT
Crossover design
3-armed trial
157 people with episodic or chronic cluster headache admitted to hospital for treatment
In review [28]
Adverse effects
32/94 (45%) with subcutaneous sumatriptan 12 mg
34/101 (34%) with subcutaneous sumatriptan 6 mg
15/96 (16%) with placebo

Significance not assessed
[30]
RCT
Crossover design
3-armed trial
157 people with episodic or chronic cluster headache admitted to hospital for treatment
In review [28]
Pressure sensation on the head, neck, or right temple
3/94 (3%) with subcutaneous sumatriptan 12 mg
5/101 (5%) with subcutaneous sumatriptan 6 mg
1/96 (1%) with placebo

Significance not assessed
[30]
RCT
Crossover design
3-armed trial
157 people with episodic or chronic cluster headache admitted to hospital for treatment
In review [28]
Feeling of heaviness
5/94 (5%) with subcutaneous sumatriptan 12 mg
5/101 (5%) with subcutaneous sumatriptan 6 mg
1/96 (1%) with placebo

Significance not assessed
Intranasal sumatriptan versus placebo:
We found no systematic review, but found one double-blind crossover RCT.[31]
Headache relief
Intranasal sumatriptan compared with placebo Intranasal sumatriptan may be more effective at reducing pain at 30 minutes, at reducing the duration of attacks, and at relieving the number of attacks in people with episodic or chronic cluster headache (low quality-evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Headache relief
[31]
RCT
Crossover design
118 people; 75% with episodic cluster headache; 25% with chronic cluster headache; 154 attacks were treated Headache relief 30 minutes
44/77 (57%) attacks with intranasal sumatriptan (20 mg)
20/77 (26%) attacks with placebo

P = 0.002
Effect size not calculatedintranasal sumatriptan
Freedom from pain
[31]
RCT
Crossover design
118 people; 75% with episodic cluster headache; 25% with chronic cluster headache; 154 attacks were treated Pain free 30 minutes
36/77 (47%) attacks with intranasal sumatriptan (20 mg)
14/77 (18%) attacks with placebo

P = 0.003
Effect size not calculatedintranasal sumatriptan
Time to relief
[31]
RCT
Crossover design
118 people; 75% with episodic cluster headache; 25% with chronic cluster headache; 154 attacks were treated Mean time to initial relief
12.4 minutes with intranasal sumatriptan (20 mg)
17.6 minutes with placebo

P = 0.01
Effect size not calculatedintranasal sumatriptan
Adverse effects
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects
[31]
RCT
Crossover design
118 people; 75% with episodic cluster headache; 25% with chronic cluster headache; 154 attacks were treated Adverse effects
with intranasal sumatriptan (20 mg)
with placebo
Further information on studies
Headache severity in the RCT was assessed using a pain scale ranging from 0 (no pain) to 4 (very severe pain). Headache relief was measured as a decrease in the severity of headache to grade 1 or 0 (from a pretreatment grade of 2, 3, or 4).
Headache severity was assessed using a pain scale ranging from 0 (no pain) to 4 (very severe pain), and headache relief was defined as a change from pretreatment grade 2, 3, or 4 to grade 1 or 0.
Headache response at 30 minutes was defined as a reduction in headache severity from very severe, severe, or moderate, to nil or mild. The method of randomisation was not reported. People treated two headache attacks at least 24 hours apart with either sumatriptan 20 mg or placebo, and then used the alternative treatment for two further headache attacks. The 24-hour delay between crossover of treatments would have allowed washout preventing carry-over effects in the post-crossover analysis.
Comment
None.
Substantive changes
No new evidence

Zolmitriptan (intranasal) for aborting cluster headache
Summary
Zolmitriptan used intranasally reduces the severity and duration of cluster headache attacks once they have begun.
Benefits and harms
Intranasal zolmitriptan versus placebo:
We found no systematic review, but found two double-blind crossover RCTs.[32] [33] Both RCTs used a 5-point ordinal scale (none, mild, moderate, severe, or very severe) to assess headache severity before and after treatment. Headache relief was defined as a reduction in headache from very severe, severe, or moderate, to mild or none.
Headache relief
Intranasal zolmitriptan compared with placebo Intranasal zolmitriptan 5 mg and 10 mg may be more effective at increasing relief from headache and reducing pain at 30 minutes in people with episodic or chronic cluster headaches (very low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Headache response
[32]
RCT
Crossover design
3-armed trial
92 people; 59 (64%) with episodic cluster headache and 33 (36%) with chronic cluster headache; 189 attacks in total Headache response 30 minutes
38/63 (61%) attacks with zolmitriptan 10 mg
14/61 (23%) attacks with placebo

P <0.002 for intranasal zolmitriptan 10 mg v placebo
The method of randomisation was not reported
Effect size not calculatedintranasal zolmitriptan
[32]
RCT
Crossover design
3-armed trial
92 people; 59 (64%) with episodic cluster headache and 33 (36%) with chronic cluster headache; 189 attacks in total Headache response 30 minutes
27/65 (42%) attacks with zolmitriptan 5 mg
14/61 (23%) attacks with placebo

P <0.002 for intranasal zolmitriptan 5 mg v placebo
The method of randomisation was not reported
Effect size not calculatedintranasal zolmitriptan
[33]
RCT
Crossover design
3-armed trial
78 people; 52 people treating first cluster headache attack, 37 (71%) had episodic cluster headache, and 15 (29%) had chronic cluster headache; 151 attacks in total Headache response 10 minutes
25% (attacks) with zolmitriptan 10 mg
10% (attacks) with placebo
Absolute numbers not reported

P <0.05
Effect size not calculatedintranasal zolmitriptan
[33]
RCT
Crossover design
3-armed trial
78 people; 52 people treating first cluster headache attack, 37 (71%) had episodic cluster headache, and 15 (29%) had chronic cluster headache; 151 attacks in total Headache response 20 minutes
39% attacks with zolmitriptan 5 mg
20% attacks with placebo
Absolute numbers not reported

P <0.01
Effect size not calculatedintranasal zolmitriptan
[33]
RCT
Crossover design
3-armed trial
78 people; 52 people treating first cluster headache attack, 37 (71%) had episodic cluster headache, and 15 (29%) had chronic cluster headache; 151 attacks in total Headache response 30 minutes
31/49 (63%) attacks with zolmitriptan 10 mg
15/50 (30%) attacks with placebo

P <0.01
Effect size not calculatedintranasal zolmitriptan
[33]
RCT
Crossover design
3-armed trial
78 people; 52 people treating first cluster headache attack, 37 (71%) had episodic cluster headache, and 15 (29%) had chronic cluster headache; 151 attacks in total Headache response 30 minutes
26/52 (50%) attacks with zolmitriptan 5 mg
15/50 (30%) attacks with placebo

P <0.05
Effect size not calculatedintranasal zolmitriptan
Freedom from pain
[32]
RCT
Crossover design
3-armed trial
92 people; 59 (64%) with episodic cluster headache and 33 (36%) with chronic cluster headache; 189 attacks in total Free from pain 30 minutes
31/63 (50%) attacks with zolmitriptan 10 mg
10/61 (16%) attacks with placebo

P <0.003 for intranasal zolmitriptan 10 mg v placebo
The method of randomisation was not reported
Effect size not calculatedintranasal zolmitriptan
[32]
RCT
Crossover design
3-armed trial
92 people; 59 (64%) with episodic cluster headache and 33 (36%) with chronic cluster headache; 189 attacks in total Free from pain 30 minutes
18/65 (28%) attacks with zolmitriptan 5 mg
10/61 (16%) attacks with placebo

P <0.003 for intranasal zolmitriptan 5 mg v placebo
The method of randomisation was not reported
Effect size not calculatedintranasal zolmitriptan
[33]
RCT
Crossover design
3-armed trial
78 people; 52 people treating first cluster headache attack, 37 (71%) had episodic cluster headache, and 15 (29%) had chronic cluster headache; 151 attacks in total Free from pain 30 minutes
47% attacks with zolmitriptan 10 mg
20% attacks with placebo
Absolute numbers not reported

P <0.01 for intranasal zolmitriptan 10 mg v placebo
Effect size not calculatedintranasal zolmitriptan
[33]
RCT
Crossover design
3-armed trial
78 people; 52 people treating first cluster headache attack, 37 (71%) had episodic cluster headache, and 15 (29%) had chronic cluster headache; 151 attacks in total Free from pain 30 minutes
39% attacks with zolmitriptan 5 mg
20% attacks with placebo
Absolute numbers not reported

P <0.01 for intranasal zolmitriptan 5 mg v placebo
Effect size not calculatedintranasal zolmitriptan
Adverse effects
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects
[32]
RCT
Crossover design
3-armed trial
92 people; 59 (64%) with episodic cluster headache and 33 (36%) with chronic cluster headache; 189 attacks in total Adverse effects
with zolmitriptan 10 mg
with zolmitriptan 5 mg
with placebo

The method of randomisation was not reported
[33]
RCT
Crossover design
3-armed trial
78 people; 52 people treating first cluster headache attack, 37 (71%) had episodic cluster headache, and 15 (29%) had chronic cluster headache; 151 attacks in total Adverse effects
33% with zolmitriptan 10 mg
25% with zolmitriptan 5 mg
16% with placebo
Absolute numbers not reported

P <0.05 for both intranasal zolmitriptan 10 mg and 5 mg v placebo
Effect size not calculatedplacebo
Further information on studies
Headache response was defined as at least a 2-point reduction on a 5-point pain-intensity scale at 30 minutes.
Comment
None.
Substantive changes
Zolmitriptan (intranasal) to abort cluster headache New option for which we found two RCTs.[32] [33] Both RCTs found that intranasal zolmitriptan improved headache relief and pain at 30 minutes compared with placebo. Categorised as Beneficial.

High-dose and high-flow-rate oxygen
Summary
There is consensus that high-dose and high-flow-rate oxygen is effective for abortive treatment of episodic or chronic cluster headache.
Benefits and harms
High-dose and high-flow-rate oxygen versus placebo:
We found two systematic reviews (search date 1998[28] and 2008),[34] both of which identified the same RCT.[35]
Headache relief
High-dose and high-flow-rate oxygen compared with placebo (air) High-dose and high-flow-rate oxygen may be more effective at relieving pain in people with a cluster headache (low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Headache relief
[35]
RCT
Crossover design
19 men with cluster headache
In review [28] [34]
Complete or substantial relief in 80% or more of attacks
9/16 (56%) with oxygen (100% at 6 L/minute for up to 15 minutes)
1/14 (7%) with air

RR 7.88
95% CI 1.13 to 54.66
RR calculated by review[34]
See further information on studies for methodological issues
Large effect sizeoxygen
[35]
RCT
Crossover design
19 men with cluster headache
In review [28] [34]
Average pain relief score
1.93 with oxygen (100% at 6 L/minute for up to 15 minutes)
0.77 with air

P <0.01
See further information on studies for methodological issues
Effect size not calculatedoxygen
Adverse effects
No data from the following reference on this outcome.[28] [34] [35]
Further information on studies
The RCT used classification criteria for cluster headache defined by the Ad Hoc Committee on Classification of Headache, as the trial predates the International Headaches Society classification criteria. Pain relief was assessed using a pain relief score (0 = no relief, 1 = slight relief, 2 = substantial relief, and 3 = complete relief). Each person was treated with either oxygen or air for a maximum of six individual cluster headaches, after which the alternative treatment was given. Eleven people used both gases (6 people improved and did not complete the crossover; 2 people were given the same gas both times). Method of randomisation was not reported. The RCT did not carry out a statistical assessment.
Comment
Clinical guide:
There is consensus based on observational evidence that high-dose and high-flow-rate oxygen reduces the severity of attacks in people with episodic or chronic cluster headache.[37] The advantage of oxygen inhalation treatment is that it has no established adverse effects. It can be readily combined with other abortive and preventive treatments. It can be used several times daily, as opposed to subcutaneous or intranasal triptans, which can be used only up to a maximum of two (subcutaneous) or three (intranasal) times daily. The main drawback with oxygen inhalation treatment is the practical limitation imposed by the bulky equipment, and, although small portable cylinders are available, most people find these cumbersome and inconvenient. Furthermore, it forces the person to sit still during treatment — a behaviour usually incompatible with the excruciating pain of cluster headache. Some people are unable to hold the face mask against the face, as skin contact worsens the pain. People need to be cautioned that oxygen is highly combustible, and fire precautions need to be observed: in particular, the danger of smoking needs to be pointed out.
Substantive changes
High-dose and high-flow-rate oxygen One systematic review added identified no new evidence assessing the effects of high-dose and high-flow-rate oxygen to abort cluster headache.[34] Categorisation unchanged (Likely to be beneficial by consensus).

Octreotide (subcutaneous)
Summary
There is consensus that subcutaneous octreotide is effective for abortive treatment of cluster headache.
Benefits and harms
Subcutaneous octreotide versus placebo:
We found no systematic review. We found one crossover RCT. [38]
Headache relief
Subcutaneous octreotide compared with placebo Subcutaneous octreotide seems more effective at relieving headache at 30 minutes in people with episodic or chronic cluster headaches (moderate-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Headache relief
[38]
RCT
Crossover design
57 people; 41 (72%) with episodic cluster headache, 15 (26%) with chronic cluster headache, and 1 (2%) unclassifiable Headache relief 30 minutes
24/46 (52%) with octreotide 100 micrograms
16/45 (36%) with placebo

P <0.01
Effect size not calculatedoctreotide
Freedom from pain
[38]
RCT
Crossover design
57 people; 41 (72%) with episodic cluster headache, 15 (26%) with chronic cluster headache, and 1 (2%) unclassifiable Pain free 30 minutes
15/46 (33%) with octreotide 100 micrograms
6/45 (13%) with placebo

P = 0.04
Effect size not calculatedoctreotide
Time to pain relief
[38]
RCT
Crossover design
57 people; 41 (72%) with episodic cluster headache, 15 (26%) with chronic cluster headache, and 1 (2%) unclassifiable Mean time to initial relief
18.3 minutes with octreotide 100 micrograms
18.1 minutes with placebo

Significance not assessed
Adverse effects
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects
[38]
RCT
Crossover design
57 people; 41 (72%) with episodic cluster headache, 15 (26%) with chronic cluster headache, and 1 (2%) unclassifiable Adverse effects
with octreotide 100 micrograms
with placebo
Further information on studies
The severity of headache before and after treatment was assessed using an ordinal scale of headache severity (none, mild, moderate, severe, or very severe). Headache relief was defined as a reduction in headache from very severe, severe, or moderate, to mild or nil.
Comment
Clinical guide:
There is consensus based on observational evidence that octreotide is effective.[37]
Substantive changes
No new evidence

Zolmitriptan (oral) for aborting cluster headache
Summary
Oral zolmitriptan reduces severity of attacks in people with episodic cluster headache, but we don't know how effective it is in people with chronic cluster headache.
Benefits and harms
Oral zolmitriptan versus placebo:
We found no systematic review. We found one double-blind crossover RCT comparing oral zolmitriptan 10 mg, oral zolmitriptan 5 mg, and placebo for the treatment of acute attacks.[39]
Headache relief
Oral zolmitriptan compared with placebo Oral zolmitriptan at both 5 mg and 10 mg may be more effective at relieving pain at 30 minutes in people with episodic cluster headache, and zolmitriptan 10 mg may be more effective at reducing headache severity. However, we don’t know whether oral zolmitriptan is more effective at relieving chronic cluster headaches (low-quality evidence)
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Headache response
[39]
RCT
Crossover design
3-armed trial
91 (73%) people with episodic cluster headache
Subgroup analysis
Headache response 30 minutes
47% with zolmitriptan 10 mg
29% with placebo
Absolute numbers not reported

P = 0.02
Effect size not calculatedzolmitriptan
[39]
RCT
Crossover design
3-armed trial
91 (73%) people with episodic cluster headache
Subgroup analysis
Headache response 30 minutes
40% with zolmitriptan 5 mg
19% with placebo
Absolute numbers not reported

Reported as not significant
P value not reported
Not significant
[39]
RCT
Crossover design
3-armed trial
33 (27%) people with chronic cluster headache
Subgroup analysis
Headache response 30 minutes
25% with zolmitriptan 10 mg
16% with zolmitriptan 5 mg
31% with placebo
Absolute numbers not reported

Among group difference reported as not significant
P value not reported
Not significant
Freedom from pain
[39]
RCT
Crossover design
3-armed trial
91 (73%) people with episodic cluster headache
Subgroup analysis
Mild or no pain 30 minutes
47/79 (60%) with zolmitriptan 10 mg
35/83 (42%) with placebo

P <0.01 for zolmitriptan 10 mg v placebo
Effect size not calculatedzolmitriptan
[39]
RCT
Crossover design
3-armed trial
91 (73%) people with episodic cluster headache
Subgroup analysis
Mild or no pain 30 minutes
47/83 (57%) with zolmitriptan 5 mg
35/83 (42%) with placebo

P <0.01 for zolmitriptan 5 mg v placebo
Effect size not calculatedzolmitriptan
[39]
RCT
Crossover design
3-armed trial
33 (27%) people with chronic cluster headache
Subgroup analysis
Mild or no pain 30 minutes
12/32 (38%) with zolmitriptan 10 mg
15/32 (47%) with placebo

Reported as not significant (zolmitriptan 10 mg v placebo)
P value not reported
Not significant
[39]
RCT
Crossover design
3-armed trial
33 (27%) people with chronic cluster headache
Subgroup analysis
Mild or no pain 30 minutes
15/31 (48%) with zolmitriptan 5 mg
15/32 (47%) with placebo

Reported as not significant (zolmitriptan 5 mg v placebo)
P value not reported
Not significant
Adverse effects
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects
[39]
RCT
Crossover design
3-armed trial
124 people; 91(73%) with episodic cluster headache, 33 (27%) with chronic cluster headache; 340 attacks in total Adverse effects
37/111 (33%) with zolmitriptan 10 mg
25/114 (22%) with zolmitriptan 5 mg
15/115 (13%) with placebo

Significance not assessed
[39]
RCT
Crossover design
3-armed trial
124 people; 91 (73%) with episodic cluster headache, 33 (27%) with chronic cluster headache; 340 attacks in total Chest symptoms (including tightness, heaviness, or pressure)
4/111 (3.6%) with zolmitriptan 10 mg
1/114 (<1%) with zolmitriptan 5 mg
4/115 (3.5%) with placebo

Significance not assessed
Further information on studies
Headache response was defined as at least a 2-point reduction on a 5-point pain-intensity scale at 30 minutes. Follow-up in the RCT was 73%, but analysis was by intention to treat.
Comment
None.
Substantive changes
No new evidence

Hyperbaric oxygen
Summary
We don't know whether hyperbaric oxygen is effective for abortive treatment of episodic or chronic cluster headache, as little research has been conducted.
Benefits and harms
Hyperbaric oxygen therapy versus placebo:
We found two systematic reviews (search dates 1998[28] and 2008),[34] both of which identified the same controlled clinical trial.[40] The double-blind controlled clinical trial compared hyperbaric oxygen therapy (HBOT) versus placebo.[40]
Headache relief
Hyperbaric oxygen compared with placebo Hyperbaric oxygen may be more effective at reducing the duration of attacks and at relieving pain at 13 minutes in people with episodic cluster headaches (very low-quality evidence)
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Headache relief
[40] 13 people with episodic cluster headache 10 to 15 days into a cluster bout
In review [28] [34]
Interruption of attack 5 to 13 minutes
6/7 (86%) with HBOT
0/6 (0%) with placebo

RR 11.38
95% CI 0.77 to 167.85
RR calculated by review[34]
Not significant
Adverse effects
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects
[40] 13 people with episodic cluster headache 10 to 15 days into a cluster bout
In review [28] [34]
Adverse effects
with HBOT
with placebo
Further information on studies
People receiving HBOT were placed into a hyperbaric chamber 5 minutes after onset of the attack, and the pressure was gradually increased to 2.0 atmosphere absolute for 30 minutes. People receiving placebo were placed in the same environment without receiving HBOT. The mean duration of the last three attacks occurring before the trial was calculated and compared with the duration of the attacks occurring during the intervention phase. The RCT did not carry out a between group statistical assessment. However, it found that HBOT, but not placebo, significantly reduced the duration of cluster headache attacks compared with baseline (absolute numbers not reported; P <0.01 for HBOT).
Comment
Clinical guide:
It is difficult to comment on the efficacy of HBOT, given the limited controlled data available in the literature. However, it is noteworthy that the available data point towards a beneficial effect — which is not surprising considering the beneficial effect of normobaric oxygen. HBOT has been associated with adverse effects, including: damage to the ears, sinuses, and lungs from the effects of pressure; temporary worsening of short-sightedness; claustrophobia; and oxygen poisoning. Although serious adverse effects are rare, HBOT cannot be regarded as an entirely benign intervention.[41] The clinical utility of HBOT is likely to remain limited in the foreseeable future, owing to the lack of general availability.
Substantive changes
Hyperbaric oxygen One systematic review added identified no new evidence assessing the effects of hyperbaric oxygen to abort cluster headache.[34] Categorisation unchanged (Unknown effectiveness).

Lidocaine (intranasal)
Summary
We don't know whether intranasal lidocaine is effective for abortive treatment of cluster headache.
Benefits and harms
Lidocaine (intranasal):
We found no systematic review or RCTs.
Further information on studies
None.
Comment
Clinical guide:
Small observational studies without a matched control group (the most recent published in 1995) found that intranasal lidocaine 4% spray or solution may be effective in at least one third of people.[42] [43] [44]
Substantive changes
No new evidence

Sumatriptan (oral) for aborting cluster headache
Summary
We don't know whether oral sumatriptan is effective as abortive treatment of episodic or chronic cluster headaches.
Benefits and harms
Sumatriptan (oral) for aborting cluster headache:
We found no systematic review or RCTs of oral sumatriptan for the abortive treatment of episodic or chronic cluster headache.
Further information on studies
None.
Comment
None.
Substantive changes
No new evidence

Greater occipital nerve injections (betamethasone plus xylocaine)
Summary
There is consensus that greater occipital nerve injections are effective for the prevention of episodic or chronic cluster headaches.
Benefits and harms
Single greater occipital nerve injection versus placebo:
We found no systematic review. We found one RCT comparing ipsilateral greater occipital nerve injection versus placebo.[45]
Headache relief
Greater occipital nerve injections compared with placebo Greater occipital nerve injections of betamethasone plus xylocaine may be more effective at reducing the frequency of attacks in the short term in people with episodic or cluster headaches (low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Headache relief
[45]
RCT
23 people; 16 (70%) with episodic cluster headache, 7 (30%) with chronic cluster headache Attack free 1 week
11/13 (85%) with ipsilateral greater occipital nerve injection
0/10 (0%) with placebo

P = 0.0001
Effect size not calculatedbetamethasone
[45]
RCT
23 people; 16 (70%0 with episodic cluster headache, 7 (30%) with chronic cluster headache Attack free within 72 hours 4 weeks
8/13 (61%) with ipsilateral greater occipital nerve injection
0/10 (0%) with placebo

P = 0.0026
Effect size not calculatedbetamethasone
Adverse effects
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects
[45]
RCT
23 people; 16 (70%) with episodic cluster headache, 7 (30%) with chronic cluster headache Adverse effects
with ipsilateral greater occipital nerve injection
with placebo
Further information on studies
Cluster headache attacks resumed within 2 months after completion of the trial in 3/8 (38%) responders, whereas 5/8 (62%) responders (one person with chronic cluster headache) remained attack free for 4 to 26 months. People with episodic cluster headache were included only if the typical duration of their cluster bout was at least 4 weeks, and if they had been in a new bout for no longer than 1 week. All participants continued their usual acute treatment, and also continued other preventive treatment if the dose of preventive medication had been stable for 2 weeks.
Comment
Clinical guide:
There is consensus based on observational evidence that greater occipital nerve injections are effective for the prevention of episodic or chronic cluster headache.[37]
Substantive changes
No new evidence

Corticosteroids (oral)
Summary
There is consensus that corticosteroids are effective for the prevention of episodic or chronic cluster headache.
Benefits and harms
Corticosteroids versus placebo:
We found one systematic review (search date 1998),[28] which identified one small crossover RCT.[46] The RCT compared prednisolone versus placebo for 15 months. We found no RCTs of corticosteroids other than prednisolone in people with cluster headache.
Headache relief
Prednisolone compared with placebo Prednisolone may be more effective at reducing the frequency of cluster headache attacks (very low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Headache relief
[46]
RCT
Crossover design
19 people with cluster headache unresponsive to various drugs, including methysergide and ergotamine
In review [28]
Pain free 10 days
17/19 (89%) with prednisolone 20 mg every alternate day
with placebo

P = 0.03
See further information on studies for methodological issues
Effect size not calculatedprednisolone
Adverse effects
No data from the following reference on this outcome.[46]
Further information on studies
Cluster headache was defined using the classification criteria provided by Kunkle and colleagues and Bickerstaff, as the trial pre-dated the International Headache Society classification criteria. Methodological issues: The RCT gave no information about the details of crossover, no washout period was reported, and it was unclear whether results were reported before or after crossover. There were also insufficient data about outcomes, and absolute figures and significance values were unclear. Because of these methodological issues, no conclusions can be drawn from this RCT.
Comment
One retrospective study of prednisolone (10–80 mg/day) in 19 people (9 with episodic cluster headache; 10 with chronic cluster headache) reported greater than 50% relief in 73% of people, and complete relief in 58%.[49] Recurrence of headaches was reported in 79% of people when the prednisolone dose was tapered. Another observational study reported that, of 77 people with episodic cluster headache unresponsive to methysergide, prednisolone relieved 77% and partially improved 12%.[11] Prednisolone was also found to provide marked relief in 40% of people with chronic cluster headache, and was more effective than methysergide in this group. Headache relief was not defined in either study.
Clinical guide:
There is consensus based on observational evidence that corticosteroids are effective for the prevention of episodic and chronic cluster headache.[37] Corticosteroids are usually used as an initial treatment in conjunction with other preventive interventions such as verapamil and lithium, which have a slower onset of action, until verapamil and lithium are effective. An alternative strategy is to withhold corticosteroids in reserve until the patient is at the peak of the cluster bout, in case the alternative preventive strategy implemented is ineffective. In some European countries, prednisolone has been discontinued. In countries where prednisolone in not available, prednisone is used, with response rates comparable to those reported for prednisolone.[50] Systemic corticosteroids can cause the same adverse effects when used for cluster headache as in other diseases. The shortest course of prednisolone and dexamethasone reported to be associated with osteonecrosis of the femoral head is a 30-day course for prednisolone and a 7-day course for dexamethasone.[51] It is therefore prudent to restrict the duration of the courses of corticosteroids to these limits, and to consider limiting each patient to twice-yearly courses of treatment.
Substantive changes
No new evidence

Lithium (oral)
Summary
We found no direct information from RCTs about whether lithium is better than no active treatment for the prevention of cluster headache. There is current consensus that lithium, although commonly used and believed to be effective, is less effective than verapamil and causes more adverse effects.
Benefits and harms
Lithium versus placebo:
We found one systematic review (search date 1998), which identified no RCTs of sufficient quality.[28] The searches in the review were restricted to English language studies. We found no subsequent RCTs comparing lithium versus placebo for the prevention of cluster headache.
Lithium versus verapamil:
See option on verapamil.
Further information on studies
None.
Comment
Clinical guide:
A non-systematic review of case reports and case series (all conducted in the 1970s) suggested that lithium may be an effective preventive treatment for cluster headache, but found that the response was less robust in episodic than in chronic cluster headache.[52] Collectively, in over 28 clinical trials involving 468 people, good results were reported in 236/304 (78%) people with chronic cluster headache and in 103/164 (63%) people with episodic cluster headache.[52] There is current consensus based on observational evidence that lithium, although commonly used and believed to be effective, is less effective than verapamil and causes more adverse effects.[37]
Substantive changes
No new evidence

Summary
There is consensus that verapamil is more effective and has fewer adverse effects than lithium when used in prevention of chronic cluster headaches.
Benefits and harms
Verapamil versus placebo:
We found one systematic review (search date 1998), which identified no RCTs comparing verapamil versus placebo.[28] The searches in the systematic review were restricted to English language studies. We found one subsequent RCT.[53]
Headache relief
Verapamil compared with placebo Verapamil may be more effective at reducing the frequency of attacks at 2 weeks in people with episodic cluster headaches (very low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Headache frequency
[53]
RCT
30 people with episodic cluster headache Reduction in headache frequency >50% 2 weeks
12/15 (80%) with verapamil 360 mg daily
0/15 (0%) with placebo

Significance not assessed
Method of randomisation was unclear
Mean number of attacks
[53]
RCT
30 people with episodic cluster headache Mean number of attacks first week
1.1 with verapamil 360 mg daily
1.7 with placebo

Significance not assessed
Method of randomisation was unclear
[53]
RCT
30 people with episodic cluster headache Mean number of attacks second week
0.6 with verapamil 360 mg daily
1.65 with placebo

P <0.001
Method of randomisation was unclear
Effect size not calculatedverapamil
Adverse effects
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects
[53]
RCT
30 people with episodic cluster headache Constipation
8/15 (53%) with verapamil 360 mg daily
0/15 (0%) with placebo

Significance not assessed
Method of randomisation was unclear
[53]
RCT
30 people with episodic cluster headache Mean decrease in blood pressure after treatment
11 mm Hg with verapamil 360 mg daily
2 mm Hg with placebo

P <0.05
Method of randomisation was unclear
Effect size not calculatedplacebo
[53]
RCT
30 people with episodic cluster headache Mean decrease in heart rate after treatment
10 bpm with verapamil 360 mg daily
1 bpm with placebo

P <0.05
Method of randomisation was unclear
Effect size not calculatedplacebo
Verapamil versus lithium:
We found one systematic review (search date 1998),[28] which identified one RCT (30 people with chronic cluster headache, crossover design) comparing verapamil 360 mg daily versus lithium carbonate 900 mg daily, each given for 8 weeks.[54] The RCT did not compare verapamil versus lithium directly. Instead, it reported changes in both groups from baseline. We therefore have not reported results from this RCT.[54]
Further information on studies
None.
Comment
Clinical guide:
In clinical practice, verapamil at doses of up to 960 mg daily is often used for the prevention of cluster headache, with anecdotal success in those with poor response at lower doses. There is consensus based on observational evidence that verapamil is more effective than lithium and causes fewer adverse effects.[37] It is important when using verapamil to closely monitor the ECG for changes suggestive of heart block (prolongation of PR interval, change in cardiac axis, or broadening of QRS complex). Serial ECGs are recommended during dose titration, and should probably be monitored in the long term, because PR prolongation can develop during maintenance treatment.[55] [56]
Substantive changes
No new evidence

Baclofen (oral)
Summary
We found no direct information from RCTs about the effects of baclofen for prevention of cluster headaches. However, baclofen is not routinely used for cluster headache prophylaxis.
Benefits and harms
Baclofen (oral):
We found no systematic review or RCTs.
Further information on studies
None.
Comment
Clinical guide:
Baclofen is not routinely used for cluster headache prophylaxis.
Substantive changes
No new evidence

Botulinum toxin (intramuscular)
Summary
We found no direct information from RCTs about the effects of botulinum toxin for prevention of cluster headaches. However, botulinum toxin is not routinely used for cluster headache prophylaxis.
Benefits and harms
Botulinum toxin (intramuscular):
We found one systematic review (search date 2003), which identified no RCTs.[57] We found no subsequent RCTs.
Further information on studies
None.
Comment
Clinical guide:
Botulinum toxin is not routinely used for cluster headache prophylaxis.
Substantive changes
No new evidence

Capsaicin (intranasal)
Summary
We don't know whether capsaicin is effective for prevention of cluster headache. We found no direct information about the effects of capsaicin in people with chronic cluster headaches.
Capsaicin is associated with transient adverse effects, such as burning sensations, lacrimation, and rhinorrhoea.
Benefits and harms
Ipsilateral versus contralateral capsaicin:
We found one systematic review (search date 1998),[28] which identified one RCT.[58] The searches in the systematic review were restricted to English language studies.
Headache relief
Ipsilateral compared with contralateral capsaicin Applying capsaicin ipsilaterally may be more effective at reducing the frequency of attacks of episodic cluster headache (very low-quality evidence)
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Frequency of attacks
[58]
RCT
51 people with episodic cluster headache
In review [28]
Number of attacks per 10-day period after treatment first to third 10-day period
with ipsilateral intranasal capsaicin (300 micrograms)
with contralateral intranasal capsaicin (300 micrograms)
Absolute results reported graphically

P <0.01
See further information on studies for methodological issues
Effect size not calculatedipsilateral intranasal capsaicin
[58]
RCT
51 people with episodic cluster headache
In review [28]
Number of attacks per 10-day period after treatment fourth and fifth 10-day period
with ipsilateral intranasal capsaicin (300 micrograms)
with contralateral intranasal capsaicin (300 micrograms)
Absolute results reported graphically

P <0.05
See further information on studies for methodological issues
Effect size not calculatedipsilateral intranasal capsaicin
[58]
RCT
51 people with episodic cluster headache
In review [28]
Greater than 50% reduction in the number of attacks
8/26 (31%) with ipsilateral intranasal capsaicin (300 micrograms)
0/25 (0%) with contralateral intranasal capsaicin (300 micrograms)

Significance not assessed
See further information on studies for methodological issues
Adverse effects
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects
[58]
RCT
51 people with episodic cluster headache
In review [28]
Adverse effects
with ipsilateral intranasal capsaicin (300 micrograms)
with contralateral intranasal capsaicin (300 micrograms)

See further information on studies for methodological issues
Further information on studies
Thirteen of 26 (50%) people given ipsilateral capsaicin were rendered pain free for the remainder of the trial. The method of randomisation was not specified. Participants in the RCT were told that they might be receiving an alternative treatment, the effect of which could not be predicted. The authors assert that this approach approximated a single-blind study design.
Comment
Intranasal capsaicin produces an intense burning sensation, lacrimation, and rhinorrhoea that lasts for about 20 minutes, although these symptoms progressively decrease and disappear after five to eight applications. Because of this irritant local effect, it is difficult to conduct double-blind studies of intranasal capsaicin.
Substantive changes
No new evidence

Chlorpromazine
Summary
We found no direct information from RCTs about chlorpromazine for the prevention of cluster headache. Chlorpromazine is not routinely used in clinical practice because it can be associated with severe adverse effects.
Benefits and harms
Chlorpromazine:
We found no systematic review or RCTs.
Comment
Clinical guide:
Chlorpromazine is not routinely used in clinical practice for cluster headache prophylaxis. Furthermore, its use needs to be balanced against the potential adverse effects. Tardive dyskinesia can be permanent even after a few doses. Dystonic reactions and akathisia can occur, occasionally developing into a severe sense of restlessness or agitation. Drowsiness occurs in many people.
Substantive changes
No new evidence

Civamide (intranasal)
Summary
We don’t know whether intranasal civamide is more effective than placebo at preventing the frequency, intensity, and number of severe headaches in people with episodic cluster headaches. We found no direct information from RCTs assessing civamide in people with chronic cluster headache.
Civamide has been associated with nasal burning sensations and lacrimation.
Benefits and harms
Civamide (intranasal) versus placebo:
We found no systematic review. We found one RCT in people with episodic cluster headache.[59] We found no RCTs of civamide in people with chronic cluster headache.
Headache relief
Intranasal civamide compared with placebo We don’t know whether intranasal civamide is more effective than placebo at preventing the frequency, intensity, and number of severe headaches in people with episodic cluster headaches (very low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Headache frequency
[59]
RCT
28 people with episodic cluster headache Decrease from baseline 1 to 7 days after treatment completed
–55.5% (absolute number of headaches a week decreased from 12.5 to 5.6) with civamide (100 microlitres of 0.025% solution)
–25.9% (absolute number of headaches a week decreased from 10.8 to 7.3) with placebo (100 microlitres of the vehicle)

P value for % decrease = 0.03
See further information on studies for methodological issues
Effect size not calculatedcivamide
[59]
RCT
28 people with episodic cluster headache Decrease from baseline 8 to 14 days after treatment completed
–66.9% (absolute number of headaches a week decreased from 12.5 to 4.1) with civamide (100 microlitres of 0.025% solution)
–32.3% (absolute number of headaches a week decreased from 10.8 to 7.2) with placebo (100 microlitres of the vehicle)

P value for decrease in number of headaches = 0.09
P value for % decrease = 0.07
See further information on studies for methodological issues
Not significant
[59]
RCT
28 people with episodic cluster headache Decrease from baseline 14 to 18 days after treatment completed
–70.6% (absolute number of headaches a week decreased from 12.5 to 4.2) with civamide (100 microlitres of 0.025% solution)
–34.7% (absolute number of headaches a week decreased from 10.8 to 7.2) with placebo (100 microlitres of the vehicle)

P value for decrease in the number of headaches = 0.07
P value for % decrease = 0.07
See further information on studies for methodological issues
Not significant
[59]
RCT
28 people with episodic cluster headache Decrease from baseline 1 to 20 days after treatment completed
–61.4% (absolute number of headaches a week decreased from 12.5 to 4.9) with civamide (100 microlitres of 0.025% solution)
–30.9% (absolute number of headaches a week decreased from 10.8 to 7.2) with placebo (100 microlitres of the vehicle)

P value for % decrease = 0.054
The difference was of borderline significance
See further information on studies for methodological issues
Not significant
[59]
RCT
28 people with episodic cluster headache Number of severe headaches
with civamide (100 microlitres of 0.025% solution)
with placebo (100 microlitres of the vehicle)
Absolute results not reported

Reported as not significant
P value not reported
See further information on studies for methodological issues
Not significant
Pain severity
[59]
RCT
28 people with episodic cluster headache Cluster headache pain intensity
with civamide (100 microlitres of 0.025% solution)
with placebo (100 microlitres of the vehicle)
Absolute results not reported

Reported as not significant
P value not reported
See further information on studies for methodological issues
Not significant
Adverse effects
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Nasal burning
[59]
RCT
28 people with episodic cluster headache Nasal burning
14/18 (78%) with civamide (100 microlitres of 0.025% solution)
1/10 (10%) with placebo (100 microlitres of the vehicle)

P = 0.001
See further information on studies for methodological issues
Effect size not calculatedplacebo
Lacrimation
[59]
RCT
28 people with episodic cluster headache Lacrimation
9/18 (50%) with civamide (100 microlitres of 0.025% solution)
0/10 (0%) with placebo (100 microlitres of the vehicle)

P = 0.01
See further information on studies for methodological issues
Effect size not calculatedplacebo
Further information on studies
The RCT was randomised in a ratio of two civamide (18 people) to one placebo (10 people). Only people who received at least 3 days of treatment were included in the analysis. Although the authors report that this RCT was double blind, the irritant nature of nasally applied civamide is likely to have led to unblinding.
Comment
Clinical guide:
Intranasal civamide is not routinely used in clinical practice for cluster headache prophylaxis.
Substantive changes
No new evidence

Clonidine (transdermal)
Summary
We found no direct information from RCTs about transdermal clonidine for the prevention of cluster headache.
Benefits and harms
Clonidine (transdermal):
We found no systematic review or RCTs.
Further information on studies
None.
Comment
None.
Substantive changes
No new evidence

Ergotamine and dihydroergotamine (oral or intranasal)
Summary
We don't know whether ergotamine or dihydroergotamine are effective for prevention of cluster headache as we found no direct information from RCTs.
Benefits and harms
Ergotamine and dihydroergotamine (oral or intranasal):
We found one systematic review (1998), which identified no RCTs.[28] The searches in the systematic review were restricted to English language studies. We found no subsequent RCTs.
Further information on studies
None.
Comment
Clinical guide:
Oral ergotamine was first reported to be effective as a preventive treatment in 81% of people with cluster headache in a case series published in 1947.[60] In 1956, it was reported in a case series that a rectal suppository of ergotamine plus caffeine or intramuscular ergotamine injections at bedtime were effective in preventing nocturnal attacks.[61] Ergotamine was routinely recommended for the prevention of cluster headache until the efficacy of verapamil and lithium became evident. It is now rarely used in clinical practice. Additionally, a retrospective cohort study found that repetitive intravenous dihydroergotamine given in hospital over 3 days was useful in the abortive treatment of cluster headache.[62] Ergot derivatives should not be combined or used with methysergide and triptans.
Substantive changes
No new evidence

Gabapentin (oral)
Summary
We don't know whether gabapentin is effective for prevention of cluster headache as we found no direct information from RCTs.
Benefits and harms
Gabapentin (oral):
We found no systematic review or RCTs.
Further information on studies
None.
Comment
We found one small observational study assessing gabapentin 900 mg daily in 12 people (8 people with episodic cluster headache; 4 with chronic cluster headache), which found that all participants were rendered pain free within 8 days.[63] People with episodic cluster headache discontinued gabapentin after 60 days of treatment without recurrence of the attacks. The four people with chronic cluster headache remained pain free at 4-month follow-up. This high response rate needs to be reproduced in controlled trials.
Clinical guide:
In clinical practice, specialists use gabapentin for cluster headache prophylaxis when patients have failed trials of preventive agents routinely used, such as verapamil, lithium, and corticosteroids.
Substantive changes
No new evidence

Leuprolide
Summary
We don't know whether leuprolide is effective for prevention of cluster headache as we found no direct information from RCTs.
Benefits and harms
Leuprolide:
We found one systematic review (search date 1998),[28] which identified one RCT.[64] The searches in the systematic review were restricted to English language studies. The RCT (60 men with chronic cluster headache) compared a single dose of intramuscular leuprolide (a synthetic slow-release GnRH analogue) versus placebo.[64] The RCT did not compare leuprolide versus placebo directly. Instead, it reported changes in both groups from baseline. We therefore have not reported results from this RCT. We found no RCTs on the effects of leuprolide for episodic cluster headache. The RCT reported that leuprolide significantly decreased libido compared with baseline (significance figures not reported).[64]
Further information on studies
None.
Comment
Clinical guide:
Leuprolide is rarely used in clinical practice for cluster headache prophylaxis.
Substantive changes
No new evidence

Summary
We don't know whether melatonin is effective for prevention of cluster headache as we found no direct information from RCTs.
Benefits and harms
Melatonin:
We found one systematic review (search date 1998),[28] which identified one RCT.[65] The RCT (20 people; 18 with episodic cluster headache; 2 with chronic cluster headache) compared oral melatonin 10 mg daily versus placebo for 2 weeks. The RCT did not compare melatonin versus placebo directly. Instead, it reported changes in both groups from baseline. We have therefore not reported results from this RCT.[65] The RCT reported no adverse effects associated with melatonin.[65]
Further information on studies
None.
Comment
Clinical guide:
Melatonin is not routinely used in cluster headache prophylaxis.
Substantive changes
No new evidence

Methysergide (oral)
Summary
We don't know whether methysergide is effective for prevention of cluster headache as we found no direct information from RCTs.
Benefits and harms
Methysergide (oral):
We found one systematic review (search date 1998), which identified no RCTs.[28] The searches in the systematic review were restricted to English language studies. We found no subsequent RCTs.
Further information on studies
None.
Comment
Clinical guide:
A narrative review of observational studies published in 1967, most with no matched controls, found that methysergide was an effective preventive drug for people with cluster headache.[66] It reported that methysergide 3 mg to 12 mg daily was effective in 73% of people with episodic cluster headache and chronic cluster headache. A subsequent observational study found that methysergide was effective in 65% of people with episodic cluster headache and in 20% with chronic cluster headache, but that in up to 20% of people it seemed to lose effectiveness with repeated use.[11] Study design and duration were not reported. Another prospective cohort study of methysergide 3 mg to 12 mg daily in people with episodic and chronic cluster headache found a beneficial preventive effect in 31% of people, with no difference in treatment response between the episodic and chronic groups.[67] In addition, a retrospective analysis of 164 people with cluster headache (type not specified) found a satisfactory response in only 26% of people.[67] Hence, the efficacy data on methysergide from observational studies seem to suggest that it is effective, albeit that the data are inconsistent. Prolonged treatment with methysergide has been associated with fibrotic reactions (retroperitoneal, pulmonary, pleural, and cardiac) although these are rare.[68] Ideally, methysergide should be used in people with short cluster bouts, preferably for less than 3 to 4 months. If prolonged use is intended, then the risk of fibrotic reactions can be minimised by giving methysergide for 6 months followed by a 1-month drug holiday, before restarting methysergide. Some clinicians use prolonged methysergide with careful monitoring, which includes auscultation of the heart and yearly echocardiogram, chest x ray, and abdominal magnetic resonance imaging.[69] All people receiving methysergide should remain under the supervision of the treating physician, and should be examined regularly for the development of visceral fibrosis or vascular complications.
Substantive changes
No new evidence

Pizotifen (oral)
Summary
We don't know whether pizotifen is effective for prevention of cluster headache as we found no direct information from RCTs.
Benefits and harms
Pizotifen (oral):
We found one systematic review (search date 1998), which identified no RCTs.[28] The searches in the systematic review were restricted to English language studies. We found no subsequent RCTs.
Further information on studies
None.
Comment
One small, single-blind, non-randomised, crossover-design controlled trial (28 people with episodic cluster headache) found that pizotifen significantly reduced the "headache index" — a composite score of headache attack, duration, and severity — compared with placebo.[70] Adverse effects of pizotifen included drowsiness, nausea, anxiety, and increased weight. This non-RCT has various methodological flaws that probably contribute to an overestimation of the effectiveness of pizotifen. All participants were given placebo first followed by pizotifen, and therefore the improvement in some people while taking pizotifen probably represents natural history of the cluster bout. Furthermore, the single-blind design may also have introduced bias. A review of seven small observational studies reported that pizotifen had only a modest effect in cluster headache prophylaxis — being effective in 38% of people with cluster headache.[71]
Substantive changes
No new evidence

Sodium valproate (oral)
Summary
We don't know whether sodium valproate is effective for prevention of cluster headache.
Benefits and harms
Sodium valproate (oral) versus placebo:
We found two systematic reviews (search dates 1998[28] and not reported).[72] The first review identified no RCTs.[28] The second review identified one RCT comparing sodium valproate versus placebo for 2 weeks.[73]
Headache relief
Sodium valproate compared with placebo We don’t know whether sodium valproate is more effective than placebo for prophylaxis of cluster headaches (very low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Headache frequency
[73]
RCT
96 people, 73 with ECH and 17 with CCH
In review [72]
Proportion of people with >50% reduction in the average number of attacks 2 weeks
50% with sodium valproate (1000 mg to 2000 mg daily)
62% with placebo
Absolute numbers not reported

P = 0.23
See further information on studies for methodological issues
Not significant
Adverse effects
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects
[73]
RCT
96 people, 73 with ECH and 17 with CCH
In review [72]
Adverse effects
40% with sodium valproate (1000 mg to 2000 mg daily)
28% with placebo
Absolute numbers not reported

Significance not assessed
See further information on studies for methodological issues
Nausea and vomiting
[73]
RCT
96 people, 73 with ECH and 17 with CCH
In review [72]
Nausea and vomiting
12% with sodium valproate (1000 mg to 2000 mg daily)
4% with placebo
Absolute numbers not reported

Significance not assessed
See further information on studies for methodological issues
Somnolence
[73]
RCT
96 people, 73 with ECH and 17 with CCH
In review [72]
Somnolence
12% with sodium valproate (1000  to 2000 mg daily)
2% with placebo
Absolute numbers not reported

Significance not assessed
See further information on studies for methodological issues
Further information on studies
The results may have been affected by the mean duration of previous cluster bouts at baseline in people with episodic cluster headache being shorter in the placebo group than in the intervention group, although the difference between groups was not significant (78.3 days with sodium valproate v 62.4 days with placebo; reported as not significant; P value not reported). Consequently, the high response rate in the placebo group may be attributable to the spontaneous remission of the cluster bout in addition to a true placebo response. Because of these weaknesses in trial methods, the authors of the review reported that no conclusions could be drawn about the effectiveness of sodium valproate for the prophylaxis of cluster headache.
Comment
None.
Substantive changes
No new evidence

Sumatriptan (oral) for preventing cluster headache
Summary
We don't know whether oral sumatriptan is effective for prevention of cluster headache.
Benefits and harms
Sumatriptan (oral) versus placebo:
We found one systematic review (search date 1998),[28] which identified one RCT.[74]
Headache relief
Oral sumatriptan compared with placebo Oral sumatriptan seems no more effective than placebo at preventing attacks of episodic or cluster headaches (moderate-quality evidence)
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Headache frequency
[74]
RCT
169 people; 90 (53%) with episodic cluster headache, 78 (47%) with chronic cluster headache
In review [28]
At least 50% reduction in number of attacks from observation week to study treatment week
20/89 (23%) with sumatriptan (100 mg three times a day)
17/79 (22%) with placebo

P = 0.88
Not significant
[74]
RCT
169 people; 90 (53%) with episodic cluster headache, 78 (47%) with chronic cluster headache
In review [28]
At least 50% reduction in number of severe/very severe attacks from observation week to study treatment week
32/74 (43%) with sumatriptan (100 mg three times a day)
27/64 (42%) with placebo

P = 0.84
Not significant
Adverse effects
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects
[74]
RCT
169 people; 90 (53%) with episodic cluster headache, 78 (47%) with chronic cluster headache
In review [28]
Adverse effects
31/89 (35%) with sumatriptan (100 mg three times a day)
19/79 (24%) with placebo

Significance not assessed
Further information on studies
People were initially observed for 1 week, and those experiencing a minimum of seven attacks entered the intervention stage of the trial. All participants were initially treated with a subcutaneous injection of sumatriptan 6 mg, and were then randomised to receive either oral sumatriptan or placebo. Headache severity was assessed using a 5-point scale, ranging from 0 (no pain) to 4 (very severe pain). Adverse effects The RCT found that one person treated with sumatriptan developed cardiac flutter and chest pain, and a second person reported numbness and pressure in the chest with shortness of breath. A third person developed pericarditis, which was thought unlikely to be drug related.
Comment
Clinical guide:
There is some consensus among neurologists that oral sumatriptan has no place in the preventive management of cluster headache, as it is ineffective.
Substantive changes
No new evidence

Topiramate (oral)
Summary
We don't know whether topiramate is effective for prevention of cluster headache.
Benefits and harms
Topiramate (oral):
We found no systematic review or RCTs.
Further information on studies
None.
Comment
Clinical guide:
Observational studies without matched control groups have found that topiramate may be effective for prophylaxis of cluster headache in about 50% of people.[75] [76] [77] [78] [79] In clinical practice, topiramate is used for cluster headache prophylaxis when patients have failed trials of routinely used preventive agents such as verapamil, lithium, and corticosteroids.
Substantive changes
No new evidence

Tricyclic antidepressants
Summary
We don't know whether tricyclic antidepressants are effective for prevention of cluster headache.
Benefits and harms
Tricyclic antidepressants:
We found no systematic review or RCTs.
Further information on studies
None.
Comment
Clinical guide:
There is some consensus among neurologists that tricyclic antidepressants have no place in the preventive management of cluster headache, as they are ineffective.
Substantive changes
No new evidence
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