12.1. Introduction
Cluster headache is a strictly unilateral headache that occurs in association with cranial autonomic features (red eye on same side as headache, lacrimation, small pupil, drooping eyelid, eyelid oedema, nasal congestion, watery nose, forehead and facial sweating). It is an excruciating disorder and is probably one of the most painful conditions known to mankind with female sufferers describing each attack as being worse than childbirth. In most people, it has a striking circannual and circadian periodicity.
Cluster headache is a disorder with highly distinctive clinical features. Several of the terms used to describe cluster headache can be confusing so have been defined here. A cluster headache or attack is an individual episode of pain that can last from a few minutes to some hours. A cluster bout or period refers to the duration over which recurrent cluster attacks are occurring; it usually lasts some weeks or months. A remission is the pain-free period between two cluster bouts.
Cluster headache is classified according to the duration of the bout. About 80–90% of sufferers have episodic cluster headache (ECH), which is diagnosed when they experience recurrent bouts. The remaining 10–20% of sufferers have chronic cluster headache (CCH) in which either no remission occurs within one year or the remissions last less than one month. Most people with ECH have one or two annual cluster periods, each lasting between one and three months. Often, a striking periodicity is seen with the cluster periods, with the bouts occurring in the same month of the year.
The prevalence of cluster headache is estimated to be 0.2%. The male:female ratio is 2.5–7.2:1. It can begin at any age though the most common age of onset is the third or fourth decade of life.
Treatment for cluster headache relies on therapy to abort the individual attack, and prophylactic therapy aims to prevent or suppress attacks during the cluster bout (considered in chapter 16 of this guideline). Acute attack therapy must be fast-acting, be easily bioavailable, and provide effective relief from the symptoms. A low adverse-effect profile is also desirable. In routine clinical practice, a wide range of headache abortive treatments including aspirin, paracetamol, oxygen, triptans, ergots, NSAIDs, and opioids are used. The mechanism of action of the effective agents is largely unknown.
12.1.1. Clinical question
In people with cluster headache, what is the clinical evidence and cost-effectiveness for acute pharmacological treatment with: aspirin, paracetamol, oxygen, triptans, ergots, NSAIDs, and opioids?
A literature search was conducted for RCTs comparing the clinical effectiveness of different pharmacological interventions for acute treatment of cluster headache. The interventions we included in our search were paracetamol, NSAIDs, weak and strong opioids, triptans, oxygen, ergotamine and dihydroergotamine and placebo. We looked for any studies that compared the effectiveness of two or more of these treatments (or placebo). The initial protocol did not include placebo comparisons, however due to the limited amount of evidence available the guideline development group decided to amend the protocol to include placebo so that the review did not omit important evidence (see protocol C.2.4).
12.2. Matrix of treatment comparisons
Below is a matrix showing where evidence was identified. A box filled with a number represents the number of studies found, which are reviewed in this chapter. A box filled with - represents where no evidence was found. In this case, no section on this comparison is included in the chapter. The GDG were interested in the use of aspirin, paracetamol, NSAIDs, and opioids for the acute treatment of cluster headaches, but no evidence was identified in the review.
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| Paracetamol | - | |
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| NSAIDS (including aspirin at appropriate dose) | - | - | |
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| Opioids-weak | - | - | - | |
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| Opioids-strong | - | - | - | - | |
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| Triptans | 5 | - | - | - | - | |
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| Oxygen | 2 | - | - | - | - | - | |
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| Ergots | 1 | - | - | - | - | - | 1 |
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| Placebo | Paracetamol | NSAIDs | Opioids – weak | Opioids – strong | Triptans | Oxygen |
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Two Cochrane reviews were identified on the acute treatment of cluster headaches. One of these on the use of normobaric or hyperbaric oxygen therapy for treatment of cluster headache was excluded as it included studies in children aged less than twelve years of age16, any studies relevant to our protocol were included. The second Cochrane review140 did meet the review protocol, however the data were re-analysed to allow addition of new data. One study from the review was not included 11 as both the population and data analysis were unclear.
12.2.1. 100% Oxygen vs air
12.2.1.1. Clinical evidence
See evidence tables in appendix section E.2.4 and forest plots in –, appendix G.2.3.
Two studies were identified comparing 100% oxygen to air40,80. Populations were recruited from neurology departments, support groups and also from outpatient clinics. Studies analysed included both high flow (12 L/min) oxygen and low flow (6 L/min) oxygen as interventions.
Both studies reported data on reduction in pain at 30 minutes, however data from one study 80 could not be meta-analysed because the results were not reported in a useable format.
Data on adverse events was reported differently across studies and could not be meta-analysed. None of the studies reported functional health status or health related quality of life data.
100% oxygen vs air – Quality assessment.
100% oxygen vs air – Clinical summary of findings.
100% oxygen vs air – Quality assessment.
100% oxygen vs air – Clinical summary of findings.
12.2.1.2. Economic evidence
No economic evidence for oxygen in the treatment of cluster headache was identified.
Providers of home oxygen therapy vary across England and Wales and it was not possible to obtain any information on the cost of this service from them.
We found some national data from the Primary Care Commissioning publication on Home Oxygen Service185 where it was estimated that the Home Oxygen Service costs around £175 per new person and around £69 per 6-month check-up, based on the 2008/9 Reference Cost data obtained from 20 submissions for an outpatient ‘Oxygen Assessment and Review’ service (currency code DZ38Z). These submissions comprised various service setups and the Home Oxygen Service can be expected to have smaller unit costs because of its scale, and the comparatively low resource usage of the half-hour 6-month check-ups.
This information relates to the provision of oxygen for various conditions (e.g. chronic obstructive pulmonary disease) and no specific cost could be determined for people with cluster headache.
12.2.1.3. Evidence statements
Clinical
One study with 109 people with cluster headache showed that 100% oxygen is more clinically effective than air in reducing pain at 30 minutes. [Moderate quality].
One study with 19 people with cluster headache suggested that 100% oxygen may be more clinically effective than air in reducing pain at 30 minutes, but there is some uncertainty. [Low quality].
One study with 109 people with cluster headache showed that 100% oxygen is more clinically effective than air at producing headache response at one hour. [Moderate quality].
No studies reported outcome data for time to freedom from pain, functional health status and health related quality of life or incidence of serious adverse events.
Economic: No economic evidence was found for this question. The cost of home oxygen service was estimated at £175 per new person and around £69 per 6-month check-up. However, these figures are not specific to people with cluster headache and costs are expected to be smaller due to a better efficient use of resources achieved with the new setup of service provision.
12.2.1.4. Recommendations and link to evidence
See recommendations and link to evidence in section 12.3.
12.2.2. 100% oxygen vs ergot
12.2.2.1. Clinical evidence
See evidence tables in appendix section E.2.4 and forest plots in , appendix G.2.3.
One study was identified comparing 100% oxygen to ergotamine 132,132, this was a crossover trial that looked at an outpatient headache clinic population comparing low flow oxygen (7 L/min) and sublingual ergotamine tartrate (dose not stated). ITT with last observation carried forward only was available for data analysis132,132.
100% oxygen vs ergot – Quality assessment.
100% oxygen vs ergot – Clinical summary of findings.
12.2.2.2. Economic evidence
No economic evaluations comparing 100% oxygen with ergotamine were identified. We calculated the cost per episode of different pharmacological treatments based on the unit cost reported in the BNF62111 (see below). The cost of 100% oxygen is reported in section 12.2.1.2.
The costs of adverse effects and further events were not estimated.
12.2.2.3. Evidence statement
Clinical
One study with 50 people with cluster headache suggested that 100% oxygen may be more effective than ergotamine in reducing pain at 30 minutes, but the effect size is too small to be clinically important and there is considerable uncertainty. [Very low quality].
No studies reported outcome data for headache response, time to freedom from pain, functional health status and health related quality of life or incidence of serious adverse events.
Economic
No economic evidence was found for this question. A simple cost analysis showed a difference in costs between oxygen and ergotamine but it is difficult to compare the two estimates because the cost of oxygen is a long-term estimate (£175 per new patient and £69 per 6-month check-up for oxygen service) while the cost of ergotamine is a short-term cost (£0.34 per episode).
12.2.2.4. Recommendations and link to evidence
See recommendations and link to evidence in section 12.3.
12.2.3. Triptan vs placebo
12.2.3.1. Clinical evidence
See evidence tables in appendix section E.2.4 and forest plots in –, appendix G.2.3.
Five studies were identified comparing triptan to placebo. All studies included were crossover trials that included populations from neurology departments and headache clinics; two studies were carried out on an inpatient population.
The triptans considered in this review were zolmitriptan and sumatriptan which were pooled for analysis; the routes of administration were either nasal or subcutaneous, also pooled for analysis (see protocol C.2.4). No heterogeneity was observed.
Data on adverse events was reported differently across studies and could not be meta-analysed. None of the studies reported functional health status or health related quality of life data. Time to freedom from pain was reported in one study259; the data could not be meta-analysed as only the mean time to freedom from pain was reported.
Triptan vs placebo – Quality assessment.
Triptan vs placebo – Clinical summary of findings.
12.2.3.2. Economic evidence
No relevant economic evaluations comparing triptans with placebo were identified. We calculated the cost per episode of different pharmacological treatments based on the unit cost reported in the BNF62111 (see in section 12.2.2.2).
12.2.3.3. Evidence statements
Clinical
One study with 92 people with cluster headache showed that triptans are more clinically effective than placebo at reducing pain at 30 minutes. [Moderate quality].
One study with 118 people with cluster headache showed that the time to freedom from pain was lower with triptans than placebo, but the difference is uncertain as no comparative analysis could be carried out. [Low Quality].
Five studies with 494 people with cluster headache showed that triptans are more clinically effective than placebo in producing headache response at 15 or 30 minutes. [Moderate quality].
No studies reported outcome data for functional health status and health related quality of life or incidence of serious adverse events.
Economic
No economic evidence was found for this question. A simple cost analysis showed the cost per episode is between £5.90 and £12.16 for nasal spray triptans and £21.24 for subcutaneous triptans.
12.2.3.4. Recommendations and link to evidence
See recommendations and link to evidence in section 12.3.
12.2.4. Ergots vs placebo
12.2.4.1. Clinical evidence
See evidence tables in appendix section E.2.4.
One study was identified comparing ergots to placebo228,228. This was a crossover study reporting intramuscular administration of ergots in inpatients. The only outcome that was reported was the mean time to freedom from pain and data could not be meta-analysed.
Ergots vs placebo – Quality assessment.
Ergots vs placebo – Clinical summary of findings.
12.2.4.2. Economic evidence
No relevant economic evaluations comparing ergots with placebo were identified. We calculated the cost per episode of different pharmacological treatments based on the unit cost reported in the BNF62111 (see in section 12.2.2.2).
12.2.4.3. Evidence statement
Clinical
One study with 8 people with cluster headache showed that the time to freedom from pain was shorter with ergots than placebo, but the difference is uncertain as no comparative analysis could be carried out. [Moderate quality].
No studies reported outcome data for reduction in pain at 30 minutes, headache response, functional health status and health related quality of life or incidence of serious adverse events.
Economic: No economic evidence was found for this question. A simple cost analysis showed the cost per episode is around £0.22 34 for ergots.
