Triptans for acute cluster headache
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
The objective of the review will be to assess the efficacy and tolerability of the triptan class of drugs compared to placebo and other active interventions in the acute treatment of episodic and chronic cluster headache in adult patients.
Background
Description of the condition
Cluster headache is a most painful form of primary headache. Diagnosis is clinical with emphasis on pain, periodicity and autonomic features. The International Association for the Study of Pain (IASP) defines cluster headache as 'unilateral, excruciatingly severe attacks of pain principally in the ocular, frontal and temporal areas recurring in separate bouts with daily or almost daily attacks for weeks to months usually with ipsilateral lacrimation, conjunctival injection, photophobia and nasal stuffiness and/or rhinorrhoea' (Merksey 1994). The diagnostic criteria of the International Headache Society (IHS), which are more commonly used in clinical trials, similarly describe cluster headache as 'attacks of severe, strictly unilateral pain which is orbital, supraorbital, temporal or in any combination of these sites, lasting 15 to180 minutes and occurring from once every other day to eight times per day' and associated with one or more of various ipsilateral symptoms (conjunctival injection, lacrimation, nasal congestion, rhinorrhoea, forehead and facial sweating, miosis, ptosis or eyelid oedema) (IHS 2004).
Whatever classification is used, it is important to note a few key definitions used in the descriptions of cluster headache. An 'attack' is an individual episode of headache, and a 'cluster period' is a series of such attacks. The major division of cluster headache is between episodic and chronic types. Episodic cluster headache is defined as 'cluster headache attacks occurring in periods lasting 7 days to 1 year separated by pain‐free periods [remissions] lasting 1 month or longer', while chronic cluster headache is defined as 'attacks occurring for more than 1 year without remission or with remissions lasting less than 1 month' (IHS 2004).
The prevalence of cluster headache is estimated to be 0.02% to 0.4%, with a male preponderance (D'Alessandro 1986). Onset is commonest between 20 to 40 years of age (Ekbom 1978). Cluster headache pain has a rapid onset and lasts from 15 minutes to 3 hours.
Treatment for cluster headache attacks can be either preventative or acute. Preventative treatment aims to decrease the incidence of attacks; acute therapy is directed at alleviating the symptoms of an individual attack when it occurs. This review will look at acute therapies only. Given the severity, rapid onset and short time to peak intensity, treatment has to be swift and effective. Attacks are commonly treated with inhaled oxygen, intranasal lignocaine or injectable ergotamine.
Description of the intervention
Triptans are selective agonists at the ligand gated, G‐protein linked serotonergic, or 5‐hydroxytriptamine receptors. Several drugs within the 'triptan' class are licensed for use in primary headache. These drugs have been extensively studied for the acute treatment of migraine. Because cluster headache shares some clinical features with migraine, triptans have also been studied for the acute treatment of cluster headache using the oral and the more rapid intranasal or subcutaneous routes of administration (Plosker 1994; Rapoport 2007).
How the intervention might work
The specific receptors found to be involved in headache are the 5‐HT 1B, 1D and 1F subtypes. The supposed methods of action of triptans in migraine are a vasoconstrictor effect on the carotid artery circulation, peripheral neuronal inhibition and inhibition of neurons in the trigeminal nerve complex (Ferrari 2002). It is postulated that a neurovascular pathogenesis underlies cluster headache, and the effects of triptans in migraine are also relevant to treatment of cluster headache.
More specifically, magnetic resonance angiography studies have demonstrated a segmental vasodilatory effect of ophthalmic and internal carotid arteries in the distribution of the trigeminal nerve during an attack. Blockades of the branches of this cranial nerve have been used therapeutically to halt cluster headache (Waldenlind 1993). If the serotonergic agonist m‐chlorophenylpiperazine is administered in subjects with cluster headache, the subsequent attenuated prolactin and cortisol levels suggest a level of dysfunction of the serotonergic system (Leone 1997). Alcohol, nitrates and carbon dioxide are known to precipitate cluster headache. Similar inflammatory metabolic intermediaries such as calcitonin gene related peptide (CGRP), substance P, somatostatin and histamine, all with vasodilatory properties, are also known to provoke attacks (Cluster Headache Study Group 1991).
Taken together, these findings suggest that cluster headache may involve a central lesion which triggers a peripheral response. Such a lesion may be found in the carotid sinus which then causes acetyl choline release from the autonomic nervous system and a perivascular neurogenic response with the release of inflammatory mediators and resulting typical pain and neurovascular response (Moskowitz 1988).
Serotonin agonists may therefore be useful. It is thought that they may readjust an underlying altered nervous system and, by gaining access to the trigeminal system, abort cluster headache attacks.
Why it is important to do this review
Although cluster headache affects a relatively small proportion of people, it is an extremely painful and disabling condition. There is currently no systematic review of the evidence for the efficacy and tolerability of the triptan class of drugs for acute cluster headache. The proposed review will fill this gap using methods that allow comparison between individual drugs and routes of administration in standardised trials.
Objectives
The objective of the review will be to assess the efficacy and tolerability of the triptan class of drugs compared to placebo and other active interventions in the acute treatment of episodic and chronic cluster headache in adult patients.
Methods
Criteria for considering studies for this review
Types of studies
Randomised, double‐blind, placebo‐controlled studies using a triptan to treat a discrete cluster headache episode will be included. Studies must have a minimum of 10 participants per treatment arm and report dichotomous data for at least one of the primary outcomes specified below. Studies reporting treatment of consecutive headache episodes will be accepted if outcomes for the first, or each, episode are reported separately. Crossover studies will be accepted if there is adequate washout between treatments.
Types of participants
Studies must include adults (at least 18 years of age) with cluster headache. The diagnosis of cluster headache specified by the International Headache Society will be used (IHS 1988 or IHS 2004), although other definitions will be considered if they conform in general to IHS diagnostic criteria. There will be no restrictions on cluster headache frequency, duration or type (episodic or chronic). Participants taking stable prophylactic therapy to reduce headache frequency will be accepted; details on the prophylactic therapy prescribed or allowed will be provided in the 'Characteristics of included studies' table.
Types of interventions
Included studies must use either a single dose of any triptan to treat a cluster headache episode when pain is of moderate to severe intensity, or investigate different dosing strategies and/or timing of the first dose in relation to headache intensity. There will be no restriction on dose or route of administration, provided the medication can be self‐administered.
A placebo comparator is essential to demonstrate that triptans are effective in this condition, and the main comparisons will be for triptan versus placebo. Where studies have both a placebo and active comparator, data will be sought for direct comparison of triptan versus the active comparator. Active‐controlled trials without a placebo, such as equivalence trials, will be considered as secondary evidence if the trial is judged to have validity by accepted criteria (McAlister 2001). Studies to demonstrate prophylactic efficacy in reducing the number or frequency of cluster headaches will not be included.
Types of outcome measures
Measures of pain intensity or pain relief should be made by the patient (not the investigator or carer) using a standard 5‐point categorical scale (pain intensity: none, mild, moderate, severe, very severe/excruciating; pain relief: none, a little, some, a lot, complete) or 100 mm visual analogue scale (VAS) (IHS Trial Guidelines 1995; Moore 2003).
Primary outcomes
The primary outcomes to be considered are:
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Headache relief (assessed on the 5‐point pain relief scale described above or defined as a reduction in pain intensity from moderate/severe/very severe to none/mild) at 30 minutes or later times, without use of rescue medication;
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Pain‐free at 30 minutes or later times, without use of rescue medication.
Secondary outcomes
Secondary outcomes to be considered are:
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Relief of headache‐associated symptoms;
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Time to headache relief;
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Time to pain‐free;
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Use of rescue medication;
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Adverse events: any, serious, withdrawal, reported within 24 hours post dose;
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Recurrence of headache (defined as the return of headache to a moderate or severe pain intensity within 24 hours of initial medication).
Search methods for identification of studies
Electronic searches
The following databases will searched:
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Cochrane CENTRAL
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MEDLINE (via OVID)
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EMBASE (via OVID)
See Appendix 1 for the search strategy for MEDLINE (via OVID). This will be modified for searching the other databases. There will be no language restrictions.
Searching other resources
Reference lists of retrieved studies and review articles will be searched for additional studies. Grey literature and abstracts will not be searched.
Data collection and analysis
Selection of studies
Two review authors will independently carry out the searches and select studies for inclusion. Titles and abstracts of all studies identified will be viewed on screen, and any that clearly do not satisfy inclusion criteria will be excluded. Full copies of the remaining studies will be read to identify those suitable for inclusion. Disagreements will be settled by discussion with a third review author.
Data extraction and management
Two review authors will independently extract data from included studies using a standard data extraction form. Disagreements will be settled by discussion with a third review author. Data will be entered into RevMan 5.0 by one author.
Assessment of risk of bias in included studies
Methodological quality will be assessed using the Oxford Quality Scale (Jadad 1996).
The scale is used is as follows:
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Is the study randomised? If yes, give one point.
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Is the randomisation procedure reported and is it appropriate? If yes, add one point; if no, deduct one point.
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Is the study double blind? If yes, add one point.
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Is the double blind method reported and is it appropriate? If yes, add one point; if no, deduct one point.
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Are the reasons for patient withdrawals and dropouts described? If yes, add one point.
The scores for each study will be reported in the 'Characteristics of included studies' table.
A risk of bias table will also be completed, using assessments of randomisation, allocation concealment and blinding.
Measures of treatment effect
Dichotomous data
Relative risk (or 'risk ratio', RR) will be used to establish statistical difference. Numbers needed to treat (NNT) and pooled percentages will be used as absolute measures of benefit or harm.
The following terms will be used to describe adverse outcomes in terms of harm or prevention of harm:
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When significantly fewer adverse outcomes occur with triptans than with control (placebo or active) we will use the term the number needed to treat to prevent one event (NNTp).
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When significantly more adverse outcomes occur with triptans than with control (placebo or active) we will use the term the number needed to harm or cause one event (NNH).
Time‐to‐event data
Time‐to‐event data will be weighted by study size and presented as the weighted mean of the median or mean.
Unit of analysis issues
We will accept randomisation to individual patient only.
Dealing with missing data
The most likely source of missing data is in crossover studies. Where this is an issue only first‐period data will be used.
Assessment of heterogeneity
Heterogeneity of studies will be assessed visually (L'Abbe 1987).
Assessment of reporting biases
No formal tests are planned.
Data synthesis
Studies using a single dose of a triptan in established pain of at least moderate intensity will be analysed separately from studies in which medication is taken before pain is well established or in which a second dose of medication is permitted.
Data will be combined for analysis where there are at least two studies and 200 participants (Moore 1998). Relative risk of benefit or harm will be calculated with 95% confidence intervals (CIs) using a fixed‐effect model (Morris 1995). NNT, NNTp and NNH with 95% CIs will be calculated using the pooled number of events by the method of Cook and Sackett (Cook 1995). A statistically significant difference from control will be assumed when the 95% CI of the relative risk of benefit or harm does not include the number one.
Subgroup analysis and investigation of heterogeneity
Issues for subgroup analysis are drug, dose and route of administration.
Sensitivity analysis
Sensitivity analysis is anticipated for study quality (Oxford Quality score of 2 versus 3 or more), and for headache type (episodic versus chronic cluster headache). A minimum of two studies and 200 participants must be available for any sensitivity analysis.
