ArticlesOral triptans (serotonin 5-HT1B/1D agonists) in acute migraine treatment: a meta-analysis of 53 trials
Introduction
Migraine is a common, chronic, multifactorial neurovascular disorder, typically characterised by recurrent disabling attacks of severe headache, autonomic nervous system dysfunction and, in up to a third of patients, neurological aura symptoms.1, 2 Ergot derivatives used to be the only specific treatments for migraine attacks, although they had many limitations.3, 4 Improved understanding of the neurobiology of migraine and 5-HT (5-hydroxytryptamine serotonin) receptors have resulted in a new class of selective 5-HT1B/1D agonists, known as the triptans.5 They have three main mechanisms of action: cranial vasoconstriction, peripheral trigeminal inhibition, and inhibition of transmission through second order neurons of the trigeminocervical complex.6 The relative importance of each of these mechanisms remains uncertain.7, 8 By contrast with ergots, triptans have selective pharmacology, simple and consistent pharmacokinetics, evidence-based prescribing instructions, well established efficacy, modest side-effects, and a well established safety record; they are, however, also contraindicated in the presence of cardiovascular disease.9 Despite the higher price, triptans were preferred over ergots in most patients.3, 4
Given that seven different triptans will soon be clinically available, physicians need evidence-based guidelines to select the triptans with the highest likelihood of success. Direct active comparator trials were available for only a few triptans and it is unlikely that they will ever all be compared. Although such studies were deemed the gold standard for comparing drugs, there were also some important caveats, complicating their interpretation.10 The triptan trials were very similar in study methods and populations, facilitating meta-analysis to summarise the efficacy and tolerability of the different triptans across studies.11, 12 Previous triptan meta-analyses were based on summary data from published trials only, and only analysed a limited number of agents, doses, and outcome and adverse event variables.13, 14
Although oral absorption of many drugs is delayed during migraine attacks,15 most patients prefer oral formulations;16 they account for more than 80% of all triptan prescriptions (H Mansbach, GlaxoSmithKline, personal communication). We shall therefore concentrate on the oral formulations. Sumatriptan is also available in parenteral formulations; these are discussed elsewhere.10
Section snippets
Clinical assessment in acute migraine trials
Typically, patients were instructed to treat a migraine headache when pain is moderate or severe on a 4-point pain severity scale (0=no pain; l=mild; 2=moderate; 3=severe pain) and within 6–8 h of onset.11 The primary endpoint in most studies was the proportion of patients with a headache response (ie, improvement to mild or no pain 2 h post-dose). More recently, the proportion of patients who become pain free 2 h post-dose has become the preferred and clinically most relevant primary endpoint.
Results
Sumatriptan is the first and most widely prescribed triptan: most European countries use 100 mg as the primary oral dose, whereas North America and some other countries use 50 mg.10, 29 We selected the 100 mg dose as the single reference dose for a number of reasons.10
Figure 1A shows the mean absolute and placebo-subtracted rates and 95% CI of the headache response at 2 h. Compared with 100 mg sumatriptan (mean 59% [95% CI 57–60]), 10 mg rizatriptan and 80 mg eletriptan showed higher, and 2·5
Discussion
We used two complementary approaches for comparing the efficacy and tolerability of the oral triptans: a large meta-analysis of all the eligible, high-quality, randomised, placebo-controlled clinical trials and a separate analysis of all direct comparative studies. Both approaches give very similar results. Our meta-analysis used studies of a fundamentally similar design so that summary estimates of the efficacy and tolerability of the full range of compounds could be derived. The use of
References (35)
Migraine
Lancet
(1998)The pharmacology of headache
Prog Neurobiol
(2000)- et al.
Headache after frequent use of new serotonin agonists zolmitriptan and naratriptan
Lancet
(1999) - et al.
Meta-analysis in clinical trials
Control Clin Trials
(1986) - et al.
Effects of encapsulation on absorption of sumatriptan tablets: data from healthy volunteers and patients during a migraine
Clin Ther
(2001) - et al.
Mechanism and management of headache
(1998) Quality standards subcommittee of the American Academy of Neurology: practice parameter—appropriate use of ergotamine tartrate and dihydroergotamine in the treatment of migraine and status migrainosus
Neurology
(1995)- et al.
Ergotamine in the acute treatment of migraine—a review and European consensus
Brain
(2000) - et al.
Serotonin and migraine
Ann N Y Acad Sci
(1990) - et al.
Controversies in headache. The mode of action of sumatriptan is vascular? A debate
Cephalalgia
(1994)
5-HT1B/1D agonists in migraine: comparative pharmacology and its therapeutic implications
CNS Drugs
Tolerability of sumatriptan: clinical trials and post-marketing experience
Cephalalgia
Methodology of clinical trials of sumatriptan in migraine and cluster headache
Eur Neurol
Guidelines for controlled trials of drugs in migraine: 2nd edn
Cephalalgia
Efficacy and adverse events of subcutaneous, oral, and intranasal sumatriptan used for migraine treatment: a systematic review based on number needed to treat
Cephalalgia
A comparative review of pharmacology, pharmacokinetics and efficacy of triptans in migraine
Drugs
Cited by (894)
High performance liquid chromatographic method optimized by Box-Behnken design model to determine caffeine in pharmaceutical preparations and urine samples
2024, Journal of Chromatography B: Analytical Technologies in the Biomedical and Life SciencesThe 5-HT<inf>1B</inf> and 5-HT<inf>1D</inf> agonists in acute migraine therapy: Ergotamine, dihydroergotamine, and the triptans
2024, Handbook of Clinical NeurologyEvidence-based symptomatic treatment of migraine
2024, Handbook of Clinical NeurologyPhytocannabinoids: Pharmacological effects, biomedical applications, and worldwide prospection
2023, Journal of Traditional and Complementary Medicine