Elsevier

The Lancet

Volume 358, Issue 9294, 17 November 2001, Pages 1668-1675
The Lancet

Articles
Oral triptans (serotonin 5-HT1B/1D agonists) in acute migraine treatment: a meta-analysis of 53 trials

https://doi.org/10.1016/S0140-6736(01)06711-3Get rights and content

Summary

Background

The triptans, selective serotonin 5-HT1B/1D agonists, are very effective acute migraine drugs with a well-developed scientific rationale. Seven different triptans will soon be clinically available, making evidence-based selection guidelines necessary. Triptan trials have similar designs, facilitating meta-analysis; this will provide a foundation for using triptans in clinical practice.

Method

We asked pharmaceutical companies and the principal investigators of company-independent trials for raw patient data of all double-blind, randomised, controlled, clinical trials of oral triptans in migraine. We calculated summary estimates across studies for important efficacy and tolerability parameters, and separately summarised direct comparator trials.

Results

53 clinical trials (12 unpublished) involving 24 089 patients, met the criteria for inclusion. Mean results for 100 mg sumatriptan were 59% (95% CI 57–60) for 2 h headache response (improvement from moderate or severe to mild or no pain); 29% (27–30) for 2 h pain free (improvement to no pain); 20% (18–21) for sustained pain free (pain free by 2 h and no headache recurrence or use of rescue medication 2–24 h post dose); and 67% (63–70) for consistency (response in at least two of three treated attacks); placebo-subtracted proportions for patients with at least one adverse event (AE) were 13% (8–18), for at least one central nervous system AE 6% (3–9), and for at least one chest AE 1·9% (1·0–2·7). Compared with these data, 10 mg rizatriptan showed better efficacy and consistency, and similar tolerability; 80 mg eletriptan showed better efficacy, similar consistency, but lower tolerability; 12·5 mg almotriptan showed similar efficacy at 2 h but better other results; 2·5 mg naratriptan and 20 mg eletriptan showed lower efficacy and (the first two) better tolerability; 2·5 mg and 5 mg zolmitriptan, 40 mg eletriptan, and 5 mg rizatriptan showed very similar results. The results of the 22 trials that directly compared triptans show the same overall pattern. We received no data on frovatriptan, but publicly available data suggest lower efficacy.

Interpretation

At marketed doses, all oral triptans were effective and well tolerated. 10 mg rizatriptan, 80 mg eletriptan, and 12·5 mg almotriptan provide the highest likelihood of consistent success.

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

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