Triptans (Serotonin, 5-HT_1B/1DAgonists) in Migraine: Detailed Results and Methods of A Meta-Analysis of 53 Trials

Abstract

The triptans, selective serotonin 5-HT1B/1D agonists, are very effective acute migraine drugs. Soon, seven different triptans will be clinically available at 13 different oral doses, making evidence-based selection guidelines necessary. Triptan trials have similar designs, facilitating meta-analysis. We wished to provide an evidence-based foundation for using triptans in clinical practice, and to review the methodological issues surrounding triptan trials. We asked pharmaceutical companies and the principal investigators of company-independent trials for the 'raw patient data' of all double-blind, randomized, controlled, clinical trials with oral triptans in migraine. All data were cross-checked with published or presented data. We calculated summary estimates across studies for important efficacy and tolerability parameters, and compared these with those from direct, head-to-head, comparator trials. Out of 76 eligible clinical trials, 53 (12 not yet published) involving 24089 patients met the criteria for inclusion. Mean results (and 95% confidence intervals) for sumatriptan 100 mg, the first available and most widely prescribed oral triptan, are 59% (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 out of three treated attacks); placebo-subtracted proportions for patients with at least one adverse event (AE) are 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: rizatriptan 10 mg shows better efficacy and consistency, and similar tolerability; eletriptan 80 mg shows better efficacy, similar consistency, but lower tolerability; almotriptan 12.5 mg shows similar efficacy at 2 h but better sustained pain-free response, consistency, and tolerability; sumatriptan 25 mg, naratriptan 2.5 mg and eletriptan 20 mg show lower efficacy and better tolerability; zolmitriptan 2.5 mg and 5 mg, eletriptan 40 mg, and rizatriptan 5 mg show 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 substantially lower efficacy. The major methodological issues involve the choice of the primary endpoint, consistency over multiple attacks, how to evaluate headache recurrence, use of placebo-subtracted proportions to control for across-study differences, and the difference between tolerability and safety. In addition, there are a number of methodological issues specific for direct comparator trials, including encapsulation and patient selection. At marketed doses, all oral triptans are effective and well tolerated. Differences among them are in general relatively small, but clinically relevant for individual patients. Rizatriptan 10 mg, eletripta...

Acute pharmacotherapy of migraine, tension-type headache, and cluster headache

“…Trimebutine is also a prokinetic drug and in one RCT the combination of trimebutine plus rizatriptan (73% pain-free) was superior to rizatriptan alone (42% pain-free) [35,36]. The 42% pain-free is similar to what was found in a meta-analysis for rizatriptan 10 mg [7,8] and the combination with trimebutine thus resulted in a considerable increase of efficacy. One cannot exclude, however, that trimebutine per se has an antimigraine effect and further placebo-controlled studies are needed.…”

“…Rizatriptan 10 mg resulted in 70% being pain-free [20] and sumatriptan 100 mg resulted in 58% being pain-free [21] in double-blind, placebo-controlled RCTs. These results are considerable higher than the 30% pain-free found for most triptans when moderate or severe attacks are treated [7,8]. If patients can distinguish the mild phase of migraine from a tension-type headache, treatment with a triptan in the mild phase can be recommended.…”

“…The 5-HT1B/1D receptor agonists, the triptans, have been compared in several meta-analyses of placebo-controlled RCTs [6][7][8][9][10] and in head-to-head comparative RCTs [10]. An example of such a meta-analysis is shown in Table 1.…”

Lessons from placebo effects in migraine treatment

“…In view of this, there is clearly a need to attempt to disentangle adverse effects associated with placebo from those associated with active medications, in order to arrive at a more accurate profile of the tolerability and safety of the active medication. In placebo-controlled trials of migraine, adverse effects may occur with placebo in >30% of patients [19], and in triptan trials the mean (±SD) proportion of patients reporting an AE on placebo was 23.4±14.1% (range 5%-74%) [20].…”

Use of Most Bothersome Symptom as a Coprimary Endpoint in Migraine Clinical Trials: A Post‐Hoc Analysis of the Pivotal ZOTRIP Randomized, Controlled Trial

“…Primary efficacy endpoints in clinical trials of acute migraine medications have evolved over time and have included headache response/relief (improvement from moderate to severe pain at baseline to mild or no pain 2‐hour post‐dose); pain freedom at 2 hours post‐dose; and the co‐primary endpoints of pain relief, nausea, photophobia, and phonophobia 1, 2. In February 2018, the US Food and Drug Administration (FDA) issued a final guidance document for developing drugs for the acute treatment of migraine 1.…”