The Oral Triptans
Abstract & Commentary
Source: Ferrari MD, et al. Oral triptans (serotonin 5-HT 1B/1D agonists) in acute migraine treatment: A meta-analysis of 53 trials. Lancet. 2001;358:1668-1675.
Sumatriptan SQ was approved for use in migraine in 1991. Since then, 2 additional formulations of sumatriptan (oral and nasal spray) and 6 new "second generation" oral triptans (zolmitriptan, rizatriptan, naratriptan, eletriptan, almotriptan, frovatriptan) have come on the market. All of these represent the most important contribution to the treatment of migraine in the last 50 years. Nevertheless, all the choices can easily confuse the clinician. Ferrari and colleagues have provided us with an essential framework with which to analyze and compare the various choices. While direct comparator trials are the gold standard for making comparisons, it is unlikely that all the triptans will ever be compared and probably unnecessary. Triptan trials themselves are similar in design and study population facilitating a meta-analysis to summarize the efficacy and tolerability of triptans across studies.
Ferrari et al pooled and analyzed the raw data from 24,089 patients enrolled in 53 of all 76 total clinical trials involving triptans. The trials had to meet the following inclusion criteria: randomized, placebo-controlled treatment of moderate-to-severe migraine within 8 hours of onset. Several efficacy parameters were assessed based on patient headache rating on a standard 4-point scale: time-to-pain relief, time-to-pain free, headache recurrence, and sustained 24-hour pain free. Tolerability and safety were assessed by expressed adverse events. Limited data were available for frovatriptan.
Sumatriptan 100 mg—the first oral and widely prescribed worldwide triptan—was chosen as the single reference point. Mean results for sumatriptan 100 mg were 59% (95% CI, 57-60) 2-hour pain relief; 29% (27-30) pain free; 20% (18-21) sustained pain free; and 67% (63-70) consistent responses in at least 2 out of 3 attacks. In terms of safety and tolerance, placebo subtracted proportions for patients with at least 1 adverse event were 13% (8-18), for at least 1 CNS AE 6% (3-9), and for at least 1 chest AE 1.9% (1.0-2.7). Similar symptoms were calculated for each triptan and overall comparisons were made. Rizatriptan 10 mg showed better efficacy and consistency and similar tolerability. Eletriptan 80 mg showed better efficacy and similar consistency but lower tolerability. Almotriptan 12.5 mg showed similar efficacy but better consistency and slightly better tolerability. Naratriptan 2.5 mg, eletriptan 20 mg, and frovatriptan 2.5 mg showed lower efficacy, but better tolerability. Sumatriptan 50 mg; zolmitriptan 2.5 mg and 5 mg; rizatriptan 5 mg; and eletriptan 40 mg all showed similar results to sumatriptan 100 mg. Subset analysis of the 22 direct comparator trials showed the same overall patterns. Ferrari et al concluded that all triptans are effective and well tolerated. Rizatriptan 10 mg, eletriptan 80 mg, and almotriptan 12.5 mg apparently provide the highest likelihood of consistent success.
Commentary
The current meta-analysis provides the best current outline in which to assess the current oral triptan class of drugs. Meta-analysis can be fraught with the danger of over interpretation, and lack in depth what they achieve in scope. However, given the similar variables, in all, the current study is useful and seems to match clinical experience. Ferrari et al’s study confirms and helps stratify the triptans based upon efficacy. There appear to be 4 tiers of efficacy. Sumatriptan SQ (not included in the meta-analysis because it is not an oral preparation) ranks as the most effective triptan with 2-hour pain relief approaching 80%. Second-tier oral drugs approaching 60-70% 2-hour efficacy include rizatriptan 10 mg, almotriptan 12.5 mg, zolmitriptan 5 mg, and eletriptan 80 mg. Third tier with 50-60% 2-hour efficacy are sumatriptan 50 mg and 100 mg, zolmitriptan 2.5 mg, and rizatriptan 5 mg. The lowest tier with 40-50% response are naratriptan 2.5 mg, eletriptan 20 mg, and frovatriptan 2.5 mg. (See Table.)
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However, several simple guidelines for using any of the triptans need to be kept in mind:
1. They are all valid choices and individual patients may respond to 1 or all of them in idiosyncratic and unpredictable ways. Therefore, it is reasonable for an individual patient to try 1 or all triptans to find the best.
2. All triptans are safe and well tolerated.
3. Don’t be misled by recurrent data. By definition, recurrence requires an initial response. Naratriptan and frovatriptan have low 2-hour efficacy rates and, therefore, low 24-hour recurrence rates. Sustained pain-free response is the more accurate measure of longer-term efficacy.
4. Early triptan use means better efficacy. Early treatment of migraine was not part of the initial triptan protocols not included in this meta analysis. Presently, current migraine studies find efficacy ranges in 80-90% when using triptans during the mild-to-moderate attacks of migraine.
Despite their revolutionary role in migraine treatment, triptans remain underused. Simple and combination analgesics are too often the first medication of choice. The current study should reassure clinicians that there is not a bad choice among the group. The pharmaceutical industry should do more to educate patients and practitioners to expand the overall market instead of petitioning for triptan bragging rights. —Jeffrey Reich
Dr. Reich, Assistant Professor, Neurology, New York Presbyterian Hospital-Cornell Campus, is Assistant Editor of Neurology Alert.
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