Is sustained pain freedom and no adverse events a clinically relevant endpoint in acute migraine treatment?

In a recent paper (1) the authors state that “the challenge for acute migraine treatment is to provide patients with a treatment that offers a rapid onset of complete and sustained pain relief with minimal or no adverse effects, thus restoring the patient’s ability to function normally”. Then a large randomised, placebo-controlled clinical trial with telcagepant and zolmitriptan for acute migraine treatment (2) is analysed for proportions of attacks with sustained pain freedom and no adverse events (SPF2NAE), and related composite efficacy-plus-tolerability endpoints (1). Telcagepant 300 mg (26.9%) was similar to zolmitriptan 5 mg (31.3%) for pain freedom at two hours, but telcagepant was superior (14.2%) to zolmitriptan (8.8%) for SPF2NAE (p < .05) (effect size difference = 5.4% [95% confidence intervals: 0.7%–10.7%]).

Clinically, the patient has to choose between being among 50 of 351 (telcagepant 300 mg) or among 30 of 341 (zolmitriptan 5 mg) who have a sustained pain-free response without adverse events (AEs). This is an impossible choice. This SPF2NAE response is generated by a post-hoc analysis of a large-parallel-group, randomised controlled trial (RCT) and with the current responses (2) treating moderate-to-severe headaches, the clinical relevance is dubious. Treating mild migraine headache results in higher rates of sustained pain freedom (SPF) (3,4). Thus, almotriptan 12.5 mg for mild headache resulted in 45.6% SPF in one RCT (3), whereas rizatriptan 10 mg for mild headache resulted in 42.6% and 48.0% SPF in two studies (4). Both were superior to placebo (3,4). The incidence of AEs for almotriptan was 5% (placebo, 5%) (3), and for rizatriptan it was 21.0% and 21.8% (placebo, 12.4% and 9.5%) (4). The apparent result, calculated from these different RCTs (3,4), would be a higher SPF2NAE for almotriptan than for rizatriptan. But would the patients prefer almotriptan (T_max = 2.6 hours) (5) if the AEs of rizatriptan (T_max = 1.0 hour) (5) were mild and transitory? There is no reasonable answer to this question. Instead, the efficacy/tolerability ratio should be studied prospectively. Why not let migraine patients directly judge the two treatments? This can be done in a placebo-controlled, three-way, crossover RCT with two active drugs, in which the patients can be asked about their preference as to what should be the primary endpoint. SPF2NAE could then be a secondary endpoint, together with pain freedom at two hours, SPF, and incidence of AEs.