Why is the therapeutic effect of acute antimigraine drugs delayed? A review of controlled trials and hypotheses about the delay of effect.

Abstract

In randomised controlled trials (RCTs) of oral drug treatment of migraine attacks, efficacy is evaluated after 2hours. The effect of oral naratriptan 2.5mg with a maximum blood concentration (Tmax ) at 2hours increases from 2 to 4hours in RCTs. To check whether such a delayed effect is also present for other oral antimigraine drugs, we hand-searched the literature for publications on RCTs reporting efficacy. Two triptans, 3 nonsteroidal anti-inflammatory drugs (NSAIDs), a triptan combined with an NSAID and a calcitonin gene-related peptide receptor antagonist were evaluated for their therapeutic gain with determination of time to maximum effect (Emax ). Emax was compared with known Tmax from pharmacokinetic studies to estimate the delay to pain-free. The delay in therapeutic gain varied from 1-2hours for zolmitriptan 5mg to 7hours for naproxen 500mg. An increase in effect from 2 to 4hours was observed after eletriptan 40mg, frovatriptan 2.5mg and lasmiditan 200mg, and after rizatriptan 10mg (Tmax =1h) from 1 to 2hours. This strongly indicates a general delay of effect in oral antimigraine drugs. A review of 5 possible effects of triptans on the trigemino-vascular system did not yield a simple explanation for the delay. In addition, Emax for triptans probably depends partly on the rise in plasma levels and not only on its maximum. The most likely explanation for the delay in effect is that a complex antimigraine system with more than 1 site of action is involved.