Response to ‘Preclinical pharmacological profile of the selective 5-HT 1F receptor agonist lasmitidan. A comment’,Maggioni et al.

In their letter to the Editor, Maggioni et al. (1) question the contribution of 5-HT_1F receptor agonism to migraine relief on the grounds that naratriptan, which has high affinity and agonist efficacy at 5-HT_1F receptors in vitro, is clinically a less efficacious anti-migraine agent than rizatriptan, which has only low affinity for 5-HT_1F receptors. However, such an extrapolation of in vitro data to the clinical setting fails to take into account the neural mechanism of action of the 5-HT_1F agonist lasmiditan versus the vascular site of action of 5-HT_1B/1D agonists (triptans).

Because triptans were developed in an era when migraine was considered to be a vascular disease, they were developed as cerebral vasoconstrictors, acting at vascular 5-HT_1B receptors (2). As a class, triptans are considered to be poorly brain penetrant (3). With the focus of developing new treatment approaches without the cardiovascular safety liability of triptans, selective 5-HT_1F agonists were developed as a unique class of neurally acting anti-migraine agents that lack vasoconstrictor activity (4–6). Unlike triptans, 5-HT_1F agonists were developed to be centrally active in order to target 5-HT_1F autoreceptors located on the trigeminal nociceptive pathway. Hence the affinity of naratriptan for 5-HT_1F receptors would not be expected to contribute to its clinical efficacy because this drug was developed for its 5-HT_1B vasoconstrictor activity, which does not require CNS penetration. High affinity at 5-HT_1F receptors in vitro is not relevant clinically if the drug cannot reach the site of action in the CNS. Lasmiditan, unlike triptans, was designed to be CNS penetrant in order to reach centrally located 5-HT_1F receptors.

Even within the triptan class, it is perilous to extrapolate from in vitro affinity at the 5-HT_1B vasoconstrictor receptor to clinical efficacy. Naratriptan has almost 10-fold higher potency at the 5-HT_1B receptor than sumatriptan, and has equal potency and affinity with sumatriptan at the 5-HT_1D receptor (7). Thus, if the 5-HT_1B/1D hypothesis regarding the action of triptans to alleviate migraine is correct, then one would expect naratriptan to be at least as efficacious, if not more so, than sumatriptan.

With regard to the perceived poorer clinical efficacy of naratriptan relative to rizatriptan, this may simply be a matter of dose. Whilst the standard oral dose of naratriptan is 2.5 mg, in dose ranging clinical studies, higher doses (7.5 mg and 10 mg) demonstrated greater efficacy, but were associated with increased side effects (8). Hence, one has to question whether the clinically used doses of naratriptan result in sufficient drug levels to optimally activate even 5-HT_1B receptors on blood vessels, let alone access 5-HT_1F receptors in the CNS.

Finally, multiple clinical trials have clearly established robust anti-migraine efficacy of selective 5-HT_1F agonists, including lasmiditan (9–11).