Evaluation of LY573144 (lasmiditan) in a preclinical model of medication overuse headache

Abstract

Background Medication overuse is a significant issue that complicates the treatment of headache disorders. The most effective medications for the acute treatment of migraine all have the capacity to induce medication overuse headache (MOH). Novel acute migraine-specific treatments are being developed. However, because the mechanism(s) underlying medication overuse headache are not well understood, it is difficult to predict whether any particular acute medication will induce MOH in susceptible individuals. LY573144 (lasmiditan), a 5-HT1F receptor agonist, has recently been shown to be effective in the acute treatment of migraine in phase 3 trials. The aim of this study is to determine whether frequent administration of lasmiditan induces behaviors consistent with MOH in a pre-clinical rat model. Methods Sprague Dawley rats were administered six doses of lasmiditan (10 mg/kg), sumatriptan (10 mg/kg), or sterile water orally over 2 weeks and cutaneous allodynia was evaluated regularly in the periorbital and hindpaw regions using von Frey filaments. Testing continued until mechanosensitivity returned to baseline levels. Rats were then submitted to bright light stress (BLS) or nitric oxide (NO) donor administration and were again evaluated for cutaneous allodynia in the periorbital and hindpaw regions hourly for 5 hours. Results Both lasmiditan and sumatriptan exhibited comparable levels of drug-induced cutaneous allodynia in both the periorbital and hindpaw regions, which resolved after cessation of drug administration. Both lasmiditan and sumatriptan pre-treatment resulted in cutaneous allodynia that was evoked by either BLS or NO donor. Conclusions In a pre-clinical rat model of MOH, oral lasmiditan, like sumatriptan, induced acute transient cutaneous allodynia in the periorbital and hindpaw regions that after resolution could be re-evoked by putative migraine triggers. These results suggest that lasmiditan has the capacity to induce MOH through persistent latent peripheral and central sensitization mechanisms.

The American Headache Society Consensus Statement: Update on integrating new migraine treatments into clinical practice

“…As stated previously, rimegepant (as with ubrogepant and lasmiditan) does not constrict blood vessels and may have a role in patients with cardiovascular contraindications to triptans 76 . Repeated acute treatment with rimegepant does not appear to be associated with medication‐overuse headache, 66,67 which makes it similar to ubrogepant 65 and may distinguish it from lasmiditan 68 …”

“…Patients who continue to overuse acute medication while receiving preventive therapy may require an escalation in the preventive dose or a change in acute or preventive therapy; expert consensus generally supports the addition of a second preventive treatment in these patients. Among newer medications, repeated treatment with the CGRP receptor antagonists (i.e., ubrogepant and rimegepant) does not appear to be associated with medication‐overuse headache 65–67 ; preclinical models suggest repeated use of lasmiditan may induce medication‐overuse headache through persistent latent peripheral and central sensitization mechanisms, although clinical studies are lacking 68,69 . Acute treatment with an approved neuromodulatory device may reduce the use of acute medication 70 …”

“…Patients given a prescription for lasmiditan should be cautioned not to drive within 8 h after taking their medication. Frequent use of lasmiditan may potentially cause medication‐overuse headache 68 …”

“…Among newer medications, repeated treatment with the CGRP receptor antagonists (i.e., ubrogepant and rimegepant) does not appear to be associated with medication-overuse headache [65][66][67] ; preclinical models suggest repeated use of lasmiditan may induce medication-overuse headache through persistent latent peripheral and central sensitization mechanisms, although clinical studies are lacking. 68,69 Acute treatment with an approved neuromodulatory device may reduce the use of acute medication. 70…”

“…Frequent use of lasmiditan may potentially cause medication-overuse headache. 68 The safety, tolerability, and efficacy of coadministering lasmiditan with a triptan or a gepant has not been assessed.…”