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-HT_1F 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.

中文翻译：

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LY573144（lasmiditan）在药物过度使用性头痛的临床前模型中的评估。

背景

药物过度使用是一个重要问题，使头痛疾病的治疗复杂化。用于急性偏头痛治疗的最有效药物都具有诱发药物过度使用性头痛 (MOH) 的能力。正在开发新型急性偏头痛特异性治疗方法。然而，由于药物过度使用性头痛的潜在机制尚不清楚，因此很难预测任何特定的急性药物是否会在易感个体中诱发 MOH。LY573144 (lasmiditan) 是一种 5-HT _1F受体激动剂，最近在 3 期试验中显示可有效治疗偏头痛。本研究的目的是确定在临床前大鼠模型中频繁给药 lasmiditan 是否会诱导与 MOH 一致的行为。

方法

Sprague Dawley 大鼠在 2 周内口服六剂 lasmiditan (10 mg/kg)、舒马曲坦 (10 mg/kg) 或无菌水，并使用 von Frey 细丝定期评估眶周和后爪区域的皮肤异常性疼痛。测试一直持续到机械敏感性恢复到基线水平。然后让大鼠接受强光应激 (BLS) 或一氧化氮 (NO) 供体给药，并再次评估眶周和后爪区域的皮肤异常性疼痛，持续 5 小时。

结果

lasmiditan 和舒马曲坦在眶周和后爪区域均表现出相当水平的药物诱发的皮肤异常性疼痛，在停止给药后消退。lasmiditan 和舒马曲坦预处理均导致皮肤异常性疼痛，由 BLS 或 NO 供体引起。

结论

在 MOH 的临床前大鼠模型中，口服 lasmiditan 与舒马曲坦一样，在眶周和后爪区域诱导急性短暂性皮肤异常性疼痛，缓解后可能被推定的偏头痛触发因素重新诱发。这些结果表明，lasmiditan 具有通过持久的潜在外周和中枢敏化机制诱导 MOH 的能力。