Glutamate receptor antagonists with the potential for migraine treatment

ABSTRACT

Introduction: Preclinical, clinical, and other (e.g., genetic) evidence support the concept that migraine susceptibility may at least partially result from a glutamatergic system disorder. Therefore, the receptors of the glutamatergic system are considered relatively new targets for investigational drugs to treat migraine. Investigational and established glutamate receptor antagonists (GluRAs) have been shown to possess antinociceptive properties in preclinical models of trigeminovascular nociception and have been evaluated in clinical trials. This review focuses on preclinical and clinical studies of GluRAs for the treatment of migraine.

Areas covered: A PubMed database search (from 1987 to December 2016) and a review of published studies on GluRAs in migraine were conducted.

Expert opinion: All published clinical trials of investigational GluRAs have been unsuccessful in establishing benefit for acute migraine treatment. Clinical trial results contrast with the preclinical data, suggesting that glutamate (Glu) does not play a decisive role after the attack has already been triggered. These antagonists may instead be useful for migraine prophylaxis.

Improving patient care requires further investigating and critically analyzing the role of Glu in migraine, designing experimental models to study more receptors and their corresponding antagonists, and identifying biomarkers to facilitate trials designed to target specific subgroups of migraine patients.

KEYWORDS:

• Acute treatment
• animal migraine models
• clinical trials
• cortical spreading depression
• glutamate
• glutamate receptor antagonists
• migraine
• prophylaxis

Article highlights

• Clinical trials with investigational glutamate receptors antagonists (selurampanel, tezampanel, LY466195 and raseglurant) in the acute treatment of migraine yielded unexceptional results, at best similar to those of already available drugs, but with CNS side effects that would likely limit tolerability.

• Because of the limitations of phase II trials, it was not possible to identify whether these investigational agents, which appear to lack vascular effects, might serve as useful alternatives in subgroups of patients, such as those with contraindications to triptans.

• The results of these clinical trials suggest that the role of the glutamatergic system is not decisive when the acute migraine attack has already been triggered. Because of the involvement of this system in the central sensitization processes, the investigational glutamate receptor antagonists might be useful in migraine prevention, but this potential has not yet been explored, and their development appears to have stopped.

• Nevertheless, the assessment of established NMDA receptor antagonists, such as ketamine and memantine, continues in independent studies for the acute treatment and prophylaxis of migraine. Indeed, the benefit/risk profile of these drugs in migraine therapy remains to be determined.

• To find effective new drugs and improve patient care, it is important to further investigate and critically analyze the role of glutamate in migraine. Moreover, experimental migraine models that allow studying more receptors together with their corresponding antagonists (to identify the most promising candidates) are needed. Finally, researchers should discover biomarkers of disease and response to drugs to facilitate the design of clinical trials that target specific subgroups of migraine patients.

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Declaration of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.