New target for the pharmacological treatment of insomnia?

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By Dr. Simon Kyle

While sleep-promoting hypnotic medications are often prescribed for poor sleep, such medications are indicated for short term use only, and are not the treatment of choice for chronic insomnia. These benzodiazepine-receptor agonists have been associated with residual side-effects and increased tolerance, leading to the potential for addiction. There is therefore a search for new pathways and drug targets that may advance pharmacological management of insomnia.

In a recent trial published in the December issue of SLEEP, a team led by Emiliangelo Ratti, investigated whether Vestipitant, a Neurokinin-1 (NK-1) receptor antagonist, might have therapeutic benefits, while not inducing next day impairment through sedation. Based on evidence that Substance P (acting through NK-1 receptors) is involved in the regulation of stress, arousal and sleep, researchers sought to investigate whether antagonizing NK-1 receptors could be therapeutic in primary insomnia. Earlier work with healthy controls showed that infusion of Substance P reduced total sleep time. Antagonism of NK1 receptors may, therefore, have a de-arousing and sleep promoting effect.

100 patients with primary insomnia were randomized to receive either Vestipitant or a placebo for 28 days. Investigators assessed objective (polysomnography) and subjective sleep on nights 1/2 and nights 27/28. The team found that those who received Vestipitant evidenced reduced wakefulness during the night and increased overall total sleep time after 2 nights. These positive effects were maintained at 28 days (increasing total sleep time by 15 minutes relative to placebo). Intriguingly, with respect to subjective measures, the only significant effect was found for reports of sleep quality. Cognitive tasks suggested no residual negative daytime effects and reporting of adverse effects were similar across both groups.

While results indicate a possible new mechanism of action for objective sleep improvements, further studies are required to determine clinical benefits in primary insomnia. As the authors report, “Patient-reported outcomes may be considered to be as important as objective sleep measures, and so a lack of improvement in such measures may limit the clinical potential of vestipitant”. Fuurther trials are required to determine if Vestipitant can improve subjective measures of sleep and daytime functioning.

Ratti, E., Carpenter, D.J., Zamuner, et al. (2013). Efficacy of vestipitant, a neurokinin-1 receptor antagonist, in primary insomnia. SLEEP, 36(12), 1823-1830.

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