Pharmacological management of insomnia with a focus on GABAA receptor positive allosteric modulators and orexin receptor antagonists

The scientific literature regarding the effectiveness of two insomnia treatments: GABA_A receptor positive allosteric modulators, and orexin receptor antagonists is reviewed. In this review, we define insomnia, present epidemiological statistics on insomnia, and provide a rationale for use of medications targeting GABA_A and orexin receptors for management of insomnia. Following this, we present results of a PRISM guideline-based literature search spanning multiple databases, including PubMed, Google Scholar, ScienceDirect as well as curated searches through Baker Library at Harvard Business School covering publications evaluating insomnia therapies based on targeting GABA_A and orexin receptors available as of March 2025. We conclude that orexin receptor antagonists, notably lemborexant, were found to be more effective, safer, and improve quality of life greater when compared to GABA_A receptor positive allosteric modulators for short and long-term treatment of insomnia. While GABA_A receptor positive allosteric modulators are effective for short-term use, which typically spans two to four weeks, they present a greater number of contraindications than orexin receptor antagonists, and orexin receptor antagonists are superior at preserving the natural sleep architecture. Adverse events are particularly exacerbated when GABA_A receptor positive allosteric modulators are used for longer treatment durations spanning months, whereas orexin receptor antagonists tend to show a more favorable profile over similar long-term use. Nevertheless, there is an observed dose-response relationship with orexin receptor antagonists that may increase the risk of abuse at higher dosages. Approval for use of orexin receptor antagonists for management of insomnia is more restrictive in European countries than that seen in other regions around the globe. Taken together, the findings advocate for increased accessibility of orexin receptor antagonists in Europe for management of primary insomnia.