Dual orexin receptor antagonists for the treatment of insomnia: systematic review and network meta-analysis

Abstract

Background Several randomized clinical trials (RCTs) have shown that dual orexin receptor antagonists (DORAs) are effective in the treatment of chronic insomnia. However, the superiority of one particular DORA over the others remains unclear.

Objective To perform a network meta-analysis to evaluate the efficacy of different DORAs in patients with chronic insomnia.

Methods The Medline, Embase, and Cochrane Central databases were searched for RCTs that compared DORA with placebo in patients ≥ 18 years of age with a diagnosis of insomnia disorder. We pooled outcomes for wake time after sleep onset (WASO), latency to persistent sleep (LPS), total sleep time (TST), and adverse events (AEs).

Results We included 10 RCTs with 7,806 patients, 4,849 of whom received DORAs as the intervention. Overall, we found that DORAs were associated with the improvement of all analyzed efficacy outcomes. Concerning TST, an apparent dose-dependent pattern was noticed, with higher doses relating to a longer TST. Lemborexant 10mg provided the largest reduction in WASO (at month 1) in minutes (standardized mean difference [SMD] = -25.40; 95% confidence interval [95%CI] = -40.02–-10.78), followed by suvorexant 20/15mg (SMD = -25.29; 95%CI = -36.42–-14.15), which also appeared to provide the largest decrease in long-term WASO (SMD = -23.70; 95%CI = -35.89–-11.51). The most frequent AEs were somnolence, nasopharyngitis, and headache, with rates of up to 14.8%.

Conclusion Our results suggest that DORAs are associated with greater efficacy when compared with placebo in the treatment of insomnia, a complex 24-hour sleep disorder. Additionally, dosing might play an important role in the management of chronic insomnia.

Resumo

Antecedentes Inúmeros ensaios clínicos randomizados (ECRs) têm demonstrado que os antagonistas duais do receptor de orexina (dual orexin receptor antagonists, DORAs, em inglês) são eficazes no tratamento da insônia. Contudo, restam dúvidas quanto à superioridade de um DORA com relação aos outros.

Objetivo Realizar uma meta-análise em rede para avaliar a eficácia de diferentes DORAs em pacientes com insônia.

Métodos Foram feitas buscas nas bases de dados Medline, Embase e Cochrane Central por ECRs que comparassem DORAs e placebo em pacientes ≥ 18 anos de idade com diagnóstico de insônia. Os seguintes desfechos foram selecionados: tempo desperto após o início do sono (wake time after sleep onset, WASO, em inglês), latência para o sono persistente (latency to persistent sleep, LPS, em inglês), tempo total de sono (total sleep time, TST, em inglês), e efeitos adversos (EAs).

Resultados Incluímos 10 ensaios clínicos com 7,806 pacientes, 4,849 dos quais receberam DORAs como intervenção. Os DORAs foram associados à melhoria de todos os desfechos de eficácia analisados. Em relação ao TST, um aparente padrão de dependência da dose foi identificado, com doses maiores se associando a um maior TST. Lemborexant 10 mg proporcionou a maior redução em WASO (no primeiro mês) em minutos (diferença padronizada das médias [standardized mean difference, [SMD], em inglês) = -25.40; intervalo de confiança de 95% [IC95%] = -40.02–-10.78), seguido de suvorexant 20/15mg (SMD = -25.29; IC95% = -36.42–-14.15), o qual também proporcionou a maior diminuição em WASO no longo prazo (SMD = -23.70; IC95% = -35.89–-11.51). Os EAs mais frequentes foram sonolência, nasofaringite e cefaleia, com taxas de até 14.8%.

Conclusão Nossos resultados sugerem que os DORAs estão associados a uma maior eficácia quando comparados com placebo no tratamento da insônia, um complexo transtorno do sono de 24 horas. Além disso, a dosagem pode desempenhar um papel importante no manejo da insônia crônica.

Keywords

Orexin Receptor Antagonists - Sleep Initiation and Maintenance Disorders

Palavras-chave

Antagonistas dos Receptores de Orexina - Distúrbios do Início e da Manutenção do Sono

Authors' Contributions

RBR: writing of the original draft; JPMT: formal analysis and supervision. All authors contributed to the conception and design of the study, as well as to data collection. All authors read and approved the final manuscript.

Publikationsverlauf

Eingereicht: 03. Oktober 2022

Angenommen: 15. Januar 2023

Artikel online veröffentlicht:
31. Mai 2023

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