Antagonistas duais do receptor de orexina para o tratamento da insônia: revisão sistemática e metanálise em rede

Rocha, Rebeka Bustamante; Bomtempo, Fernanda Ferreira; Nager, Gabriela Borges; Cenci, Giulia Isadora; Telles, João Paulo Mota

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Arquivos de Neuro-Psiquiatria

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Sumário

Original Article • Arq. Neuropsiquiatr. 81 (5) • 2023 • https://doi.org/10.1055/S-0043-1768667 copiar

Antagonistas duais do receptor de orexina para o tratamento da insônia: revisão sistemática e metanálise em rede

Autoria SCIMAGO INSTITUTIONS RANKINGS

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 insónia, um complexo transtorno do sono de 24 horas. Além disso, a dosagem pode desempenhar um papel importante no manejo da insónia crônica.

Palavras-chave:
Antagonistas dos Receptores de Orexina; Distúrbios do Início e da Manutenção do Sono

Study	Dual orexin receptor antagonist (DORA)	Insomnia disorder diagnostic criteria	Total number of patients (n)	Patient interventions/PLA (n)	Duration of the treatment	Age groups in years	Age in years: mean(±SD)	ISI, Mean(±SD)	Pooled outcomes	Sleep parameter assessment tool
Herring et al.¹⁴14 Herring WJ, Connor KM, Ivgy-May N, et al. Suvorexant in Patients With Insomnia: Results From Two 3-Month Randomized Controlled Clinical Trials. Biol Psychiatry 2016;79(02):136–148. Doi: 10.1016/j.biopsych.2014.10.003 https://doi.org/10.1016/j.biopsych.2014.... (2016): trial 1	SUV	DSM-4	1,021	SUV 20/15 mg (254); SUV 40/30 mg (383); PLA (384)	3 months	18–64; ≥ 65	SUV 20/15mg:^* Notes: Dosing according to age group, with higher doses for non-elderly individuals and lower doses for elderly individuals; ISI: 0–7 = no clinically significant insomnia; 8–14 = subthreshold insomnia; 15–21 = clinical insomnia (moderate severity); 22–28 = clinical insomnia (severe). 55(± 16); SUV 40/30 mg:^ Notes: *Dosing according to age group, with higher doses for non-elderly individuals and lower doses for elderly individuals; ISI: 0–7 = no clinically significant insomnia; 8–14 = subthreshold insomnia; 15–21 = clinical insomnia (moderate severity); 22–28 = clinical insomnia (severe). 56(± 15); PLA: 56(± 15)	SUV 20/15 mg:^* Notes: Dosing according to age group, with higher doses for non-elderly individuals and lower doses for elderly individuals; ISI: 0–7 = no clinically significant insomnia; 8–14 = subthreshold insomnia; 15–21 = clinical insomnia (moderate severity); 22–28 = clinical insomnia (severe). : 16(± 4) SUV 40/30 mg^ Notes: *Dosing according to age group, with higher doses for non-elderly individuals and lower doses for elderly individuals; ISI: 0–7 = no clinically significant insomnia; 8–14 = subthreshold insomnia; 15–21 = clinical insomnia (moderate severity); 22–28 = clinical insomnia (severe). : 16(± 4) PLA: 16(± 4)	WASO at month 1; WASO at month 3; LPS at month 1; TST at month 3	Electronic sleep diary; polysomnography
Herring et al.¹⁴14 Herring WJ, Connor KM, Ivgy-May N, et al. Suvorexant in Patients With Insomnia: Results From Two 3-Month Randomized Controlled Clinical Trials. Biol Psychiatry 2016;79(02):136–148. Doi: 10.1016/j.biopsych.2014.10.003 https://doi.org/10.1016/j.biopsych.2014.... (2016): trial 2	SUV	DSM-4	1,009	SUV 20/15 mg (239); SUV 40/30 mg (387); PLA (383)	3 months	18–64; ≥ 65	SUV 20/15mg:^* Notes: Dosing according to age group, with higher doses for non-elderly individuals and lower doses for elderly individuals; ISI: 0–7 = no clinically significant insomnia; 8–14 = subthreshold insomnia; 15–21 = clinical insomnia (moderate severity); 22–28 = clinical insomnia (severe). 56(± 16); SUV 40/30 mg:^ Notes: *Dosing according to age group, with higher doses for non-elderly individuals and lower doses for elderly individuals; ISI: 0–7 = no clinically significant insomnia; 8–14 = subthreshold insomnia; 15–21 = clinical insomnia (moderate severity); 22–28 = clinical insomnia (severe). 57(± 15); PLA: 57(± 15)	SUV 20/15mg^* Notes: Dosing according to age group, with higher doses for non-elderly individuals and lower doses for elderly individuals; ISI: 0–7 = no clinically significant insomnia; 8–14 = subthreshold insomnia; 15–21 = clinical insomnia (moderate severity); 22–28 = clinical insomnia (severe). : 17(± 4) SUV 40/30mg^ Notes: *Dosing according to age group, with higher doses for non-elderly individuals and lower doses for elderly individuals; ISI: 0–7 = no clinically significant insomnia; 8–14 = subthreshold insomnia; 15–21 = clinical insomnia (moderate severity); 22–28 = clinical insomnia (severe). : 16(± 4) PLA: 16(± 4)
Michelson et al.¹⁵15 Michelson D, Snyder E, Paradis E, et al. Safety and efficacy of suvorexant during 1-year treatment of insomnia with subsequent abrupt treatment discontinuation: a phase 3 randomised, double-blind, placebo-controlled trial. Lancet Neurol 2014;13(05):461–471 (2014)	SUV	DSM-4	779	SUV 30/40 mg (521); PLA (258)	12 months	18–64; ≥ 65	SUV 30/40 mg:^* Notes: *Dosing according to age group, with higher doses for non-elderly individuals and lower doses for elderly individuals; ISI: 0–7 = no clinically significant insomnia; 8–14 = subthreshold insomnia; 15–21 = clinical insomnia (moderate severity); 22–28 = clinical insomnia (severe). 61.3(± 14.5); PLA: 62.0(± 14.6)	SUV 30/40mg^* Notes: *Dosing according to age group, with higher doses for non-elderly individuals and lower doses for elderly individuals; ISI: 0–7 = no clinically significant insomnia; 8–14 = subthreshold insomnia; 15–21 = clinical insomnia (moderate severity); 22–28 = clinical insomnia (severe). : 14.5(± 4.4) PLA: 16(± 4)	WASO at month 1; WASO at month 12; TST at month 12
Black et al.²⁰20 Black J, Pillar G, Hedner J, et al. Efficacy and safety of almorexant in adult chronic insomnia: a randomized placebo-controlled trial with an active reference. Sleep Med 2017;36:86–94. Doi: 10.1016/j.sleep.2017.05.009 https://doi.org/10.1016/j.sleep.2017.05.... (2017)	ALM	DSM-4	709	ALM 100 mg (187); ALM 200 mg (177); ZOL 10 mg (168); PLA (177)	2 weeks	18–64	ALM 100mg:44.1; ALM 200 mg: 46.1; ZOL 10mg:45.1; PLA: 46.2	NA	Mean WASO at weeks 1 and 2; mean LPS at weeks 1 and 2	Electronic sleep diary; polysomnography
Fan et al.¹⁶16 Fan B, Kang J, He Y, Hao M, Du W, Ma S. Efficacy and safety of suvorexant for the treatment of primary insomnia among Chinese: a 6-month randomized double-blind controlled study. Neurol Asia 2017;22(01):41–47. https://www.cochranelibrary.-com/central/doi/10.1002/central/CN-01365366/full https://www.cochranelibrary.-com/central... (2017)	SUV	DSM-4	120	SUV 40 mg (60); PLA (60)	6 months	18–64	SUV 40 mg: 50.6(± 11.9); PLA: 51.4(± 12.2)	SUV 40 mg: 14.3(± 4.0) PLA: 14.1(± 3.9)	TST at month 6	Electronic sleep diary
Rosenberg et al.²³23 Rosenberg R, Murphy P, Zammit G, et al. Comparison of Lemborexant With Placebo and Zolpidem Tartrate Extended Release for the Treatment of Older Adults With Insomnia Disorder: A Phase 3 Randomized Clinical Trial. JAMA Netw Open 2019;2(12): e1918254. Doi: 10.1001/jamanetworkopen.2019.18254 https://doi.org/10.1001/jamanetworkopen.... (2019): SUNRISE 1	LEM	DSM-5	1,006	LEM 5 mg (266); LEM 10 mg (269); ZOL 6.5 mg (263); PLA (208)	1 month	≥ 55 to < 65; ≥ 65	LEM 5mg: 63.7(± 6.8); LEM 10 mg: 64.2(± 6.9); ZOL 6.5 mg: 64.3(± 7.1); PLA: 63.9(± 6.8)	LEM 5mg: 18.9(± 3.5) LEM 10mg: 19.0(± 3.3) ZOL 6.5mg 19.2(± 3.5) PLA: 19.4(± 3.6)	WASO at month 1 (nights 29 and 30)	Polysomnography
Dauvilliers et al. (2019)	DAR	DSM-5	359	DAR 5 mg (60); DAR 10 mg (58); DAR 25 mg (60); DAR 50 mg (61); ZOL 10 mg (60); PLA (60)	1 month	18–64	DAR 5 mg:42.4(± 11.4); DAR 10 mg:45.2(± 10.9); DAR 25 mg:46.4(± 11.9); DAR 50 mg:45.0(± 11.5); ZOL 10 mg: 43.7(± 11.8); PLA: 45.7(± 10.4)	DAR 5 mg: 20.8(± 2.6) DAR 10 mg: 21.2(± 3.3) DAR 25 mg: 21.3(± 2.7) DAR 50 mg: 21.1(± 2.7) ZOL 10 mg: 21.3(± 2.9) PLA: 21.3(± 2.7)	WASO at month 1 (week 4); LPS (days 1 and 2)	Electronic sleep diary; polysomnography
Kärppä et al.¹⁸18 Kärppä M, Yardley J, Pinner K, et al. Long-term efficacy and tolerability of lemborexant compared with placebo in adults with insomnia disorder: results from the phase 3 randomized clinical trial SUNRISE 2. Sleep 2020;43(09):zsaa123. Doi: 10.1093/sleep/zsaa123 https://doi.org/10.1093/sleep/zsaa123... (2020)	SUNRISE 2	LEM	DSM-5	949	LEM 5 mg (316); LEM 10 mg (315); PLA (318)	6 months	<65; ≥ 65 to < 75; ≥ 75	LEM 5 mg: 54.2(± 13.7) LEM 10 mg: 54.8(± 13.7) PLA: 54.5(± 14.0)	LEM 5 mg: 19.6(± 3.3); LEM 10 mg: 19.1(± 3.4); PLA: 19.0 WASO at month 6; TST at month 6 Electronic sleep diary
Mignot et al.²²22 Mignot E, Mayleben D, Fietze I, et al; investigators. Safety and efficacy of daridorexant in patients with insomnia disorder: results from two multicentre, randomised, double-blind, placebo-controlled, phase 3 trials. Lancet Neurol 2022;21(02): 125–139 (2022): trial 1	DAR	DSM-5	930	DAR 25 mg (310); DAR 50 mg (310); PLA (310) (3.1)	3 months	18–64; ≥ 65	DAR 25 mg: 55.8(± 15.3) DAR 50 mg: 55.5(± 15.3) PLA: 55.1 (± 15.4)	DAR 25 mg: 19.0(± 4.3); DAR 50 mg: 19.3(± 4.0); PLA: 19.2(± 4.0)	WASO at month 1; WASO at month 3; LPS at month 1; TST at month 3	Electronic sleep diary; polysomnography
Mignot et al.²²22 Mignot E, Mayleben D, Fietze I, et al; investigators. Safety and efficacy of daridorexant in patients with insomnia disorder: results from two multicentre, randomised, double-blind, placebo-controlled, phase 3 trials. Lancet Neurol 2022;21(02): 125–139 (2022): trial 2	DAR	DSM-5	924	DAR 10 mg (307); DAR 25 mg (309); PLA (308)	3 months	18–64; ≥ 65	DAR 10 mg: 57.1(± 14.0); DAR 25 mg: 56.3(± 14.4); PLA: 56.7(± 14.1)	DAR 10 mg: 19.9(± 3.8); DAR 25 mg: 19.5(± 4.0); PLA: 19.6(± 4.1)		Electronic sleep diary; polysomnography

	Inclusion criteria	Exclusion criteria
(P) Patient	Insomnia disorder (according to the DSM-5) or primary insomnia (according to the DSM-4)	Overlapping patient populations
(I) Intervention	Dual orexin receptor antagonists (DORAs)	Selective orexin receptor antagonists (SORAs)
(C) Control	Placebo or placebo and Zolpidem (active control drug)	–
(0) Outcome	Efficacy outcomes: wake time after sleep onset (WASO); latency to persistent sleep (LPS); total sleep time (TST)	–
(S) Study design	Randomized controlled trials (RCTs)	Studies not written in English; crossover design.

Study	Drug	Most frequent AE: n/N (%)
Herring et al.¹⁴14 Herring WJ, Connor KM, Ivgy-May N, et al. Suvorexant in Patients With Insomnia: Results From Two 3-Month Randomized Controlled Clinical Trials. Biol Psychiatry 2016;79(02):136–148. Doi: 10.1016/j.biopsych.2014.10.003 https://doi.org/10.1016/j.biopsych.2014.... (2016): trial 1	SUV 20/15 mg; SUV 40/30 mg	Somnolence: 13/254(5.1); 40/383(10.7)
	SUV 20/15 mg; SUV 40/30 mg	Nasopharyngitis: 18/254(7.1); 32/383 (8.4)
Herring et al.¹⁴14 Herring WJ, Connor KM, Ivgy-May N, et al. Suvorexant in Patients With Insomnia: Results From Two 3-Month Randomized Controlled Clinical Trials. Biol Psychiatry 2016;79(02):136–148. Doi: 10.1016/j.biopsych.2014.10.003 https://doi.org/10.1016/j.biopsych.2014.... (2016): trial 2	SUV 20/15 mg; SUV 40/30 mg	Somnolence: 20/239 (8.4); 40/387 (10.3)
Michelson et al.¹⁵15 Michelson D, Snyder E, Paradis E, et al. Safety and efficacy of suvorexant during 1-year treatment of insomnia with subsequent abrupt treatment discontinuation: a phase 3 randomised, double-blind, placebo-controlled trial. Lancet Neurol 2014;13(05):461–471 (2014)	SUV 30/40 mg	Somnolence: 69/521 (13.2)
Black et al.²⁰20 Black J, Pillar G, Hedner J, et al. Efficacy and safety of almorexant in adult chronic insomnia: a randomized placebo-controlled trial with an active reference. Sleep Med 2017;36:86–94. Doi: 10.1016/j.sleep.2017.05.009 https://doi.org/10.1016/j.sleep.2017.05.... (2017)	ALM 100 mg; ALM 200 mg	Headache: 18/186(9.7); 26/176 (14.8)
Fan et al.¹⁶16 Fan B, Kang J, He Y, Hao M, Du W, Ma S. Efficacy and safety of suvorexant for the treatment of primary insomnia among Chinese: a 6-month randomized double-blind controlled study. Neurol Asia 2017;22(01):41–47. https://www.cochranelibrary.-com/central/doi/10.1002/central/CN-01365366/full https://www.cochranelibrary.-com/central... (2017)	SUV 40 mg	Headache: 7/60(11.7)
Rosenberg et al.²³23 Rosenberg R, Murphy P, Zammit G, et al. Comparison of Lemborexant With Placebo and Zolpidem Tartrate Extended Release for the Treatment of Older Adults With Insomnia Disorder: A Phase 3 Randomized Clinical Trial. JAMA Netw Open 2019;2(12): e1918254. Doi: 10.1001/jamanetworkopen.2019.18254 https://doi.org/10.1001/jamanetworkopen.... (2019): SUNRISE 1	LEM 5 mg; LEM 10 mg	Headache: 17/266(6.4); 13/268 (4.9)
	LEM 5 mg; LEM 10 mg	Somnolence: 11/266 (4.1); 19/268(7.1)
Dauvilliers et al.²¹21 Dauvilliers Y, Zammit G, Fietze I, et al. A novel dual orexin receptor antagonist (act-541468) to treat insomnia: a randomized, double-blind, placebo-controlled, activere ference phase 2 study. Sleep (Basel) 2019;42:A152–A153. Doi: 10.1093/sleep/zsz067.374 https://doi.org/10.1093/sleep/zsz067.374... (2019)	DAR 5 mg; DAR 10 mg; DAR 25 mg; DAR 50 mg	Headache: 6/60(10); 5/58 (8.6); 5/60 (8.3); 5/61 (8.2)
Kärppä et al.¹⁸18 Kärppä M, Yardley J, Pinner K, et al. Long-term efficacy and tolerability of lemborexant compared with placebo in adults with insomnia disorder: results from the phase 3 randomized clinical trial SUNRISE 2. Sleep 2020;43(09):zsaa123. Doi: 10.1093/sleep/zsaa123 https://doi.org/10.1093/sleep/zsaa123... (2020) SUNRISE 2	LEM 5 mg; LEM 10 mg	Somnolence: 27/314 (8.6); 41/314 (13.1)
	LEM 5 mg; LEM 10 mg	Headache: 28/314 (8.9); 21/314 (6.7)
Mignot et al.²²22 Mignot E, Mayleben D, Fietze I, et al; investigators. Safety and efficacy of daridorexant in patients with insomnia disorder: results from two multicentre, randomised, double-blind, placebo-controlled, phase 3 trials. Lancet Neurol 2022;21(02): 125–139 (2022): trial 1	DAR 25 mg; DAR 50 mg	Nasopharyngitis: 21/310 (7); 20/308 (6)
Mignot et al.²²22 Mignot E, Mayleben D, Fietze I, et al; investigators. Safety and efficacy of daridorexant in patients with insomnia disorder: results from two multicentre, randomised, double-blind, placebo-controlled, phase 3 trials. Lancet Neurol 2022;21(02): 125–139 (2022): trial 2	DAR 25 mg; DAR 10 mg	Nasopharyngitis: 13/308 (4); 32/306 (12)

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[1] Address for correspondence João Paulo Mota Telles (email: joao.telles@fm.usp.br).