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

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

doi:10.1055/S-0043-1768667

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

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

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

Authorship SCIMAGO INSTITUTIONS RANKINGS

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 higherdoses relating to a longerTST. 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.

Keywords:
Orexin Receptor Antagonists; Sleep Initiation and Maintenance Disorders

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).