Efficacy, Safety, and Drug–Drug Interactions for Insomnia Therapy in COVID-19 Patients

Figures & data

Figure 1 The Flowchart of Article Search.

Table 1 Study Characteristics for Trials Comparing Anti-Insomnia Drug

Reference	Sample Size (Person)	Mean Age (Years)	Gender (%)	Clinical Conditions	Group	Drug	Dose (mg)	Duration (Day)	Efficacy
Rosenberg (2019)^Citation17	1006	63 (55–88)	Female (86.4%)	Insomnia	DORA	Lemborexant	5;10	30	Reduces LPS, WASO and increases TST
Castro (2020)^Citation16	67	48 (20–64)	Female (79%)	Insomnia	Z drug	Zolpidem- Sublingual	5	92	Increases TST
Krystal (2011)^Citation40	221	44 (18–64)	Female (73%)	Chronic Insomnia	TCA	Doxepin	3;6	35	Reduces LPS, WASO and increases SE, TST
Pinto (2016)^Citation42	199	48 (20–64)	Female (76%)	Insomnia	Z-drug	Zopiclone	7.5	30	Reduces LPS, WASO and increases SE, TST
Sharma (2019)^Citation32	52	54 (18–70)	Male (86%)	Insomnia and Cirrhosis	Z-drug	Zolpidem	5	30	Improves TST and SE
Connor (2016)^Citation11	324	47 (18–65)	Female (62%)	Primary Insomnia	DORA	Filorexant	2.5;5;10;20	30	Reduces LPS, WASO and increases SE, TST
Roth (2012)^Citation35	115	48 (27–77)	Female (86.6%)	Sleep disturbance Fibromyalgia	Anticonvulsants	Pregabalin	300–450	30	Reduces WASO and increases TST
Rosenberg (2014)^Citation36	237	41 (18–82)	Female (52.3%)	Insomnia, Sleep Apnea	Anticonvulsant	Gabapentin	250	28	Increase TST and decrease WASO
Sun (2013)^Citation27	19	30 (18–45)	Male (100%)	No sleep disturbance	DORA	Suvorexant	10; 50; 100	90	Reduced LPS, WASO and increased SE
Scheer (2012)^Citation39	16	56 (45–64)	Female (60%)	Hypertension (receiving beta blockers) Insomnia	Melatonin	Melatonin	2.5	21	Improved TST, SE and decreased LS
Brooks (2019)^Citation10	20	43 (18–64)	Female (60%)	Insomnia	DORA	Seltorexant	10; 20; 40	7	Reduced LPS, improves TST and SE
Dauvilliers (2020)^Citation29	360	44.7 (18–64)	Female (64%)	Insomnia	DORA	Daridorexant	5; 10; 25; 50	30	Reduced WASO
Kohsaka (2011)^Citation12	65	42 (20–65)	Male (63%)	Chronic Insomnia	Melatonin	Ramelteon	4; 8; 10; 32	12	Reduced LPS
Herring (2017)^Citation15	839	70 (65–74)	Female (65%)	Insomnia	DORA	Suvorexant	15;30	90	Reduced LPS and WASO
May (2015)^Citation41	419	43 (18–65)	Female (69%)	Non-elderly Insomnia	TCA	Esmirtazapine	3.0; 4.5	42	Reduced LPS, WASO and increased SE, TST
Murphy (2017)^Citation28	291	49 (19–80)	Female (63%)	Insomnia	DORA	Lemborexant	1; 2.5; 5;10; 15; 25	15	Reduced LPS. WASO, improved SE
Uchimura (2012)^Citation8	72	39 (21–64)	Male (59.7%)	Insomnia	Z-Drug	Eszopiclone	1; 2; 3	14	Increase TST and SE
Black (2017)^Citation18	709	45 (18–64)	Female (61.7%)	Chronic Insomnia	DORA	Almorexant	100; 200	16	Decreased LPS, WASO, and increased TST
Horoszok (2014)^Citation33	35	(20–40)	Male (100%)	Healthy	Z-Drug	Lorediplon	1; 5;10	7	Decreased WASO, increased TST and SE
Roehrs (2012)^Citation31	33	52 (32–65)	Female (52.9)	Primary Insomnia	Z-Drug	Zolpidem	10	12 months	Increases TST, decreased LPS and WASO
Dahl (2019)^Citation13	39	42 (25–64)	Male (69%)	Healthy Transient Insomnia	BZD	SM1 (Diphenhydramine, Zolpidem, Lorazepam)	50;5; 0.5	14	Increase TST, decrease WASO
Boer (2018)^Citation9	28	45 (18–65)	Female (67%)	Insomnia	DORA	Seltorexant	40	5	Increases TST, reduced LPS and WASO
Strambi (2017)^Citation14	24	41 (18–64)	Male (58%)	Insomnia	BZD	Low Dose Triazolam	0.0625;0.125; 0.25	14	Increases TST, SE and decreases WASO
Zammit (2020)^Citation30	58	69 (65–85)	Female (67%)	Insomnia	DORA	Daridorexant	5;10; 20; 50	7	Reduced LS, WASO

Abbreviations: BZD, benzodiazepine; DORA, dual orexin receptor antagonist; LPS, latency to persistent sleep; SE, sleep efficiency; TCA, tricyclic antidepressant; TST, total sleep time; WASO, wake ater sleep onset; Z-drug, nonbenzodiazepine.

Table 2 Efficacy of Changes in Sleep Parameters from Baseline

Class	Drug	Reference	Initial Testing (Short Term Testing < 2 Weeks)				Final Testing (Long Term Testing > 2 Weeks)
			LPS (min)	SE (%)	WASO (min)	TST (min)	LPS (min)	SE (%)	WASO (min)	TST (min)
Anticonvulsant	Gabapentin	Rosenberg (2019)^Citation17	−22.4	–	−42.1	63.7	−18.0	–	−35.5	51.4
	Pregabalin	Roth (2012)^Citation35	–	–		–	−27.2	16.0	−56.3	76.4
BZD	SM1	Dahl (2019)^Citation13	−18.9	–	−106.4	126.7	–	–	–	–
	Triazolam 0.0625 mg	Strambi (2017)^Citation14	−1.4	13.3	−54.8	75.4		–	–	–
	Triazolam 0.125 mg		−4.8	12.7	−55.4	82.9		–	–	–
	Triazolam 0.25 mg		1.4	11.8	−57.1	68.5		–	–	–
DORA	Almorexant 100 mg	Black (2017)^Citation18	−28.6	–	−32.1	26.0	−28.0	–	−30.8	19.3
	Almorexant 200 mg		−29.1	–	−45.9	37.0	−33.3	–	−40.5	27.0
	Seltorexant	Boer (2018)^Citation9	−29.9	7.9	−11.3	37.9	–	–	–	–
	Seltorexant 10 mg	Brooks (2019)^Citation10	−45.3	6.1	–	29.0	–	–	–	–
	Seltorexant 20 mg		−70.7	9.9	–	46.5	–	–	–	–
	Seltorexant 40 mg		−60.1	10.3	–	49.2	–	–	–	–
	Filorexant 10 mg	Connor (2016)^Citation11	−40.3	19.9	−60.4	53.1	−38.9	18.3	−53.2	45.6
	Filorexant 2.5 mg		−33.5	18.3	−57.3	40.4	−31.1	16.5	−49.9	23.4
	Filorexant 20 mg		−44.0	25.0	−79.1	64.2	−40.3	23.1	−72.9	42.2
	Filorexant 5 mg		−40.9	20.3	−57.7	48.1	−41.7	19.0	−52.5	19.9
	Daridorexant 10 mg	Dauvilliers (2020)^Citation29	−32.0	–	−32.3	62.4	−38.7	–	−42.8	77.4
	Daridorexant 25		−34.2	–	−37.7	69.7	−37.9	–	−38.9	75.1
	Daridorexant 5 mg		−25.9	–	−28.4	52.7	−20.2	–	−37.5	53.9
	Daridorexant 50 mg		−37.2	–	−47.1	81.4	−35.8	–	−48.0	81.6
	Suvorexant 15 mg	Herring (2017)^Citation15	−10.0	–	−39.3	–	−5.0	–	−26.9	–
	Suvorexant 30 mg		−17.5	–	−49.4	–	−6.7	–	−31.6	–
	Lemborexant 1 mg	Murphy (2017)^Citation28	−27.0	18.7	−52.1	–	−28.7	14.4	−32.5	–
	Lemborexant 10 mg		−21.1	22.3	−60.8	–	−11.8	21.9	−52.9	–
	Lemborexant 15 mg		−20.9	24.2	−70.4	–	−20.6	22.0	−59.0	–
	Lemborexant 2.5 mg		−20.3	18.6	−43.3	–	−18.8	18.0	−40.5	–
	Lemborexant 25 mg		−14.1	24.3	−66.9	–	−13.5	23.0	−59.7	–
	Lemborexant 5 mg		−22.7	19.9	−52.3	–	−51.9	19.9	−48.8	–
	Lemborexant 10 mg	Rosenberg (2014)^Citation36	−19.5	16.5	−59.6	−21.5	−21.5	14.1	−46.4	–
	Lemborexant 5mg		−16.6	13.6	−50.0	−19.5	−19.5	12.9	−43.9	–
	Suvorexant 10 mg	Sun (2013)^Citation27	–	–	–	–	−1.9	1.5	−3.0	7.6
	Suvorexant 100 mg		–	–	–	–	−12.5	4.2	−7.1	20.8
	Suvorexant 50 mg		–	–	–	–	−11.2	3.5	−6.8	18.3
	Daridorexant 10 mg	Zammit (2020)^Citation30	−44.6	–	−32.4	74.0	–	–	–	–
	Daridorexant 25 mg		−44.8	–	−44.2	87.5	–	–	–	–
	Daridorexant 5 mg		−37.9	–	−18.4	53.9	–	–	–	–
	Daridorexant 50 mg		−44.9	–	−61.1	104.9	–	–	–	–
Melatonin	Ramelteon 16 mg	Kohsaka (2011)^Citation12	−33.6	8.4	−5.0	40.5	–	–	–	–
	Ramelteon 32 mg		−37.4	7.6	1.8	36.7	–	–	–	–
	Ramelteon 4 mg		−32.8	8.5	−8.6	41.2	–	–	–	–
	Ramelteon 8 mg		−39.7	8.8	−3.5	42.8	–	–	–	–
	Melatonin	Scheer (2012)^Citation39	–	–	–	–	–	7.6	–	37.0
TCA	Doxepin 3 mg	Krystal (2011)^Citation40	−9.2	9.2	−26.4	35.0	−7.4	6.0	−20.6	27.7
	Doxepin 6 mg		−12.0	10.1	−28.7	40.2	−14.6	8.0	−24.3	39.2
	Esmirtazapine 3 mg	May (2015)^Citation41	−38.0	–	−55.8	78.9	−35.5	–	−49.3	–
Z drug	Zolpidem (Sublingual)	Castro (2020)^Citation16	−10.0	3.0	−43.0	–	–	–		–
	Lorediplon 1 mg	Horoszok (2014)^Citation33	−1.2	2.5	−13.4	12.2	–	–		–
	Lorediplon 10 mg		−2.0	15.4	−78.0	73.8	–	–		–
	Lorediplon 5 mg		−5.2	10.8	−52.2	51.7	–	–		–
	Zopiclone	Pinto (2016)^Citation42	–	–	–	–	−7.4	6.0	−20.6	27.7
	Zolpidem 10 mg	Roehrs (2012)^Citation31	–	–	–	–	−23.2		−23.7	34.2
	Zolpidem 5 mg	Sharma (2019)^Citation32	–	–	–	–	−14.6	8.0	−24.3	39.2
	Eszopiclone 1 mg	Uchimura (2012)^Citation8	−49.9	5.0	−33.8	78.8	–	–	–	–
	Eszopiclone 2 mg		−53.4	8.0	−38.5	93.0	–	–	–	–
	Eszopiclone 3 mg		−61.5	8.2	−37.5	93.9	–	–	–	–

Abbreviations: BZD, benzodiazepine; DORA, dual orexin receptor antagonist; LPS, latency to persistent sleep; PSG, polysomnography; SE, sleep efficiency; TCA, tricyclic antidepressant; TST, total sleep time; WASO, wake after sleep onset; Z-drug, nonbenzodiazepine.

Figure 2 Continue.

Figure 2 Comparison of Mean Changes in Polysomnography Parameters. Change of (A) LPS (B) TST (C) WASO (D) SE parameters.

Abbreviations: LPS, latency to persistent sleep; SE, sleep efficiency; TST, total sleep time; WASO, wake after sleep onset.

Table 3 Drug–Drug Interaction

Interaction	Remdesivir	Chloroquine	Hydroxychloroquine	Ivermectin	Lopinavir/Ritonavir	Azithromycin	Dexamethasone	Tocilizumab	Bamianivimab	Casirivimab	Colchicine	Fluvoxamine
Triazolam					X		A				B
Suvorexant					X		B				X	B
Doxepin		X	X		B	B						X
Zolpidem					A		B					B
Lorazepam												B
Lemborexant					X		B					X
Gabapentin		B	B									B
Pregabalin		B	B									B
Esmirtazapine		X	X		B	B	B					X
Ramelteon					B		B					X
Eszopiclon					X							B
Melatonin												X

Notes: A: Minor – Significantly minimal interaction. Alternative considerations are needed to avoid interactions. B: Moderate – Interaction is quite significant, Trying to avoid combination interactions. Used in special conditions. X: Major (High Risk)- The interactions are clinically significant. Avoid combination.

Abbreviations: BZD, benzodiazepine; DORA, dual orexin receptor antagonist; LPS, latency to persistent sleep; PSG, polysomnography; SE, sleep efficiency; TCA, tricyclic antidepressant; TST, total sleep time; WASO, wake after sleep onset; Z-drug, nonbenzodiazepine.

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