Medical Management of Sleep Disturbance During Opioid Tapering

• Sponsor: Johns Hopkins University (Other)
• Overall Status: Completed
• CT.gov ID: NCT03789214
• Collaborator: National Institute on Drug Abuse (NIDA) (NIH)
• Enrollment: 90
• Location: 1
• Arms: 3
• Actual Duration (Months): 23.3
• Patients Per Site Per Month: 3.9

Study Details

Study Description

Brief Summary

This study will evaluate whether a dual orexin-receptor antagonist approved by the FDA for sleep disturbance, suvorexant (SUVO; Belsomra), will increase total sleep time in patients with opioid use disorder (OUD) undergoing supervised withdrawal. This study is designed as a dose-finding study of SUVO compared to placebo. Briefly, OUD patients seeking supervised withdrawal will be admitted into a clinical research unit and stabilized onto buprenorphine for three days before being randomly assigned to study condition. All participants will then undergo a routine four-day buprenorphine taper, followed by a four-day post-taper phase. Participants will be randomized to receive either placebo, Low Dose SUVO, or High Dose SUVO and the investigators hypothesize that one or both doses of SUVO will improve total sleep time relative to placebo. Patients will attend a single follow-up session, 5-10 days following discharge.

Condition or Disease	Intervention/Treatment	Phase
Opioid Dependence; Opioid Withdrawal; Sleep Disturbance	Drug: Placebo oral capsule; Drug: Low Dose Suvorexant; Drug: High Dose Suvorexant	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 90 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Medical Management of Sleep Disturbance During Opioid Tapering
• Actual Study Start Date: Jul 1, 2019
• Actual Primary Completion Date: Jun 10, 2021
• Actual Study Completion Date: Jun 10, 2021

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Placebo sleep medication (Placebo oral capsule)	Drug: Placebo oral capsule; Placebo Sleep Medication
Active Comparator: Low Dose Suvorexant Low dose sleep medication	Drug: Low Dose Suvorexant; Low Dose Suvorexant
Active Comparator: High Dose Suvorexant High dose sleep medication	Drug: High Dose Suvorexant; High Dose Suvorexant

Outcome Measures

Primary Outcome Measures

1. Abuse Liability as Assessed by Visual Analogue Scale [4 nights]

   Area-under-the-curve of self-reported feelings of drug "High" on the morning after study drug administration, measured each morning on a 0-100 point visual analogue scale of the question "Last night, did you feel HIGH?". A score of "0" indicates no abuse liability and a score of 100 indicates extreme abuse liability. This will be assessed over four nights during an opioid taper.

2. Total Sleep Time During Buprenorphine Taper [Four nights during a buprenorphine taper]

   Area-under-the-curve scores of total number of minutes slept per night as measured by a 3-lead wireless electroencephalography and wrist worn actigraphy.

3. Total Sleep Time During Post-taper [Four nights following buprenorphine discontinuation]

   Area-under-the-curve scores of total number of minutes slept per night as measured by a 3-lead wireless electroencephalography and wrist worn actigraphy.

4. Subjective Opiate Withdrawal Scale During Buprenorphine Taper [Three days during a buprenorphine taper]

   Area-under-the-curve of peak daily scores on the Subjective Opiate Withdrawal Scale (SOWS) (a 16-item self-reported scale that measures individual opioid withdrawal symptoms using a 0-4 Likert scale; total range of SOWS is 0-64; lower scores indicate mild opioid withdrawal relative to higher scores which indicate more severe opioid withdrawal).

5. Subjective Opiate Withdrawal Scale During Post-taper [Three days following buprenorphine discontinuation]

   Area-under-the-curve of peak daily scores on the Subjective Opiate Withdrawal Scale (SOWS) (a 16-item self-reported scale that measures individual opioid withdrawal symptoms using a 0-4 Likert scale; total range of SOWS is 0-64; lower scores indicate mild opioid withdrawal relative to higher scores which indicate more severe opioid withdrawal).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Aged 18 years old and above

• Meets Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 criteria for OUD with evidence of physical dependence on opioids, and seeking treatment to stop using illicit opioids.

• Provides a urine sample that tests positive for opioids.

• Willing to comply with the study protocol.

• Have no clinically significant chronic medical or surgical disorders or conditions that are judged by the investigators to prevent participation.

Exclusion Criteria:

• Seeking or currently enrolled in methadone or buprenorphine maintenance treatment for OUD

• Pregnant or breast feeding

• Have evidence of physical dependence on alcohol or benzodiazepines that requires medical detoxification

• Have a known allergy to the study medications

• Past 30-day prescribed use of suvorexant or benzodiazepines for the indication of insomnia

• Current use of a Selective Serotonin Reuptake Inhibitor (SSRI) or Monoamine oxidase (MAO) inhibitor for depression or insomnia, or other medications that are contraindicated with suvorexant

• Current narcolepsy, restless leg syndrome or sleep paralysis

• High risk for current sleep apnea

• Current major depressive disorder

• Past year suicidal behavior

• Severe hepatic or renal impairment

• Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) >3x ULN

• Total bilirubin >2x Upper Limit of Normal (ULN)

• Creatinine >1.5x ULN

• Have circumstances that would interfere with study participation (e.g., impending jail)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Johns Hopkins Bayview Medical Center	Baltimore	Maryland	United States	21224

Sponsors and Collaborators

• Johns Hopkins University
• National Institute on Drug Abuse (NIDA)

Investigators

• Principal Investigator: Andrew S Huhn, PhD, Johns Hopkins University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Aug 4, 2019
• Informed Consent Form - Jun 1, 2021

More Information

Publications

None provided.

• Responsible Party: Johns Hopkins University
• ClinicalTrials.gov Identifier: NCT03789214
• Other Study ID Numbers: IRB00198426; UG3DA048734
• First Posted: Dec 28, 2018
• Last Update Posted: Aug 8, 2022
• Last Verified: Jul 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Additional relevant MeSH terms: Dyssomnias; Parasomnias; Opioid-Related Disorders; Suvorexant

Study Results

Participant Flow

Pre-assignment Detail

90 individuals were consented and screened (35 did not meet eligibility criteria), 55 were scheduled for admission (7 did not present for admission), 48 were admitted for buprenorphine induction (2 were found to be ineligible at this stage and another 6 left prior to randomization), 40 were randomized (1 left before receiving study drug and 1 was excluded because of uncontrolled precipitated withdrawal), and 38 were included in the analyses of study outcomes.

Arm/Group Title	Placebo	Low Dose Suvorexant	High Dose Suvorexant
Arm/Group Description	Placebo sleep medication (Placebo oral capsule) Placebo oral capsule: Placebo Sleep Medication	Low dose sleep medication Low Dose Suvorexant: Low Dose Suvorexant	High dose sleep medication High Dose Suvorexant: High Dose Suvorexant
Period Title: Overall Study
STARTED	12	14	12
COMPLETED	8	9	9
NOT COMPLETED	4	5	3

Baseline Characteristics

Arm/Group Title	Placebo	Low Dose Suvorexant	High Dose Suvorexant	Total
Arm/Group Description	Placebo sleep medication (Placebo oral capsule) Placebo oral capsule: Placebo Sleep Medication	Low dose sleep medication Low Dose Suvorexant: Low Dose Suvorexant	High dose sleep medication High Dose Suvorexant: High Dose Suvorexant	Total of all reporting groups
Overall Participants	12	14	12	38
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	41.0 (10.4)	36.7 (9.4)	46.3 (12.7)	41.1 (11.2)
Sex: Female, Male (Count of Participants)
Female	2 16.7%	1 7.1%	2 16.7%	5 13.2%
Male	10 83.3%	13 92.9%	10 83.3%	33 86.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	1 7.1%	0 0%	1 2.6%
Asian	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	6 50%	3 21.4%	8 66.7%	17 44.7%
White	6 50%	10 71.4%	4 33.3%	20 52.6%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Abuse Liability as Assessed by Visual Analogue Scale
Description	Area-under-the-curve of self-reported feelings of drug "High" on the morning after study drug administration, measured each morning on a 0-100 point visual analogue scale of the question "Last night, did you feel HIGH?". A score of "0" indicates no abuse liability and a score of 100 indicates extreme abuse liability. This will be assessed over four nights during an opioid taper.
Time Frame	4 nights

Outcome Measure Data

Analysis Population Description

Participants who completed the buprenorphine taper. 1 participant dropped out of the high dose suvorexant condition.

Arm/Group Title	Placebo	Low Dose Suvorexant	High Dose Suvorexant
Arm/Group Description	Placebo sleep medication (Placebo oral capsule) Placebo oral capsule: Placebo Sleep Medication	Low dose sleep medication Low Dose Suvorexant: Low Dose Suvorexant	High dose sleep medication High Dose Suvorexant: High Dose Suvorexant
Measure Participants	12	14	11
Mean (Standard Deviation) [score on a scale*days]	23.9 (33.5)	20.9 (28.7)	22.8 (31.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Low Dose Suvorexant, High Dose Suvorexant
	Comments
	Type of Statistical Test	Other
	Comments	One-way ANOVA
Statistical Test of Hypothesis	p-Value	.950
	Comments
	Method	ANOVA
	Comments

2. Primary Outcome

Title	Total Sleep Time During Buprenorphine Taper
Description	Area-under-the-curve scores of total number of minutes slept per night as measured by a 3-lead wireless electroencephalography and wrist worn actigraphy.
Time Frame	Four nights during a buprenorphine taper

Outcome Measure Data

Analysis Population Description

Participants who completed the buprenorphine taper. 1 participant dropped out of the high dose suvorexant condition.

Arm/Group Title	Placebo	Low Dose Suvorexant	High Dose Suvorexant
Arm/Group Description	Placebo sleep medication (Placebo oral capsule) Placebo oral capsule: Placebo Sleep Medication	Low dose sleep medication Low Dose Suvorexant: Low Dose Suvorexant	High dose sleep medication High Dose Suvorexant: High Dose Suvorexant
Measure Participants	12	14	11
Mean (Standard Deviation) [minutes*nights]	891.6 (287.9)	1183.6 (300.1)	1098.4 (287.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Low Dose Suvorexant, High Dose Suvorexant
	Comments
	Type of Statistical Test	Other
	Comments	One-way ANOVA
Statistical Test of Hypothesis	p-Value	.048
	Comments
	Method	ANOVA
	Comments

3. Primary Outcome

Title	Total Sleep Time During Post-taper
Description	Area-under-the-curve scores of total number of minutes slept per night as measured by a 3-lead wireless electroencephalography and wrist worn actigraphy.
Time Frame	Four nights following buprenorphine discontinuation

Outcome Measure Data

Analysis Population Description

Prior to completion of the post-taper phase, 4 participants dropped out from the placebo condition, 5 dropped out from the low-dose suvorexant condition, and 3 dropped out from the high-dose suvorexant condition.

Arm/Group Title	Placebo	Low Dose Suvorexant	High Dose Suvorexant
Arm/Group Description	Placebo sleep medication (Placebo oral capsule) Placebo oral capsule: Placebo Sleep Medication	Low dose sleep medication Low Dose Suvorexant: Low Dose Suvorexant	High dose sleep medication High Dose Suvorexant: High Dose Suvorexant
Measure Participants	8	9	9
Mean (Standard Deviation) [minutes*nights]	1049.3 (253.6)	1113.2 (342.1)	1055.9 (274.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Low Dose Suvorexant, High Dose Suvorexant
	Comments
	Type of Statistical Test	Other
	Comments	One-way ANOVA
Statistical Test of Hypothesis	p-Value	.691
	Comments
	Method	ANOVA
	Comments

4. Primary Outcome

Title	Subjective Opiate Withdrawal Scale During Buprenorphine Taper
Description	Area-under-the-curve of peak daily scores on the Subjective Opiate Withdrawal Scale (SOWS) (a 16-item self-reported scale that measures individual opioid withdrawal symptoms using a 0-4 Likert scale; total range of SOWS is 0-64; lower scores indicate mild opioid withdrawal relative to higher scores which indicate more severe opioid withdrawal).
Time Frame	Three days during a buprenorphine taper

Outcome Measure Data

Analysis Population Description

Participants who completed the buprenorphine taper. 1 participant dropped out of the high dose suvorexant condition.

Arm/Group Title	Placebo	Low Dose Suvorexant	High Dose Suvorexant
Arm/Group Description	Placebo sleep medication (Placebo oral capsule) Placebo oral capsule: Placebo Sleep Medication	Low dose sleep medication Low Dose Suvorexant: Low Dose Suvorexant	High dose sleep medication High Dose Suvorexant: High Dose Suvorexant
Measure Participants	12	14	11
Mean (Standard Deviation) [score on a scale*days]	15.5 (12.0)	10.8 (15.1)	14.8 (11.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Low Dose Suvorexant, High Dose Suvorexant
	Comments
	Type of Statistical Test	Other
	Comments	One-way ANOVA
Statistical Test of Hypothesis	p-Value	.620
	Comments
	Method	ANOVA
	Comments

5. Primary Outcome

Title	Subjective Opiate Withdrawal Scale During Post-taper
Description	Area-under-the-curve of peak daily scores on the Subjective Opiate Withdrawal Scale (SOWS) (a 16-item self-reported scale that measures individual opioid withdrawal symptoms using a 0-4 Likert scale; total range of SOWS is 0-64; lower scores indicate mild opioid withdrawal relative to higher scores which indicate more severe opioid withdrawal).
Time Frame	Three days following buprenorphine discontinuation

Outcome Measure Data

Analysis Population Description

Prior to completion of the post-taper phase, 4 participants dropped out from the placebo condition, 5 dropped out from the low-dose suvorexant condition, and 3 dropped out from the high-dose suvorexant condition.

Arm/Group Title	Placebo	Low Dose Suvorexant	High Dose Suvorexant
Arm/Group Description	Placebo sleep medication (Placebo oral capsule) Placebo oral capsule: Placebo Sleep Medication	Low dose sleep medication Low Dose Suvorexant: Low Dose Suvorexant	High dose sleep medication High Dose Suvorexant: High Dose Suvorexant
Measure Participants	8	9	9
Mean (Standard Deviation) [score on a scale*days]	17.9 (15.1)	9.0 (9.8)	6.4 (3.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Low Dose Suvorexant, High Dose Suvorexant
	Comments
	Type of Statistical Test	Other
	Comments	One-way ANOVA
Statistical Test of Hypothesis	p-Value	.067
	Comments
	Method	ANOVA
	Comments

Adverse Events

Time Frame	11 days of residential treatment and 5-10 days of follow-up (16-21 days total).
Adverse Event Reporting Description	Adverse events represent all events rated as "possibly, probably, or definitely" related to study participation before and after study drug (suvorexant or placebo) administration. All participants received buprenorphine/naloxone for three days prior to randomization, and adverse events in this section may represent events that occurred prior to study drug administration but within the 11 day experimental period because some events persisted across study phases.
Arm/Group Title	Placebo		Low Dose Suvorexant		High Dose Suvorexant		Pre-randomization
Arm/Group Description	Placebo sleep medication (Placebo oral capsule) Placebo oral capsule: Placebo Sleep Medication		Low dose sleep medication Low Dose Suvorexant: Low Dose Suvorexant		High dose sleep medication High Dose Suvorexant: High Dose Suvorexant		Pre-randomization to Suvorexant or placebo groups
All Cause Mortality
	Placebo		Low Dose Suvorexant		High Dose Suvorexant		Pre-randomization
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/14 (0%)		0/12 (0%)		0/38 (0%)
Serious Adverse Events
	Placebo		Low Dose Suvorexant		High Dose Suvorexant		Pre-randomization
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/14 (0%)		0/12 (0%)		0/38 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Low Dose Suvorexant		High Dose Suvorexant		Pre-randomization
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/12 (50%)		8/14 (57.1%)		7/12 (58.3%)		10/38 (26.3%)
Cardiac disorders
Hypertension	0/12 (0%)		0/14 (0%)		0/12 (0%)		1/38 (2.6%)
Tachycardia	0/12 (0%)		0/14 (0%)		0/12 (0%)		1/38 (2.6%)
Eye disorders
Photophobia	1/12 (8.3%)		2/14 (14.3%)		0/12 (0%)		0/38 (0%)
Blurred Vision	1/12 (8.3%)		0/14 (0%)		0/12 (0%)		0/38 (0%)
Eye Pain	0/12 (0%)		0/14 (0%)		0/12 (0%)		1/38 (2.6%)
Gastrointestinal disorders
Abdominal Cramp	1/12 (8.3%)		0/14 (0%)		0/12 (0%)		3/38 (7.9%)
Abdominal Distention	3/12 (25%)		0/14 (0%)		1/12 (8.3%)		4/38 (10.5%)
Abdominal Pain	0/12 (0%)		0/14 (0%)		1/12 (8.3%)		0/38 (0%)
Constipation	1/12 (8.3%)		2/14 (14.3%)		1/12 (8.3%)		2/38 (5.3%)
Indigestion	1/12 (8.3%)		0/14 (0%)		0/12 (0%)		4/38 (10.5%)
Diarrhea	0/12 (0%)		0/14 (0%)		0/12 (0%)		2/38 (5.3%)
Dyspensia	0/12 (0%)		0/14 (0%)		0/12 (0%)		1/38 (2.6%)
Flatulance	0/12 (0%)		0/14 (0%)		0/12 (0%)		2/38 (5.3%)
Nausea	0/12 (0%)		0/14 (0%)		0/12 (0%)		4/38 (10.5%)
General disorders
Headache	6/12 (50%)		3/14 (21.4%)		2/12 (16.7%)		5/38 (13.2%)
Appetite Decreased	0/12 (0%)		0/14 (0%)		0/12 (0%)		1/38 (2.6%)
Appetite Increased	0/12 (0%)		0/14 (0%)		0/12 (0%)		1/38 (2.6%)
Musculoskeletal and connective tissue disorders
Myalgia	0/12 (0%)		0/14 (0%)		0/12 (0%)		1/38 (2.6%)
Pain Lower Extremity	0/12 (0%)		0/14 (0%)		0/12 (0%)		1/38 (2.6%)
Nervous system disorders
Confusion	0/12 (0%)		2/14 (14.3%)		0/12 (0%)		0/38 (0%)
Dizziness	1/12 (8.3%)		0/14 (0%)		0/12 (0%)		0/38 (0%)
Dream Abnormal	4/12 (33.3%)		2/14 (14.3%)		3/12 (25%)		0/38 (0%)
Drowsiness	1/12 (8.3%)		1/14 (7.1%)		2/12 (16.7%)		1/38 (2.6%)
Euphoria	1/12 (8.3%)		2/14 (14.3%)		0/12 (0%)		0/38 (0%)
Impaired/Groggy	1/12 (8.3%)		2/14 (14.3%)		0/12 (0%)		0/38 (0%)
Insomnia	1/12 (8.3%)		0/14 (0%)		0/12 (0%)		0/38 (0%)
Light headed	1/12 (8.3%)		0/14 (0%)		0/12 (0%)		2/38 (5.3%)
Tremor	0/12 (0%)		0/14 (0%)		1/12 (8.3%)		0/38 (0%)
Stuttering/Fluency Disorder	0/12 (0%)		0/14 (0%)		0/12 (0%)		1/38 (2.6%)
Psychiatric disorders
Agitation	1/12 (8.3%)		0/14 (0%)		0/12 (0%)		0/38 (0%)
Anxiety	1/12 (8.3%)		0/14 (0%)		0/12 (0%)		1/38 (2.6%)
Irritability	1/12 (8.3%)		0/14 (0%)		0/12 (0%)		0/38 (0%)
Reproductive system and breast disorders
Prolonged Erection	0/12 (0%)		1/14 (7.1%)		0/12 (0%)		0/38 (0%)
Skin and subcutaneous tissue disorders
Pruritus	1/12 (8.3%)		0/14 (0%)		0/12 (0%)		0/38 (0%)
Sweat Increased	1/12 (8.3%)		0/14 (0%)		0/12 (0%)		0/38 (0%)
Itchy Eyes	0/12 (0%)		0/14 (0%)		0/12 (0%)		1/38 (2.6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.