ESP2: Mechanisms of Sleep Disruption Hyperalgesia

• Sponsor: Johns Hopkins University (Other)
• Overall Status: Completed
• CT.gov ID: NCT01794689
• Collaborator: National Institute on Drug Abuse (NIDA) (NIH)
• Enrollment: 100
• Location: 1
• Arms: 4
• Actual Duration (Months): 70.3
• Patients Per Site Per Month: 1.4

Study Details

Study Description

Brief Summary

Twenty percent of Americans suffer from chronic pain. Sleep disturbance is similarly prevalent and among the most common and disabling neurobehavioral problems associated with chronic pain. This research is designed to evaluate the effects of disrupted sleep patterns on mood, inflammation, the perception of pain, and pain relief. This study will help researchers understand the relationship between sleep and pain, and how sleep disturbance might influence chronic pain conditions.

Condition or Disease	Intervention/Treatment	Phase
Sleep Deprivation; Pain	Drug: Morphine; Drug: Saline Placebo; Behavioral: Forced Awakenings; Behavioral: Uninterrupted Sleep	N/A

Detailed Description

This research is being conducted in order to evaluate the effects of disrupted sleep patterns on mood, inflammation, the perception of pain, and pain relief. This study will help researchers understand the relationship between sleep and pain, and how sleep disturbance might influence chronic pain conditions. Healthy participants will undergo baseline sleep and sleep disruption conditions. Following undisturbed sleep and sleep disruption conditions, sensitivity to pain and analgesic response (via morphine or placebo administration) will be assessed using a heat-capsaicin pain model.

This study will be conducted in 2 major parts-3 screening visits (2 outpatient and 1 inpatient) and 2 experimental inpatient visits. Part 1 of the study will involve a 1-week screening period. This will involve two separate screening visits lasting about 2 hours each. At Screening Visit 1, participants will complete questionnaires, an interview, and undergo toxicology screening. At Screening Visit 2, participants will complete questionnaires, undergo a physical exam, and be familiarized with pain testing procedures. At Screening Visit 3, participants will undergo an inpatient sleep study.

Part 2 will involve two different inpatient admissions. The two admissions will be separated by at least two weeks. During each of the admissions, participants' sleep will be studied at night. The first admission will begin immediately following the overnight sleep study in Screening Visit 3. One of the admissions will be for one night and the other admission will be for three nights. For the one night admission, participants will sleep undisturbed for an 8-hour period. For the three night admission, participants will undergo sleep disruption for two nights in a row. On the third night, participants will be allowed to sleep undisturbed for 8 hours for recovery.

During both inpatient admissions, pain testing procedures will be completed that will last approximately 5 hours during the day. During testing, small amounts of blood will be drawn for analysis. Participants will be randomly assigned to two groups. Group A will be given a standard dose of morphine during pain testing. Group B will be given a placebo during pain testing.

Study Design

• Study Type: Interventional
• Actual Enrollment: 100 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Care Provider)
• Primary Purpose: Basic Science
• Official Title: Mechanisms of Sleep Disruption Hyperalgesia
• Actual Study Start Date: May 1, 2013
• Actual Primary Completion Date: Jan 1, 2018
• Actual Study Completion Date: Mar 12, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Morphine US then Morphine FA Participants randomized to receive Morphine and the Uninterrupted Sleep (US) condition first. After a polysomnography (PSG) screening night, participants were randomized to receive two consecutive nights of uninterrupted sleep (US). With a minimum of a two week washout period, participants then completed the opposing sleep condition of two nights of forced awakenings (FA). They will receive the Morphine injection (0.08mg/kg) via IV bolus over 30 seconds during each experimental quantitative sensory testing session that occurs after the US and FA sleep conditions are completed.	Drug: Morphine; 0.08mg/kg will be administered to participants randomly assigned to receive the drug via IV bolus during each quantitative sensory testing session (after one night of uninterrupted sleep and after 2 nights of forced awakenings).; Behavioral: Forced Awakenings; Participants will be awakened each hour during an 8 hour sleep opportunity period. One of the awakenings is for 60 minutes and randomly determined. The other 7 awakenings are for 20 minutes each, and are randomly scheduled to occur in either the first second or third tertile of each hour. The maximum total sleep time a participant will receive is 280 minutes.; Behavioral: Uninterrupted Sleep; Participants will receive an 8 hour period of undisturbed sleep
Placebo Comparator: Placebo US then Placebo FA Participants randomized to receive the saline placebo and the Uninterrupted Sleep (US) condition first. After a polysomnography (PSG) screening night, participants were randomized to receive two consecutive nights of uninterrupted sleep (US). With a minimum of a two week washout period, participants then completed the opposing sleep condition of two nights of forced awakenings (FA). They will receive the injection via IV bolus over 30 seconds during each experimental quantitative sensory testing session that occurs after the US and FA sleep conditions are completed.	Drug: Saline Placebo; Saline Placebo will administered to participants randomly assigned to receive the placebo via IV bolus during each quantitative sensory testing session (after one night of uninterrupted sleep and after 2 nights of forced awakenings).; Behavioral: Forced Awakenings; Participants will be awakened each hour during an 8 hour sleep opportunity period. One of the awakenings is for 60 minutes and randomly determined. The other 7 awakenings are for 20 minutes each, and are randomly scheduled to occur in either the first second or third tertile of each hour. The maximum total sleep time a participant will receive is 280 minutes.; Behavioral: Uninterrupted Sleep; Participants will receive an 8 hour period of undisturbed sleep
Experimental: Morphine FA then Morphine US Participants randomized to receive Morphine and the Forced Awakenings (FA) condition first. After a polysomnography (PSG) screening night, participants were randomized to receive two consecutive nights of forced awakenings (FA). With a minimum of a two week washout period, participants then completed the opposing sleep condition of two nights of uninterrupted sleep (US). They will receive the Morphine injection (0.08mg/kg) via IV bolus over 30 seconds during each experimental quantitative sensory testing session that occurs after the FA and US sleep conditions are completed.	Drug: Morphine; 0.08mg/kg will be administered to participants randomly assigned to receive the drug via IV bolus during each quantitative sensory testing session (after one night of uninterrupted sleep and after 2 nights of forced awakenings).; Behavioral: Forced Awakenings; Participants will be awakened each hour during an 8 hour sleep opportunity period. One of the awakenings is for 60 minutes and randomly determined. The other 7 awakenings are for 20 minutes each, and are randomly scheduled to occur in either the first second or third tertile of each hour. The maximum total sleep time a participant will receive is 280 minutes.; Behavioral: Uninterrupted Sleep; Participants will receive an 8 hour period of undisturbed sleep
Placebo Comparator: Placebo FA then Placebo US Participants randomized to receive the saline placebo and the Forced Awakenings (FA) condition first. After a polysomnography (PSG) screening night, participants were randomized to receive two consecutive nights of forced awakenings (FA). With a minimum of a two week washout period, participants then completed the opposing sleep condition of two nights of uninterrupted sleep (US). They will receive the injection via IV bolus over 30 seconds during each experimental quantitative sensory testing session that occurs after the FA and US sleep conditions are completed.	Drug: Saline Placebo; Saline Placebo will administered to participants randomly assigned to receive the placebo via IV bolus during each quantitative sensory testing session (after one night of uninterrupted sleep and after 2 nights of forced awakenings).; Behavioral: Forced Awakenings; Participants will be awakened each hour during an 8 hour sleep opportunity period. One of the awakenings is for 60 minutes and randomly determined. The other 7 awakenings are for 20 minutes each, and are randomly scheduled to occur in either the first second or third tertile of each hour. The maximum total sleep time a participant will receive is 280 minutes.; Behavioral: Uninterrupted Sleep; Participants will receive an 8 hour period of undisturbed sleep

Outcome Measures

Primary Outcome Measures

1. Spinal Sensitization as Assessed by Area of Secondary Hyperalgesia (2HA) After Two Nights of Uninterrupted Sleep and Two Nights of 8 Forced Awakenings [Next day during quantitative sensory testing after 2 nights of forced awakenings or uninterrupted sleep]

   The area of secondary hyperalgesia (2HA) to mechanical stimulation was quantified by stimulating along eight linear paths near the capsaicin treated site using a 15 gram nonpainful von Frey filament. Stimulation occurred until the participant reported a change in sensation from which a border was marked on the skin. The degree of 2HA was assessed by measuring the total surface area (mm^2) of the marked borders. Data were collapsed by group to analyze the effects of FA vs US, irrespective of randomization group. Our Primary Secondary Hyperalgesia outcome was measured prior to injection of either morphine or placebo.

Secondary Outcome Measures

1. Opioid Analgesia as Assessed by Analgesia Index (Seconds) [Next day after 2 nights of forced awakenings or uninterrupted sleep]

   After 2 nights of forced awakenings and after two nights of uninterrupted sleep, opioid analgesia will be assessed by an analgesia index. The analgesia index is calculated using withdrawal latency during cold pressor testing (lasting maximum of 300 seconds). Cold Pressor Testing is done before and after morphine or placebo injection. The difference in withdrawal time before and after morphine or placebo injection is the analgesia index with a minimum score of -300 seconds and maximum score of 300 seconds. These data were log transformed. Mean analgesia index was then calculated for each group. Higher means represent greater analgesia.

2. Mean Change in Percentage of Peripheral Blood Mononuclear Cells Expressing Interleukin-6 After LPS Stimulation [Next day after 2 nights of forced awakenings or uninterrupted sleep, every 60 minutes up to 7 hours]

   After 2 nights of forced awakenings, and two nights of uninterrupted sleep, blood is drawn (approximately every 60 minutes) during quantitative sensory testing; 4 hours pre-morphine/placebo administration and 2 hours post-morphine/placebo administration to examine markers of inflammation. Two blood samples for each participant are analyzed at 7 separate time points. The marker of inflammation assessed is the number of peripheral blood mononuclear cells expressing Interleukin-6 (IL-6), and the outcome measure represents the mean change in IL-6 levels pre and post stimulation with lipopolysaccharide (LPS). Cellular IL-6 expression was was quantified via flow cytometry.

Other Outcome Measures

1. Total Sleep Time [Next day during quantitative sensory testing after 2 nights of forced awakenings or uninterrupted sleep.]

   The degree of sleep deprivation will be assessed by total sleep time (TST) in minutes during the uninterrupted sleep condition compared to the forced awakenings conditions.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 48 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Healthy

• Age 18-48

• Meets Research Diagnostic Criteria for Normal Sleepers

• Stable sleep phase within 21:00 and 08:00

• Total sleep time between 6.5 and 8.5 hours per night

• Sleep efficiency ≥85%

• Epworth Sleepiness Scale Score <10

• Non-smoker/non-nicotine users

• Low Caffeine Users (≤2 cups per day)

Exclusion Criteria:

• Body Mass Index ≥35

• Lifetime history of chronic pain (>6 months)

• Acute pain

• Significant medical or psychiatric morbidity within 6 months

• Lifetime history of bipolar disorder, psychotic disorder, serious recurrent major depression, serious post-traumatic stress disorder, or seizure disorder

• Respiratory, hepatic, renal, or cardiac conditions that would contraindicate opioid use

• Lifetime history of alcohol or substance abuse or dependence

• Lifetime history of opioid use >36 doses or >7 days of consecutive use

• Prior adverse reaction to general anesthetics, opioids, or capsaicin

• Clinically significant abnormal complete blood count or comprehensive metabolic profile

• Positive toxicology screen for opioids or recreational drugs

• Pregnant or lactating women

• Significant pre-admission psychological distress (T-scores >64 on the Brief Symptom Inventory Global Scales)

• Significant lifetime history of serious head injury that is determined to influence pain processing or sleep systems

Contacts and Locations

Locations

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

Sponsors and Collaborators

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

Investigators

• Principal Investigator: Michael Smith, Ph.D, Johns Hopkins University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Aug 30, 2016

More Information

Publications

None provided.

• Responsible Party: Johns Hopkins University
• ClinicalTrials.gov Identifier: NCT01794689
• Other Study ID Numbers: NA_00071465; 1R01DA032922-01
• First Posted: Feb 20, 2013
• Last Update Posted: Aug 2, 2019
• Last Verified: Aug 1, 2019

• Additional relevant MeSH terms: Hyperalgesia; Sleep Deprivation; Morphine

Study Results

Participant Flow

Recruitment Details	During screening for the study we evaluated whether participants were generally healthy, pain free, and good sleepers. We screened 255 to obtain 100 participants who met criteria and were randomized to the experimental portion of the study. The experimental phase occurred at an inpatient clinical research unit.

Arm/Group Title	Morphine US Then Morphine FA	Morphine FA Then Morphine US	Placebo US Then Placebo FA	Placebo FA Then Placebo US
Arm/Group Description	Participants randomized to receive Morphine and the Uninterrupted Sleep (US) condition first. After a polysomnography (PSG) screening night, participants were randomized to receive two consecutive nights of uninterrupted sleep (US). With a minimum of a two week washout period, participants then completed the opposing sleep condition of two nights of forced awakenings (FA). They will receive the Morphine injection (0.08mg/kg) via IV bolus over 30 seconds during each experimental quantitative sensory testing session that occurs after the US and FA sleep conditions are completed.	Participants randomized to receive Morphine and the Forced Awakenings (FA) condition first. After a polysomnography (PSG) screening night, participants were randomized to receive two consecutive nights of forced awakenings (FA). With a minimum of a two week washout period, participants then completed the opposing sleep condition of two nights of uninterrupted sleep (US). They will receive the Morphine injection (0.08mg/kg) via IV bolus over 30 seconds during each experimental quantitative sensory testing session that occurs after the FA and US sleep conditions are completed.	Participants randomized to receive the saline placebo and the Uninterrupted Sleep (US) condition first. After a polysomnography (PSG) screening night, participants were randomized to receive two consecutive nights of uninterrupted sleep (US). With a minimum of a two week washout period, participants then completed the opposing sleep condition of two nights of forced awakenings (FA). They will receive the injection via IV bolus over 30 seconds during each experimental quantitative sensory testing session that occurs after the US and FA sleep conditions are completed.	Participants randomized to receive the saline placebo and the Forced Awakenings (FA) condition first. After a polysomnography (PSG) screening night, participants were randomized to receive two consecutive nights of forced awakenings (FA). With a minimum of a two week washout period, participants then completed the opposing sleep condition of two nights of uninterrupted sleep (US). They will receive the injection via IV bolus over 30 seconds during each experimental quantitative sensory testing session that occurs after the FA and US sleep conditions are completed.
Period Title: Intervention 1 (2 Nights)
STARTED	25	29	24	22
COMPLETED	20	27	21	18
NOT COMPLETED	5	2	3	4
Period Title: Intervention 1 (2 Nights)
STARTED	20	27	21	18
COMPLETED	20	27	21	18
NOT COMPLETED	0	0	0	0
Period Title: Intervention 1 (2 Nights)
STARTED	20	27	21	18
COMPLETED	20	27	21	18
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	Morphine US Then Morphine FA	Morphine FA Then Morphine US	Placebo US Then Placebo FA	Placebo FA Then Placebo US	Total
Arm/Group Description	Participants randomized to receive Morphine and the Uninterrupted Sleep (US) condition first. After a polysomnography (PSG) screening night, participants were randomized to receive two consecutive nights of uninterrupted sleep (US). With a minimum of a two week washout period, participants then completed the opposing sleep condition of two nights of forced awakenings (FA). They will receive the Morphine injection (0.08mg/kg) via IV bolus over 30 seconds during each experimental quantitative sensory testing session that occurs after the US and FA sleep conditions are completed.	Participants randomized to receive Morphine and the Forced Awakenings (FA) condition first. After a polysomnography (PSG) screening night, participants were randomized to receive two consecutive nights of forced awakenings (FA). With a minimum of a two week washout period, participants then completed the opposing sleep condition of two nights of uninterrupted sleep (US). They will receive the Morphine injection (0.08mg/kg) via IV bolus over 30 seconds during each experimental quantitative sensory testing session that occurs after the FA and US sleep conditions are completed.	Participants randomized to receive the saline placebo and the Uninterrupted Sleep (US) condition first. After a polysomnography (PSG) screening night, participants were randomized to receive two consecutive nights of uninterrupted sleep (US). With a minimum of a two week washout period, participants then completed the opposing sleep condition of two nights of forced awakenings (FA). They will receive the injection via IV bolus over 30 seconds during each experimental quantitative sensory testing session that occurs after the US and FA sleep conditions are completed.	Participants randomized to receive the saline placebo and the Forced Awakenings (FA) condition first. After a polysomnography (PSG) screening night, participants were randomized to receive two consecutive nights of forced awakenings (FA). With a minimum of a two week washout period, participants then completed the opposing sleep condition of two nights of uninterrupted sleep (US). They will receive the injection via IV bolus over 30 seconds during each experimental quantitative sensory testing session that occurs after the FA and US sleep conditions are completed.	Total of all reporting groups
Overall Participants	25	29	24	22	100
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	27.1348 (5.97835)	29.6819 (7.54226)	27.3609 (5.22747)	27.7272 (8.18124)	28.0581 (6.81392)
Sex: Female, Male (Count of Participants)
Female	14 56%	15 51.7%	12 50%	17 77.3%	58 58%
Male	11 44%	14 48.3%	12 50%	5 22.7%	42 42%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	1 4%	3 10.3%	6 25%	1 4.5%	11 11%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	10 40%	10 34.5%	6 25%	11 50%	37 37%
White	10 40%	14 48.3%	11 45.8%	10 45.5%	45 45%
More than one race	3 12%	0 0%	0 0%	0 0%	3 3%
Unknown or Not Reported	1 4%	2 6.9%	1 4.2%	0 0%	4 4%
Body Mass Index (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	26.1490 (4.16713)	25.2645 (3.95007)	25.8440 (3.63156)	25.7134 (4.17552)	25.7235 (3.93648)

Outcome Measures

1. Primary Outcome

Title	Spinal Sensitization as Assessed by Area of Secondary Hyperalgesia (2HA) After Two Nights of Uninterrupted Sleep and Two Nights of 8 Forced Awakenings
Description	The area of secondary hyperalgesia (2HA) to mechanical stimulation was quantified by stimulating along eight linear paths near the capsaicin treated site using a 15 gram nonpainful von Frey filament. Stimulation occurred until the participant reported a change in sensation from which a border was marked on the skin. The degree of 2HA was assessed by measuring the total surface area (mm^2) of the marked borders. Data were collapsed by group to analyze the effects of FA vs US, irrespective of randomization group. Our Primary Secondary Hyperalgesia outcome was measured prior to injection of either morphine or placebo.
Time Frame	Next day during quantitative sensory testing after 2 nights of forced awakenings or uninterrupted sleep

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Morphine US	Morphine FA	Placebo US	Placebo FA
Arm/Group Description	Participants that received morphine with Uninterrupted sleep (US).	Participants that received morphine with forced awakenings (FA).	Participants that received placebo with Uninterrupted sleep (US).	Participants that received placebo with forced awakenings (FA).
Measure Participants	47	47	39	39
Mean (Standard Deviation) [mm^2]	1276.25 (1096.761)	1582.67 (1590.784)	1302.93 (1301.457)	1447.9 (1322.52)

2. Secondary Outcome

Title	Opioid Analgesia as Assessed by Analgesia Index (Seconds)
Description	After 2 nights of forced awakenings and after two nights of uninterrupted sleep, opioid analgesia will be assessed by an analgesia index. The analgesia index is calculated using withdrawal latency during cold pressor testing (lasting maximum of 300 seconds). Cold Pressor Testing is done before and after morphine or placebo injection. The difference in withdrawal time before and after morphine or placebo injection is the analgesia index with a minimum score of -300 seconds and maximum score of 300 seconds. These data were log transformed. Mean analgesia index was then calculated for each group. Higher means represent greater analgesia.
Time Frame	Next day after 2 nights of forced awakenings or uninterrupted sleep

Outcome Measure Data

Analysis Population Description

Each participant had to do four visits and two testing sessions to be termed complete. The data needed for analysis for this outcome measure was obtained from some participants but not all who completed or couldn't complete the entire study. This explains the differences in the number of units analyzed.

Arm/Group Title	Morphine US	Morphine FA	Placebo US	Placebo FA
Arm/Group Description	Participants that received morphine with Uninterrupted sleep (US).	Participants that received morphine with forced awakenings (FA).	Participants that received placebo with Uninterrupted sleep (US).	Participants that received placebo with forced awakenings (FA).
Measure Participants	47	47	39	39
Measure cold pressor test	48	45	42	39
Mean (Standard Deviation) [seconds (log transformed)]	0.315 (0.540)	0.156 (0.712)	-0.124 (0.346)	-0.006 (0.263)

3. Secondary Outcome

Title	Mean Change in Percentage of Peripheral Blood Mononuclear Cells Expressing Interleukin-6 After LPS Stimulation
Description	After 2 nights of forced awakenings, and two nights of uninterrupted sleep, blood is drawn (approximately every 60 minutes) during quantitative sensory testing; 4 hours pre-morphine/placebo administration and 2 hours post-morphine/placebo administration to examine markers of inflammation. Two blood samples for each participant are analyzed at 7 separate time points. The marker of inflammation assessed is the number of peripheral blood mononuclear cells expressing Interleukin-6 (IL-6), and the outcome measure represents the mean change in IL-6 levels pre and post stimulation with lipopolysaccharide (LPS). Cellular IL-6 expression was was quantified via flow cytometry.
Time Frame	Next day after 2 nights of forced awakenings or uninterrupted sleep, every 60 minutes up to 7 hours

Outcome Measure Data

Analysis Population Description

For some participants we could not collect blood samples for all time points and testing sessions. This explains the differences in the numbers of samples analyzed at various timepoints.

Arm/Group Title	Morphine US	Morphine FA	Placebo US	Placebo FA
Arm/Group Description	Participants that received morphine with Uninterrupted Sleep (US).	Participants that received morphine with forced awakenings (FA).	Participants that received placebo with Uninterrupted Sleep (US).	Participants that received placebo with forced awakenings (FA).
Measure Participants	47	47	39	39
Measure blood samples	265	256	225	213
Timepoint 1	41.98 (21.18)	51.82 (21.13)	42.91 (19.53)	43.32 (19.04)
Timepoint 2	45.44 (22.95)	51.84 (20.34)	42.93 (21.81)	43.79 (18.01)
Timepoint 3	45.99 (19.12)	48.99 (18.96)	40.76 (20.1)	41.65 (21.87)
Timepoint 4	43.96 (18.2)	46.94 (17.81)	39.06 (20.48)	41.34 (21.36)
Timepoint 5	38.67 (17.93)	43.45 (18.3)	38.71 (19.11)	34.63 (20.74)
Timepoint 6	36.83 (19.39)	39.15 (21.23)	35.64 (18.58)	36.28 (19.38)
Timepoint 7	36.47 (18.9)	39.92 (19.6)	35.49 (17.03)	35.25 (19.35)

4. Other Pre-specified Outcome

Title	Total Sleep Time
Description	The degree of sleep deprivation will be assessed by total sleep time (TST) in minutes during the uninterrupted sleep condition compared to the forced awakenings conditions.
Time Frame	Next day during quantitative sensory testing after 2 nights of forced awakenings or uninterrupted sleep.

Outcome Measure Data

Analysis Population Description

Each participant had to do four visits to be termed complete. The data needed for analysis for this outcome measure was obtained from some participants but not all who completed or couldn't complete the entire study. This explains the differences in the numbers analyzed for each total sleep time.

Arm/Group Title	Morphine US	Morphine FA	Placebo US	Placebo FA
Arm/Group Description	Participants randomized to receive Morphine and the Uninterrupted Sleep (US) condition first. After a polysomnography (PSG) screening night, participants were randomized to receive two consecutive nights of uninterrupted sleep (US). With a minimum of a two week washout period, participants then completed the opposing sleep condition of two nights of forced awakenings (FA). They will receive the Morphine injection (0.08mg/kg) via IV bolus over 30 seconds during each experimental quantitative sensory testing session that occurs after the US and FA sleep conditions are completed.	Participants randomized to receive Morphine and the Forced Awakenings (FA) condition first. After a polysomnography (PSG) screening night, participants were randomized to receive two consecutive nights of forced awakenings (FA). With a minimum of a two week washout period, participants then completed the opposing sleep condition of two nights of uninterrupted sleep (US). They will receive the Morphine injection (0.08mg/kg) via IV bolus over 30 seconds during each experimental quantitative sensory testing session that occurs after the FA and US sleep conditions are completed.	Participants randomized to receive the saline placebo and the Uninterrupted Sleep (US) condition first. After a polysomnography (PSG) screening night, participants were randomized to receive two consecutive nights of uninterrupted sleep (US). With a minimum of a two week washout period, participants then completed the opposing sleep condition of two nights of forced awakenings (FA). They will receive the injection via IV bolus over 30 seconds during each experimental quantitative sensory testing session that occurs after the US and FA sleep conditions are completed.	Participants randomized to receive the saline placebo and the Forced Awakenings (FA) condition first. After a polysomnography (PSG) screening night, participants were randomized to receive two consecutive nights of forced awakenings (FA). With a minimum of a two week washout period, participants then completed the opposing sleep condition of two nights of uninterrupted sleep (US). They will receive the injection via IV bolus over 30 seconds during each experimental quantitative sensory testing session that occurs after the FA and US sleep conditions are completed.
Measure Participants	25	29	24	22
TST: Uninterrupted Sleep-Night 1	442.8909 (23.06461)	425.0280 (52.40921)	443.2375 (38.99631)	435.1467 (29.12669)
TST: Uninterrupted Sleep-Night 2	435.2045 (41.16120)	420.1375 (71.39364)	439.0417 (47.06713)	441.1400 (35.93814)
TST: Forced Awakenings-Night 1	217.4556 (46.00094)	225.4192 (38.47452)	235.1727 (50.91526)	252.0950 (32.70550)
TST: Forced Awakenings-Night 2	270.3333 (35.23125)	258.1083 (29.47026)	267.7714 (16.90080)	261.9941 (32.01372)

Adverse Events

Time Frame	Participants were enrolled and actively participating in the study across a time frame of four years and 7.5 months. With no scheduling difficulties each participant remained in the study for 5-6 weeks.
Arm/Group Title	Morphine US		Morphine FA		Placebo US		Placebo FA
Arm/Group Description	Participants that received morphine with Uninterrupted sleep (US).		Participants that received morphine with forced awakenings (FA).		Participants that received placebo with Uninterrupted sleep (US).		Participants that received placebo with forced awakenings (FA).
All Cause Mortality
	Morphine US		Morphine FA		Placebo US		Placebo FA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/52 (0%)		0/49 (0%)		0/42 (0%)		0/43 (0%)
Serious Adverse Events
	Morphine US		Morphine FA		Placebo US		Placebo FA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/52 (0%)		0/49 (0%)		0/42 (0%)		0/43 (0%)
Other (Not Including Serious) Adverse Events
	Morphine US		Morphine FA		Placebo US		Placebo FA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/52 (15.4%)		7/49 (14.3%)		1/42 (2.4%)		2/43 (4.7%)
Cardiac disorders
Hypotension	2/52 (3.8%)	2	0/49 (0%)	0	0/42 (0%)	0	0/43 (0%)	0
Tachycardia	0/52 (0%)	0	1/49 (2%)	1	0/42 (0%)	0	0/43 (0%)	0
Syncope	0/52 (0%)	0	0/49 (0%)	0	1/42 (2.4%)	1	0/43 (0%)	0
Gastrointestinal disorders
Nausea	6/52 (11.5%)	8	5/49 (10.2%)	8	0/42 (0%)	0	0/43 (0%)	0
Vomiting	4/52 (7.7%)	5	5/49 (10.2%)	9	0/42 (0%)	0	0/43 (0%)	0
Stomach Pain	0/52 (0%)	0	1/49 (2%)	1	0/42 (0%)	0	0/43 (0%)	0
Musculoskeletal and connective tissue disorders
Back Pain	0/52 (0%)	0	0/49 (0%)	0	0/42 (0%)	0	1/43 (2.3%)	1
Nervous system disorders
Dizziness	3/52 (5.8%)	3	2/49 (4.1%)	4	0/42 (0%)	0	0/43 (0%)	0
Headache	3/52 (5.8%)	3	0/49 (0%)	0	0/42 (0%)	0	0/43 (0%)	0
Psychiatric disorders
Claustrophobia	0/52 (0%)	0	0/49 (0%)	0	0/42 (0%)	0	1/43 (2.3%)	1
Respiratory, thoracic and mediastinal disorders
Shortness of Breath	1/52 (1.9%)	1	0/49 (0%)	0	0/42 (0%)	0	0/43 (0%)	0
Skin and subcutaneous tissue disorders
Laceration	1/52 (1.9%)	1	0/49 (0%)	0	0/42 (0%)	0	0/43 (0%)	0

Limitations/Caveats

Participants were mostly young adults, were generally healthy, pain free and good sleepers. Strict inclusion/exclusion criteria and high participant burden (laboratory pain testing, overnight sleep studies) impacted sample size and study completion.

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Certain Agreements

All Principal Investigators ARE 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.