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| ID | Type | Description | Link |
|---|---|---|---|
| 1R01DA032922-01 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institute on Drug Abuse (NIDA) | NIH |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Morphine US then Morphine FA | Experimental | 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. |
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| Placebo US then Placebo FA | Placebo Comparator | 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. |
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| Morphine FA then Morphine US | Experimental | 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. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Morphine | Drug | 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). |
| Measure | Description | Time Frame |
|---|---|---|
| Spinal Sensitization as Assessed by Area of Secondary Hyperalgesia (2HA) After Two Nights of Uninterrupted Sleep and Two Nights of 8 Forced Awakenings | 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. | Next day during quantitative sensory testing after 2 nights of forced awakenings or uninterrupted sleep |
| Measure | Description | Time Frame |
|---|---|---|
| Opioid Analgesia as Assessed by Analgesia Index (Seconds) | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Total Sleep Time | 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. | Next day during quantitative sensory testing after 2 nights of forced awakenings or uninterrupted sleep. |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Michael Smith, Ph.D | Johns Hopkins University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Johns Hopkins University Bayview Medical Center | Baltimore | Maryland | 21224 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 36314570 | Derived | Irwin MR, Olmstead R, Bjurstrom MF, Finan PH, Smith MT. Sleep disruption and activation of cellular inflammation mediate heightened pain sensitivity: a randomized clinical trial. Pain. 2023 May 1;164(5):1128-1137. doi: 10.1097/j.pain.0000000000002811. Epub 2022 Oct 27. |
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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.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | 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. |
| FG002 | 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. |
| FG003 | 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Intervention 1 (2 Nights) |
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| Washout (2 Weeks) |
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| Intervention 2 (2 Nights) |
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Spinal Sensitization as Assessed by Area of Secondary Hyperalgesia (2HA) After Two Nights of Uninterrupted Sleep and Two Nights of 8 Forced Awakenings | 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. | Posted | Mean | Standard Deviation | mm^2 | Next day during quantitative sensory testing after 2 nights of forced awakenings or uninterrupted sleep |
|
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.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Morphine US | Participants that received morphine with Uninterrupted sleep (US). |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Hypotension | Cardiac disorders | Systematic Assessment |
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.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Michael T. Smith, PhD | Johns Hopkins University | 410-550-7000 | msmith62@jhmi.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Aug 30, 2016 | Jan 22, 2019 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D012892 | Sleep Deprivation |
| D010146 | Pain |
| ID | Term |
|---|---|
| D020920 | Dyssomnias |
| D012893 | Sleep Wake Disorders |
| D009422 | Nervous System Diseases |
| D009461 | Neurologic Manifestations |
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| ID | Term |
|---|---|
| D009020 | Morphine |
| ID | Term |
|---|---|
| D009022 | Morphine Derivatives |
| D009019 | Morphinans |
| D053610 | Opiate Alkaloids |
| D000470 | Alkaloids |
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| Placebo FA then Placebo US | Placebo Comparator | 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. |
|
| Saline Placebo | Drug | 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). |
|
| Forced Awakenings | Behavioral | 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. |
|
| Uninterrupted Sleep | Behavioral | Participants will receive an 8 hour period of undisturbed sleep |
|
| Next day after 2 nights of forced awakenings or uninterrupted sleep |
| Mean Change in Percentage of Peripheral Blood Mononuclear Cells Expressing Interleukin-6 After LPS Stimulation | 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. | Next day after 2 nights of forced awakenings or uninterrupted sleep, every 60 minutes up to 7 hours |
| Protocol Violation |
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| Physician Decision |
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| Adverse Event |
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| COMPLETED |
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| NOT COMPLETED |
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| COMPLETED |
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| NOT COMPLETED |
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| BG001 | 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. |
| BG002 | 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. |
| BG003 | 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. |
| BG004 | Total | Total of all reporting groups |
| years |
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| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Body Mass Index | Mean | Standard Deviation | kg/m^2 |
|
Participants that received morphine with Uninterrupted sleep (US).
| OG001 | Morphine FA | Participants that received morphine with forced awakenings (FA). |
| OG002 | Placebo US | Participants that received placebo with Uninterrupted sleep (US). |
| OG003 | Placebo FA | Participants that received placebo with forced awakenings (FA). |
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| Secondary | Opioid Analgesia as Assessed by Analgesia Index (Seconds) | 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. | 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. | Posted | Mean | Standard Deviation | seconds (log transformed) | Next day after 2 nights of forced awakenings or uninterrupted sleep | cold pressor test | cold pressor test |
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| Secondary | Mean Change in Percentage of Peripheral Blood Mononuclear Cells Expressing Interleukin-6 After LPS Stimulation | 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. | 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. | Posted | Mean | Standard Deviation | percentage of IL-6 expression | Next day after 2 nights of forced awakenings or uninterrupted sleep, every 60 minutes up to 7 hours | blood samples | blood samples |
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| Other Pre-specified | Total Sleep Time | 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. | 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. | Posted | Mean | Standard Deviation | minutes | Next day during quantitative sensory testing after 2 nights of forced awakenings or uninterrupted sleep. |
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| 0 |
| 52 |
| 0 |
| 52 |
| 8 |
| 52 |
| EG001 | Morphine FA | Participants that received morphine with forced awakenings (FA). | 0 | 49 | 0 | 49 | 7 | 49 |
| EG002 | Placebo US | Participants that received placebo with Uninterrupted sleep (US). | 0 | 42 | 0 | 42 | 1 | 42 |
| EG003 | Placebo FA | Participants that received placebo with forced awakenings (FA). | 0 | 43 | 0 | 43 | 2 | 43 |
| Nausea | Gastrointestinal disorders | Systematic Assessment |
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| Vomiting | Gastrointestinal disorders | Systematic Assessment |
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| Dizziness | Nervous system disorders | Systematic Assessment |
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| Headache | Nervous system disorders | Systematic Assessment |
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| Stomach Pain | Gastrointestinal disorders | Systematic Assessment |
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| Back Pain | Musculoskeletal and connective tissue disorders | Systematic Assessment |
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| Laceration | Skin and subcutaneous tissue disorders | Systematic Assessment |
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| Shortness of Breath | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
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| Tachycardia | Cardiac disorders | Systematic Assessment |
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| Syncope | Cardiac disorders | Systematic Assessment |
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| Claustrophobia | Psychiatric disorders | Systematic Assessment |
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| D012816 |
| Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D001523 | Mental Disorders |
| D006571 |
| Heterocyclic Compounds |
| D006572 | Heterocyclic Compounds, Bridged-Ring |
| D006576 | Heterocyclic Compounds, 4 or More Rings |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D010616 | Phenanthrenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D011083 | Polycyclic Compounds |
| cold pressor test |
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| blood samples |
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| Timepoint 2 |
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| Timepoint 3 |
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| Timepoint 4 |
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| Timepoint 5 |
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| Timepoint 6 |
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| Timepoint 7 |
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| TST: Uninterrupted Sleep-Night 2 |
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| TST: Forced Awakenings-Night 1 |
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| TST: Forced Awakenings-Night 2 |
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