Effects of Experimental Sleep Disturbances on Receptor Function of Study Drug

  • STATUS
    Recruiting
  • End date
    Jan 31, 2023
  • participants needed
    200
  • sponsor
    Johns Hopkins University
Updated on 20 November 2021
analgesics
opioid
benzodiazepines
sleep disturbances
total sleep time
sleep problem
Accepts healthy volunteers

Summary

The overall goal of this project is to determine whether common sleep disturbance patterns, sleep continuity disturbance (SCD) and Sleep Fragmentation (SF), alter cerebral study drug receptor availability, drug-based analgesia, and drug abuse liability. The investigators specifically aim to: 1) evaluate whether experimental SCD and/or SF alter resting or pain-evoked receptor binding potential in brain regions associated with pain inhibition; 2) examine whether SCD and/or SF alters the analgesic response and abuse liability profile of a study medication; and 3) determine whether receptor binding potentials in brain regions of interest are associated with study medication analgesia and abuse liability. The investigators will also evaluate the extent to which associations differ by sleep condition or sex.

Description

Based on preclinical data and preliminary studies, the investigators hypothesize that sleep continuity disruption (SCD) and/or sleep fragmentation (SF), two sleep patterns commonly observed in both chronic pain and substance use disorders, will alter study drug receptor availability in descending pain inhibitory and reward processing pathways. The investigators further hypothesize that these forms of sleep disruption will increase risk by reducing analgesic efficacy and/or enhancing standard abuse liability measures.

The investigators will conduct a parallel group experiment that will randomize 100 healthy subjects to two nights of either experimental:

  1. SCD (frank, prolonged, nightly awakenings with curtailed sleep duration, a pattern associated with insomnia);
  2. SF (multiple, frequent, non-waking arousals with preserved sleep duration, a pattern observed in sleep apnea); or
  3. undisturbed sleep (US). Subjects will then complete a Carfentanil positron emission tomography (PET) brain imaging scan divided into two phases (resting to measure basal receptor binding potential (BP) and during pain to quantify endogenous medication release). The investigators will then use a placebo-controlled, multiple dose paradigm to evaluate the analgesic efficacy and abuse liability of a study medication. Analgesic efficacy and abuse liability will be evaluated using quantitative sensory testing and standard procedures.

Establishing whether common and treatable forms of sleep disturbance directly alter cerebral receptor availability, analgesia and abuse liability will transform the understanding of how sleep disturbance is a risk factor for substance use disorder and chronic pain and lead to novel prevention efforts and changes in pain management practice.

Objectives

AIM 1: To evaluate whether experimental SCD and/or SF alter(s) basal (resting) or pain evoked binding potentials (BP) in brain regions associated with descending pain inhibition [dorsolateral prefrontal cortex (DLPFC), anterior cingulate cortex, amygdala, insula, periaqueductal gray, and nucleus accumbens].

H1. Compared to US, SCD and SF will demonstrate altered basal BP in regions of interest.

H2. Compared to US, SCD and SF will demonstrate a blunted release of endogenous drug response (basal BP- pain evoked BP).

AIM 2: To examine whether experimental SCD and/or SF alters the analgesic response and abuse liability profile of a study medication.

H3. Compared to US, SCD and SF will diminish analgesia. H4. Compared to US, SCD and SF will increase drug high, "liking" and monetary valuation of the study medication.

AIM 3: To determine whether BPs in brain regions of interest are associated with analgesia and abuse liability and evaluate the extent to which associations differ by sleep condition or sex.

Study Design:

Participation in this study involves three visits which are completed in approximately 6 weeks. The first visit is a screening visit, where participants will fill out standardized questionnaires to assess medical and psychiatric history as well as sleep patterns. Participants will also receive a physical exam and will undergo blood testing to verify participants' health status. Participants will also be trained to use a sleep diary and devices to monitor participants' sleep at home. If the participant is still eligible, the participant will be asked to come back for a second screening visit which occurs at least one week after the first. At the second visit, sleep monitoring data will be reviewed and the participant will be introduced to the investigators' quantitative sensory testing procedures. Participants will be stimulated by heat, pressure, and cold water to assess baseline estimates of pain severity and unpleasantness. Participants will then undergo the investigators' study drug administration process, where up to three injections will be given that may contain either a drug or a placebo. Throughout this process, quantitative sensory testing will be done to assess analgesic response and questionnaires will be given to assess abuse liability.

If participants remain eligible, the participants will be asked to come for a third visit and spend four consecutive nights and days at the investigators' clinical research unit. Throughout participants' visit, participants will be completing standardized questionnaires and undergoing quantitative sensory testing. Participants will be randomized to undergo either sleep fragmentation, sleep continuity disruption, or undisturbed sleep on nights 2 and 3. On the third day, participants will have a 90 minute PET scan and will undergo a study drug administration procedure similar to what was done in the second screening visit. Participants will then stay for a fourth night of undisturbed sleep and will be discharged the following morning.

Details
Condition sleep disorder, healthy, Sleep Disorders, Sleep Disorders (Pediatric)
Treatment Sleep Fragmentation, Sleep Fragmentation, Within-Subject test of blinded study medication (stimulant, benzodiazepine, opioid, cannabinoid, over-the-counter pain medication, or placebo), Sleep Continuity Disruption, Undisturbed Sleep
Clinical Study IdentifierNCT04299490
SponsorJohns Hopkins University
Last Modified on20 November 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Healthy, 18-48 year olds meeting criteria for Normal Sleep
Sleep phase within 21:00 and 08:00
Total sleep time >6.5 and 8.5 hours/night; sleep efficiency 85%
Non-smokers/nicotine users
Low caffeine users ( 2 cups, q.d.)
Life-time history of exposure to opioids, appropriately prescribed for pain

Exclusion Criteria

BMI >35
Lifetime history of chronic pain
Acute pain
Meet clinical criteria for a sleep disorder
Significant central nervous system disease (e.g., lupus, multiple sclerosis)
Cognitive impairment, brain injury or history of closed head injury with loss of consciousness over 3 mins
Other significant medical or psychiatric morbidity within 6 months or lifetime history of bipolar disorder, psychotic disorder, seizure disorder
Use in the last three months of the following: antidepressants, neuroleptics, sedative hypnotics, isoniazid, glucocorticoids, psychostimulants, opioids
Any contraindicated medical condition
Lifetime history of alcohol or substance used disorder
Clinically significant abnormal complete blood count, hepatic, renal or metabolic panel
Positive toxicology screen for opioids or recreational drugs
Pregnant or lactating women
Significant preadmission psychological distress
Embedded metal objects or fragments or electronic devices in the head or body that would present a risk during MRI
Had exposure to ionizing radiation that in combination with the study's estimated radiation exposure would result in a cumulative exposure, exceeding recommended limits
Unable to tolerate the scanning environment/ claustrophobia
Clear my responses

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