A Phase 1 interventional study of High Morphine Dose and Low Morphine Dose in Drug Effect, sponsored by Yale University. Completed at 1 site in United States. Open to participants aged 21 Years to 50 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2021-04-27.
Sponsored by Yale University · Phase 1, Interventional, and Basic science
Preclinical research indicates acute opioid administration evokes an immune response in the periphery and brain. Here, we will translate those preclinical findings to healthy human volunteers and quantify the neuroimmune response to a morphine challenge using positron emission tomography (PET) imaging with [11C]PBR28.
Subjects will be recruited from the local community via media advertisements, flyers, and word-of-mouth. Interested individuals will undergo a phone screen and in-person medical and psychiatric examination. Up to 20 eligible individuals (see Inclusion/Exclusion criteria) will be invited to participate in this study.
In a single day, subjects will complete behavioral and physiological testing, a [11C]PBR28 PET scan, and report subjective drug effects before and after a morphine challenge. Subjects will complete either a 'High' or 'Low' morphine dose condition (single-blind): 0.07mg/kg i.m. vs. 0.04mg/kg i.m., respectively. To measure the neuroimmune response to morphine, we will use [11C]PBR28 PET imaging (120-minute scans on a High Resolution Research Tomograph with Vicra motion correction). [11C]PBR28 binds with high affinity and specificity to the 18kDa translocator protein (TSPO), which is highly expressed in microglia and has been shown to respond to inflammatory challenges. TSPO volumes of distribution (VT), i.e., TSPO availability, will be quantified in brain regions of interest using multilinear analysis-1 (MA-1) with the metabolite-corrected arterial input function. The post-morphine [11C]PBR28 PET scan will occur 2-hours after the morphine challenge.
Specific Aim 1: To determine whether an acute morphine administration increases brain TSPO availability in healthy volunteers.
Hypothesis 1: Relative to pre-morphine levels, morphine will significantly increase TSPO availability across brain regions of interest, consistent with a neuroimmune response.
Specific Aim 2: To determine whether morphine evokes a dose-dependent increase in brain TSPO availability in healthy volunteers.
Hypothesis 2: Relative to pre-morphine levels, morphine will dose-dependently increase TSPO availability across brain regions of interest.
Specific Aim 3: To determine whether morphine administration increases peripheral markers of inflammation, e.g., cytokine/chemokine concentration in plasma.
Hypothesis 3: Relative to pre-morphine levels, morphine will increase cytokine/chemokine concentrations in plasma, including IL-1B, IL-2, IL-6, IL-10, TNF-a, IFNy, MCP-1, and GM-CSF, consistent with a peripheral immune response. Exploratory Hypotheses: 1) IL-1B, IL-6, TNF-a, IFNy, MCP-1, and GM-CSF will exhibit morphine dose-dependent increases in plasma. 2) The change in IL-6, TNF-a, IFN-y, and GM-CSF levels will be positively correlated with the change in brain TSPO VT levels.
Specific Aim 4: To determine whether morphine administration alters pain sensitivity, pain tolerance, cognitive function, and reward responsiveness.
Hypothesis 4: Relative to pre-morphine levels, morphine will enhance pain tolerance and impair verbal learning/memory proficiency and impair reward responsiveness. Morphine will not alter pain sensitivity, visual attention, psychomotor processing speed, or working memory proficiency. Exploratory hypotheses: 1) The change in TSPO availability in thalamus will be positively correlated with the change in pain tolerance. 2) The change in TSPO availability in hippocampus will be inversely correlated with the change in verbal learning/memory proficiency. 3) The change in TSPO availability in caudate, ACC, and OFC will be inversely correlated with the change in reward responsiveness.
Specific Aim 5: To determine whether morphine administration alters vital signs.
Hypothesis 5: Relative to pre-morphine levels, morphine will dose-dependently reduce systolic and diastolic blood pressure. Relative to pre-morphine levels, morphine will lower heart rate.
Specific Aim 6: To measure the subjective response to morphine administration.
Hypothesis 6: Relative to pre-morphine levels, morphine will dose-dependently increase subjective ratings of 'high', 'good drug effect', 'nausea', and 'bad drug effect'. Exploratory hypotheses: 1) The change in TSPO availability in caudate, ACC, and OFC will be positively correlated with the change in 'high' and 'good drug effect'. 2) The change in TSPO availability in the insula and thalamus will be positively correlated with the change in 'nausea' and 'bad drug effect'.
Specific Aim 7: To determine whether morphine administration alters peripheral stress markers of the autonomic nervous system and HPA-axis.
Hypothesis 7: Relative to pre-morphine levels, morphine will dose-dependently increase plasma levels of epinephrine, norepinephrine, and cortisol.
Specific Aim 8: To determine whether morphine administration alters peripheral markers of neurosteroids.
Hypothesis 8: Relative to pre-morphine levels, morphine will dose-dependently increase plasma levels of allopregnanolone and pregnenolone.
Specific Aim 9: To determine whether morphine administration alters peripheral markers of the metabolic hormone ghrelin.
Hypothesis 9: Relative to pre-morphine levels, morphine will dose-dependently increase plasma levels of ghrelin.
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PBR_Morphine Study
Inclusion Criteria:
Exclusion criteria:
Medical contraindication to receive up to 0.1 mg/kg intramuscular morphine administration as determined by Study Physician. This includes:
Medical contraindications to metoclopramide, as determined by the Study Physician, including:
Subjects in this experimental arm will receive a single intramuscular morphine dose (non-dominant deltoid muscle; 0.07 mg/kg).
Drug: High Morphine Dose
Subjects in this experimental arm will receive a single intramuscular morphine dose (non-dominant deltoid muscle; 0.04 mg/kg).
Drug: Low Morphine Dose
Subjects will receive an intramuscular morphine injection (0.07mg/kg) in the non-dominant deltoid muscle. Metoclopramide (10mg; oral) will be administered PRN to reduce nausea.
Also known as: High Dose
Subjects will receive an intramuscular morphine injection (0.04mg/kg) in the non-dominant deltoid muscle. Metoclopramide (10mg; oral) will be administered PRN to reduce nausea.
Also known as: Low Dose
Change in Brain TSPO availability
Relative to pre-morphine levels, we will measure the change in brain regional TSPO availability (VT) after morphine. VT will be calculated for brain regions of interest using multi-linear analysis 1 (t\*=30) using the metabolite-corrected arterial input function.
Time frame: One 120-minute PET [11C]PBR28 scan before and one PET [11C]PBR28 scan 2hr after morphine challenge.
Change in Verbal Learning Performance
Relative to pre-morphine levels, we will measure the change in verbal learning performance after morphine via the Cogstate computerized task: International Shopping List. In this task, subjects are asked to memorize and recite (without prompt) 12 common grocery shopping items across 3 trials. Number of correct items recalled across the 3 trials is analyzed.
Time frame: This Cogstate task will be administered twice: once before and once ~40 minutes after the morphine challenge.
Change in Verbal Memory Performance
Relative to pre-morphine levels, we will measure the change in verbal memory performance after morphine via the Cogstate computerized task: International Shopping List - Delayed Recall. In this task, subjects are asked to recall (after a time delay) the 12 common grocery shopping items from the International Shopping List task. Number of correct items recalled in this one trial is analyzed.
Time frame: This Cogstate task will be administered twice: once before and once ~70 minutes after the morphine challenge.
Change in Psychomotor Speed
Relative to pre-morphine levels, we will measure the change in psychomotor speed via the Cogstate computerized task: Detection. In this task, subjects are asked to respond via button press as soon as the playing card on screen flips over. The log10 of the mean latency to respond (ms) is analyzed.
Time frame: This Cogstate task will be administered twice: once before and once ~45 minutes after the morphine challenge.
Change in Visual Attention
Relative to pre-morphine levels, we will measure the change in visual attention via the Cogstate computerized task: Identification. In this task, subjects are asked to respond via button press as soon as he/she identifies that the playing card on screen matches the target card color (red). The log10 of the mean latency to respond (ms) is analyzed.
Time frame: This Cogstate task will be administered twice: once before and once ~50 minutes after the morphine challenge.
Change in Visual Learning
Relative to pre-morphine levels, we will measure the change in visual learning via the Cogstate computerized task: One Card Learning. In this task, subjects are asked to respond via button press if he/she identifies that the on-screen playing card has been shown previously. The arc sine of the percent correctly identified is analyzed.
Time frame: This Cogstate task will be administered twice: once before and once ~55 minutes after the morphine challenge.
Change in Working Memory (easy)
Relative to pre-morphine levels, we will measure the change in working memory performance via the Cogstate computerized task: One Back. In this task, subjects are asked to respond via button press if he/she identifies that the on-screen playing card matches the card shown just prior to the current card. The log10 of the mean latency to respond (ms) is analyzed.
Time frame: This Cogstate task will be administered twice: once before and once ~60 minutes after the morphine challenge.
Change in Working Memory (hard)
Relative to pre-morphine levels, we will measure the change in working memory performance via the Cogstate computerized task: Two Back. In this task, subjects are asked to respond via button press if he/she identifies that the on-screen playing card matches the card shown two prior to the current card. The arc sine of the percent correctly identified is analyzed.
Time frame: This Cogstate task will be administered twice: once before and once ~65 minutes after the morphine challenge.
Change in Venous Cytokine/Chemokine Concentration
Relative to pre-morphine levels, we will measure the change in venous cytokine and chemokine concentrations (e.g., IL-6, IL-10, TNF-alpha, GM-CSF, and IFN-gamma) periodically after morphine via ELISA assay kit.
Time frame: Plasma samples will be collected 10-minutes before and 60-minutes, 110-minutes, and 250-minutes after the morphine challenge.
Change in Venous Cortisol Concentration
Relative to pre-morphine levels, we will measure the change in venous cortisol levels periodically after morphine via ELISA assay kit.
Time frame: Plasma samples will be collected 10-minutes before and 60-minutes, 110-minutes, and 250-minutes after the morphine challenge.
Change in Venous Epinephrine Concentration
Relative to pre-morphine levels, we will measure the change in venous epinephrine levels periodically after morphine via ELISA assay kit.
Time frame: Plasma samples will be collected 10-minutes before and 60-minutes, 110-minutes, and 250-minutes after the morphine challenge.
Change in Venous Norepinephrine Concentration
Relative to pre-morphine levels, we will measure the change in venous norepinephrine levels periodically after morphine via ELISA assay kit.
Time frame: Plasma samples will be collected 10-minutes before and 60-minutes, 110-minutes, and 250-minutes after the morphine challenge.
Change in Venous Allopregnanolone Concentration
Relative to pre-morphine levels, we will measure the change in venous allopregnanolone levels periodically after morphine via ELISA assay kit.
Time frame: Plasma samples will be collected 10-minutes before and 60-minutes, 110-minutes, and 250-minutes after the morphine challenge.
Change in Venous Pregnenolone Concentration
Relative to pre-morphine levels, we will measure the change in venous pregnenolone levels periodically after morphine via ELISA assay kit.
Time frame: Plasma samples will be collected 10-minutes before and 60-minutes, 110-minutes, and 250-minutes after the morphine challenge.
Change in Venous Ghrelin Concentration
Relative to pre-morphine levels, we will measure the change in venous ghrelin levels periodically after morphine via ELISA assay kit.
Time frame: Plasma samples will be collected 10-minutes before and 60-minutes, 110-minutes, and 250-minutes after the morphine challenge.
Change in Thermal Pain Sensitivity
Relative to pre-morphine levels, we will measure the change in thermal pain sensitivity after morphine via the Cold Pressor Task. Subjects will place their hand in a warm water bath and then a cold water bath. Subjects will be asked to indicate when he/she first experiences pain related to the cold water bath. Time to detection of pain (s) is analyzed.
Time frame: The Cold Pressor Task will be administered once before and once ~90-minutes after the morphine challenge.
Change in Thermal Pain Tolerance
Relative to pre-morphine levels, we will measure the change in thermal pain tolerance after morphine via the Cold Pressor Task. Subjects will place their hand in a warm water bath and then a cold water bath. Time to withdrawal his/her hand from the cold water bath (s; max: 90s) is analyzed.
Time frame: The Cold Pressor Task will be administered once before and once ~90-minutes after the morphine challenge.
Change in Reward Responsiveness
Relative to pre-morphine levels, we will measure the change in reward responsiveness after morphine via the computerized Probabilistic Reward Task. Reward responsiveness is calculated as the subject's propensity to modulate his/her response latency to discriminate two stimuli (short and long mouths on a face) based on prior reinforcement (monetary reward for 'correct' responses). This task allows objective measurement of an individuals' responsiveness to monetary reward.
Time frame: The Probabilistic Reward Task will be administered once before and once ~260 minutes after morphine.
Change in systolic blood pressure
Systolic blood pressure (mmHg; while seated and resting) will be measured periodically before and after morphine.
Time frame: Blood pressure will be measured 10-minutes before, and 30-minutes, 60-minutes, and 90-minutes after morphine.
Change in diastolic blood pressure
Diastolic blood pressure (mmHg; while seated and resting) will be measured periodically before and after morphine.
Time frame: Blood pressure will be measured 10-minutes before, and 30-minutes, 60-minutes, and 90-minutes after morphine.
Change in heart rate
Heart rate (beats per minute; while seated and resting) will be measured periodically before and after morphine.
Time frame: Heart rate will be measured 10-minutes before, and 30-minutes, 60-minutes, and 90-minutes after morphine.
Change in subjective drug effects
Morphine drug effects are measured via visual analogue scale (VAS 0-100mm) for the following adjectives: 'high', 'nauseous', 'good effect', 'bad effect' and 'any effect'.
Time frame: Subjective drug effects measured 10-minutes before, and 30-minutes, 60-minutes, and 90-minutes after morphine.
Plan to share: Yes — De-identified participant data will be shared upon reasonable request.
Supporting information: Study protocol, Icf
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