Stress and Opioid Misuse Risk: The Role of Endogenous Opioid and Endocannabinoid Mechanisms

Overview

The purpose of this study is to see how stress influences the effects of opioid pain medications often used to help relieve back pain. The study will help to learn more about how high stress levels could increase risk for pain medication misuse.

Detailed description

The purpose of this project is to advance mechanistic knowledge of how stress impacts differential opioid analgesic responses that enhance risk for opioid use disorder (OUD), potentially informing development of data-driven precision pain medicine algorithms to mitigate opioid related risks.

The study aims to determine whether subjective and physiological stress-related measures are associated with analgesic and misuse-relevant subjective responses to placebo-controlled oxycodone administration. The study also aims to evaluate associations between stress-related measures and both endogenous opioid (EO) function and endocannabinoid (EC) levels and to test whether EO and EC mechanisms contribute to associations between stress-related measures and oxycodone responses

Using a mixed between/within-subject design, the study will obtain baseline assessment of stress related markers followed by 3 laboratory sessions with assessment of endocannabinoids, back pain assessment, and exposure to standardized evoked pain stimuli after administration of placebo, naloxone, and oxycodone.

Interventions

• Drug Placebo
  In randomized order (crossover) across 3 laboratory sessions, participants will undergo laboratory evoked thermal pain response testing with: 1) 0.13 mg/kg of oral oxycodone (in 1mg/ml syrup) plus 20ml i.v. saline placebo, 2) 8mg of i.v. naloxone (in 20ml saline vehicle) plus oral placebo syrup (quantity matching oxycodone syrup volume), or 3) 20ml i.v. saline placebo plus oral placebo syrup (quantity matching oxycodone syrup volume). Thermal pain testing utilizes a Medoc TSAII NeuroSensory Ana
• Drug Oxycodone
  In randomized order (crossover) across 3 laboratory sessions, participants will undergo laboratory evoked thermal pain response testing with: 1) 0.13 mg/kg of oral oxycodone (in 1mg/ml syrup) plus 20ml i.v. saline placebo, 2) 8mg of i.v. naloxone (in 20ml saline vehicle) plus oral placebo syrup (quantity matching oxycodone syrup volume), or 3) 20ml i.v. saline placebo plus oral placebo syrup (quantity matching oxycodone syrup volume). Thermal pain testing utilizes a Medoc TSAII NeuroSensory Ana
• Drug Naloxone
  In randomized order (crossover) across 3 laboratory sessions, participants will undergo laboratory evoked thermal pain response testing with: 1) 0.13 mg/kg of oral oxycodone (in 1mg/ml syrup) plus 20ml i.v. saline placebo, 2) 8mg of i.v. naloxone (in 20ml saline vehicle) plus oral placebo syrup (quantity matching oxycodone syrup volume), or 3) 20ml i.v. saline placebo plus oral placebo syrup (quantity matching oxycodone syrup volume). Thermal pain testing utilizes a Medoc TSAII NeuroSensory Ana

Primary outcome measures

• Mean change in McGill Pain Questionnaire-2 (MPQ-2) ratings of low back pain from the placebo to oxycodone condition [Time frame: Across 2 laboratory assessment days (an expected average of 15 day period)]
• Mean DELTA Drug Liking subscale scores in the oxycodone condition [Time frame: One 1 laboratory assessment day]
• Composite measure of changes in MPQ-2 ratings of low back pain from the placebo to naloxone condition (standardized) plus plasma levels of endocannabinoids (standardized) [Time frame: Across 2 laboratory assessment days (an expected average of 15 day period)]

Secondary outcome measures (12)

• Mean changes in MPQ-2 ratings of ischemic task pain from the placebo to oxycodone condition [Time frame: Across 2 laboratory assessment days (an expected average of 15 day period)]
• Mean changes in Visual Analog Scale (VAS) intensity ratings of ischemic task pain from the placebo to oxycodone condition [Time frame: Across 2 laboratory assessment days (an expected average of 15 day period)]
• Mean changes in MPQ-2 ratings of heat task pain from the placebo to oxycodone condition [Time frame: Across 2 laboratory assessment days (an expected average of 15 day period)]
• Mean changes in VAS intensity ratings of heat task pain from the placebo to oxycodone condition [Time frame: Across 2 laboratory assessment days (an expected average of 15 day period)]
• DELTA Take Again subscale scores in the oxycodone condition [Time frame: 1 laboratory assessment day (an expected average of 15 day period)]
• Mean Delta Effects subscale in the oxycodone condition [Time frame: 1 laboratory assessment day (an expected average of 15 day period)]
• Mean VAS Opioid Euphoria subscale in the oxycodone condition [Time frame: 1 laboratory assessment day (an expected average of 15 day period)]
• Mean VAS Opioid Unpleasantness subscale in the oxycodone condition [Time frame: 1 laboratory assessment day (an expected average of 15 day period)]
• Mean VAS Opioid Sedation subscale in the oxycodone condition [Time frame: 1 laboratory assessment day (an expected average of 15 day period)]
• Mean change in McGill Pain Questionnaire-2 (MPQ-2) ratings of low back pain from the placebo to naloxone condition [Time frame: Across 2 laboratory assessment days (an expected average of 15 day period)]
• Mean change in McGill Pain Questionnaire-2 (MPQ-2) ratings of ischemic task pain from the placebo to naloxone condition [Time frame: Across 2 laboratory assessment days (an expected average of 15 day period)]
• Mean changes in VAS intensity ratings of ischemic task pain from the placebo to naloxone condition [Time frame: Across 2 laboratory assessment days (an expected average of 15 day period)]

Eligibility criteria

Inclusion criteria

• Intact cognitive status and ability to provide informed consent
• Ability to read and write in English sufficiently to understand and complete study questionnaires (which are only validated in English)
• Age 18 or older And
• Presence of persistent daily low back pain of at least three months duration and of at least a 3/10 in average intensity

Exclusion criteria

• History of renal or hepatic dysfunction
• Reports of current or past alcohol or substance abuse or treatment for such condition
• A reported history of PTSD, psychotic, or bipolar disorders
• Chronic pain due to malignancy (e.g., cancer) or autoimmune disorders (e.g., rheumatoid arthritis, lupus)
• Reports of recent benzodiazepine use (confirmed via rapid urine screening prior to each lab session)
• Any medical conditions (e.g., significant cardiovascular disease) that the study physician feels would contraindicate participation in the lab stressors
• Reported daily opiate use within the past 6 months, or use of any opioid analgesic medications within 3 days of study participation (confirmed through rapid urine screening prior to each lab session)
• Pregnancy (females only, to avoid fetal drug exposure - pregnancy tests conducted prior to each lab session to confirm eligibility)
• Prior allergic reaction/intolerance to oxycodone or its analogs

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Basic science

Study locations

United States · 1 center

• Vanderbilt University Medical Center — Nashville

Publications

• al'Absi M, France C, Harju A, France J, Wittmers L. Adrenocortical and nociceptive responses to opioid blockade in hypertension-prone men and women. Psychosom Med. 2006 Mar-Apr;68(2):292-8. doi: 10.1097/01.psy.0000203240.64965.bd. PMID 16554396
• Altun A, Ozdemir E, Yildirim K, Gursoy S, Durmus N, Bagcivan I. The effects of endocannabinoid receptor agonist anandamide and antagonist rimonabant on opioid analgesia and tolerance in rats. Gen Physiol Biophys. 2015 Oct;34(4):433-40. doi: 10.4149/gpb_2015017. PMID 26374993
• Altun A, Yildirim K, Ozdemir E, Bagcivan I, Gursoy S, Durmus N. Attenuation of morphine antinociceptive tolerance by cannabinoid CB1 and CB2 receptor antagonists. J Physiol Sci. 2015 Sep;65(5):407-15. doi: 10.1007/s12576-015-0379-2. Epub 2015 Apr 18. PMID 25894754
• Baker TB, Piper ME, McCarthy DE, Majeskie MR, Fiore MC. Addiction motivation reformulated: an affective processing model of negative reinforcement. Psychol Rev. 2004 Jan;111(1):33-51. doi: 10.1037/0033-295X.111.1.33. PMID 14756584
• Bedse G, Hartley ND, Neale E, Gaulden AD, Patrick TA, Kingsley PJ, Uddin MJ, Plath N, Marnett LJ, Patel S. Functional Redundancy Between Canonical Endocannabinoid Signaling Systems in the Modulation of Anxiety. Biol Psychiatry. 2017 Oct 1;82(7):488-499. doi: 10.1016/j.biopsych.2017.03.002. Epub 2017 Mar 15. PMID 28438413
• Bluett RJ, Baldi R, Haymer A, Gaulden AD, Hartley ND, Parrish WP, Baechle J, Marcus DJ, Mardam-Bey R, Shonesy BC, Uddin MJ, Marnett LJ, Mackie K, Colbran RJ, Winder DG, Patel S. Endocannabinoid signalling modulates susceptibility to traumatic stress exposure. Nat Commun. 2017 Mar 28;8:14782. doi: 10.1038/ncomms14782. PMID 28348378
• Brat GA, Agniel D, Beam A, Yorkgitis B, Bicket M, Homer M, Fox KP, Knecht DB, McMahill-Walraven CN, Palmer N, Kohane I. Postsurgical prescriptions for opioid naive patients and association with overdose and misuse: retrospective cohort study. BMJ. 2018 Jan 17;360:j5790. doi: 10.1136/bmj.j5790. PMID 29343479
• Bruehl S, Burns JW, Chung OY, Quartana P. Anger management style and emotional reactivity to noxious stimuli among chronic pain patients and healthy controls: the role of endogenous opioids. Health Psychol. 2008 Mar;27(2):204-14. doi: 10.1037/0278-6133.27.2.204. PMID 18377139

Identifiers

NCT: NCT05142267 · 210399 · R01DA050334

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗