This study will systematically evaluate whether cannabinoids can enhance the analgesic efficacy of opioids, which will advance the use of cannabinoids for the treatment of acute and/or chronic pain. Chronic pain affects over 100 million Americans. Opioids are unanimously recognized as the most effective drugs for the relief of pain and suffering6, but the US is now suffering from an epidemic of abuse, addiction and accidental deaths resulting from the increased sale and use of opioids. There is legitimate value in identifying adjuncts that might reduce reliance on opioids while maintaining adequate pain relief. Preclinical studies report that co- administering cannabinoids with opioid agonists significantly and reliably reduce the amount of opioids required for analgesia but this hypothesis has not been rigorously evaluated in humans. This proposal will conduct 2 independent studies that will evaluate the effects of a different cannabinoid (Study 1: dronabinol, Study 2: nabilone) on opioid-induced analgesia. Each study will enroll 60 healthy adults (30 men/women) to conduct a within-subject, dose-response evaluation of cannabinoids on the analgesic effect of hydromorphone (Dilaudid). Subjects will complete a Qualifying session and 6 experimental sessions that will occur once weekly and will require subjects to admit themselves into the clinical research unit the night before the session to complete the study session. Subjects will receive a dose of hydromorphone (1mg, IM) and a double-blind oral dose of study drug or placebo the morning of each experimental session, and will undergo quantitative sensory testing (QST; a comprehensive pain testing battery), provide self-report ratings of drug effects, and complete a neurocognitive battery. QST testing will comprehensively and systematically measure pain sensitivity, and provide information on the full range of analgesic effects possible across a wide variety of pain measures, including threshold responses (thermal, pressure), temporal summation, cold pressor, conditioned pain modulation, and capsaicin sensitization. Primary outcomes will be magnitude and duration of pain as a function of study drug dose. Additional primary aims include proxy measures of abuse liability and neurocognitive performance. All measures will be assessed as a function of sex, due to substantial evidence that men/women differ with regard to pain perception, endogenous cannabinoid receptor density, and opioid response. We hypothesize that cannabinoids will shift the analgesic curve of hydromorphone and enhance analgesia effects. This will be the 1st human laboratory study to evaluate combinations of cannabinoids and opioids using QST, and results will identify whether a signal for this medication combination exists that should be advanced into randomized controlled trial evaluations with clinical pain populations. This study will also assess aspects that would impact drug development (abuse liability, neurocognitive impairment), as well as the effects of sex and cannabinoid type on outcomes. Results from this study will help advance the acceptance of cannabinoids from use with only treatment-refractory pain conditions to widespread societal use for clinical pain.

Public Health Relevance

Cannabinoids are currently used to treat chronic pain in patients who are not responding to opioid medications, however research suggests that combining these two medications together may be useful for other pain conditions as well. In addition, there is reason to believe that combining cannabinoids and opioid medications will reduce the amount of opioids that are needed to relieve pain. This study will use several laboratory measures of pain to determine whether two different cannabinoids can reduce the amount of opioids that are needed to reduce pain, and will investigate whether this is true for both men and women.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA040644-04
Application #
9700089
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Lin, Yu
Project Start
2016-08-01
Project End
2021-06-30
Budget Start
2019-07-01
Budget End
2020-06-30
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
Dunn, Kelly E; Barrett, Frederick S; Bigelow, George E (2018) Naloxone formulation for overdose reversal preference among patients receiving opioids for pain management. Addict Behav 86:56-60
Dunn, Kelly E; Brands, Bruna; Marsh, David C et al. (2018) Characterizing the subjective, observer-rated, and physiological effects of hydromorphone relative to heroin in a human laboratory study. Psychopharmacology (Berl) 235:971-981
Huhn, Andrew S; Garcia-Romeu, Albert Perez; Dunn, Kelly E (2018) Opioid Overdose Education for Individuals Prescribed Opioids for Pain Management: Randomized Comparison of Two Computer-Based Interventions. Front Psychiatry 9:34
Huhn, Andrew S; Sweeney, Mary M; Brooner, Robert K et al. (2018) Prefrontal cortex response to drug cues, craving, and current depressive symptoms are associated with treatment outcomes in methadone-maintained patients. Neuropsychopharmacology :
Dunn, Kelly E; Finan, Patrick H; Andrew Tompkins, D et al. (2018) Frequency and correlates of sleep disturbance in methadone and buprenorphine-maintained patients. Addict Behav 76:8-14
Huhn, Andrew S; Dunn, Kelly E (2017) Why aren't physicians prescribing more buprenorphine? J Subst Abuse Treat 78:1-7
Dunn, Kelly E; Yepez-Laubach, Claudia; Nuzzo, Paul A et al. (2017) Randomized controlled trial of a computerized opioid overdose education intervention. Drug Alcohol Depend 173 Suppl 1:S39-S47
Huhn, Andrew S; Tompkins, D Andrew; Dunn, Kelly E (2017) The relationship between treatment accessibility and preference amongst out-of-treatment individuals who engage in non-medical prescription opioid use. Drug Alcohol Depend 180:279-285
Dunn, Kelly E; Barrett, Frederick S; Yepez-Laubach, Claudia et al. (2016) Opioid Overdose Experience, Risk Behaviors, and Knowledge in Drug Users from a Rural versus an Urban Setting. J Subst Abuse Treat 71:1-7