Enhancing Medication-based Analgesia in Humans- STUDY 2

Study Overview
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Brief Summary
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This is a single-group, within-subject, double-blind, double-dummy, placebo and active-controlled study evaluated whether the FDA-approved cannabinoid cannabidiol (CBD; Epidiolex) would enhance analgesia, subjective reports, and cognitive performance when compared to the FDA-approved opioid hydromorphone (Dilaudid). This is study 2 is a series of studies.

Detailed Description
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This was a human laboratory systematic examination of whether adding the FDA-approved cannabinoid cannabidiol (CBD; Epidiolex; oral) to the FDA-approved opioid hydromorphone (Dilaudid; oral) would change the experience of hydromorphone as rated by laboratory measures of pain, subjective reports of drug effects, and cognitive performance. Subjects are healthy individuals with no history of drug use disorder. Study subjects and staff were completed blinded to the study drugs and the class of drugs under investigation and were informed that subjects may receive opioids, stimulants, cannabinoids, benzodiazepines, over the counter medications, and/or placebo. All participants completed all sessions. Sessions lasted up to 8-hours and were conducted at least 7 days apart on an outpatient basis. Primary outcomes were collected from participants prior to dosing and at several hour periods post-dosing.

Official Title
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Evaluating Cannabidiol (CBD) to Enhance the Analgesic Effect of Hydromorphone in Humans

Conditions
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Pain, Cannabis, Opioid Use

Intervention / Treatment
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* Drug: Within-subject test of blinded study medications


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 18-75 Urine sample tests negative for common illicit substances of abuse, including cannabis Medically cleared to take study medications Are not pregnant or breast feeding Willing to comply with the study protocol. Exclusion Criteria: Meet DSM-5 criteria for alcohol/substance use disorder Taking opioids for pain Previous adverse reaction to a cannabinoid product Prescribed and taking stimulants or benzodiazepines Answer yes to item 1 of the Brief Pain Inventory indicating chronic pain Self-report any illicit drug or cannabinoid use in the past 7 days Presence of any clinically significant medical/psychiatric illness judged by the investigators to put subject at elevated risk for experiencing an adverse event History of seizure disorder Have a known allergy to the study medications or sesame seed oil ALT or AST levels >3x ULN and/or Bilirubin levels >2x ULN during Screening Current (past 60-day) suicidal thoughts or past year history of suicidal behavior Taking medications contraindicated with hydromorphone or cannabidiol Have a history of clinically significant cardiac arrhythmias or vasopastic disease Have an abnormal and clinically-significant ECG

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Interventional Model Description: Within-subject study
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo+Placebo<br>Within-subject double-blind, double-dummy administration of placebo + placebo. Order of dose randomized session days 2-5. | Drug: Within-subject test of blinded study medications<br>* Within-subject double-blind, double-dummy, study design wherein all participants received all doses in 8-hour outpatient sessions. Primary outcomes assessed during 8-hour outpatient sessions and included laboratory pain testing, subjective reports of drug effects, and cognitive performance, evaluated as a function of study medication condition.<br>|
| Active Comparator: Hydromorphone+Placebo<br>Within-subject double-blind, double-dummy administration of hydromorphone (oral) 4mg + placebo. Always administered during session 1. | Drug: Within-subject test of blinded study medications<br>* Within-subject double-blind, double-dummy, study design wherein all participants received all doses in 8-hour outpatient sessions. Primary outcomes assessed during 8-hour outpatient sessions and included laboratory pain testing, subjective reports of drug effects, and cognitive performance, evaluated as a function of study medication condition.<br>|
| Experimental: Hydromorphone (oral) 4mg + Cannabidiol 50mg<br>Within-subject double-blind, double-dummy administration of hydromorphone (oral) 4mg + cannabidiol (oral) 50mg. Order of dose randomized session days 2-5. | Drug: Within-subject test of blinded study medications<br>* Within-subject double-blind, double-dummy, study design wherein all participants received all doses in 8-hour outpatient sessions. Primary outcomes assessed during 8-hour outpatient sessions and included laboratory pain testing, subjective reports of drug effects, and cognitive performance, evaluated as a function of study medication condition.<br>|
| Experimental: Hydromorphone (oral) 4mg + Cannabidiol 100mg<br>Within-subject double-blind, double-dummy administration of hydromorphone (oral) 4mg + cannabidiol (oral) 100mg. Order of dose randomized session days 2-5. | Drug: Within-subject test of blinded study medications<br>* Within-subject double-blind, double-dummy, study design wherein all participants received all doses in 8-hour outpatient sessions. Primary outcomes assessed during 8-hour outpatient sessions and included laboratory pain testing, subjective reports of drug effects, and cognitive performance, evaluated as a function of study medication condition.<br>|
| Experimental: Hydromorphone (oral) 4mg + Cannabidiol 200mg<br>Within-subject double-blind, double-dummy administration of hydromorphone (oral) 4mg + cannabidiol (oral) 200mg. Order of dose randomized session days 2-5. | Drug: Within-subject test of blinded study medications<br>* Within-subject double-blind, double-dummy, study design wherein all participants received all doses in 8-hour outpatient sessions. Primary outcomes assessed during 8-hour outpatient sessions and included laboratory pain testing, subjective reports of drug effects, and cognitive performance, evaluated as a function of study medication condition.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak Cold Pressor Tolerance | Peak amount of time participant submerged hand in cold pressor (5 degree circulating cold water) laboratory test of pain as a function of double- blinded study medications (range 0 -300). | 8 hour study session | 
| Peak Self-report Rating of Drug Effect (0-100), as Measured by the Visual Analog Rating Scale | Peak self-report rating of Drug Effect on a 0 (none at all) to 100 (extremely) visual analog scale as a function of double- blinded study medication, wherein higher values indicate stronger subjectively-experienced drug effects. | 8 hour study session | 
| Peak Number Accurate on Circular Lights | Peak number accuracy on the Circular Lights fine motor task as a function of double-blinded study drug administration. Participants were provided 60 seconds to press buttons that are lit in randomized order and displayed automatically on a circular lights wall mounted unit. The primary outcome is the number of lit buttons that were accurately pressed within 60 seconds, which is a metric to assess fine motor impairment. Lower numbers are indicative of greater drug-related impairment. There is no upper limit on the circular lights task. | 8 hour study session | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Clinical Trial, Analgesia, Phase II, Abuse potential