Opioid Withdrawal, Opioid Craving, Opioid Use Disorder
Conditions
Brief summary
This pilot study will examine the safety of the cannabinoid cannabidiol (Epidiolex) in a human laboratory model of clinically relevant withdrawal. The study will be a residential within-subject comparison; all participants will receive placebo dosing and active cannabidiol. Results may be used to support an R01 grant application to more closely examine this hypothesis.
Detailed description
Based on preclinical research and emerging human research, cannabidiol (CBD; a major constituent of the cannabis plant) is a promising pharmacotherapy for the treatment of opioid withdrawal. Most recently, CBD decreased cue-induced craving and anxiety (two common withdrawal symptoms) among abstinent heroin-dependent individuals relative to placebo. As of June 2018, Epidiolex, an oral formulation of plant-derived pure CBD, has been approved by the U.S. Food and Drug Administration (FDA) for treating severe forms of epilepsy and can be prescribed for other off-label indications. Epidiolex has a low side effect and high safety profile. Given the recent FDA approval of Epidiolex, and a growing interest to develop existing pharmaceuticals to address issues related to Opioid Use Disorder (OUD) and its recovery, the investigators are proposing a pilot study to examine the safety of Epidiolex in a human laboratory model of clinically relevant withdrawal. The study will be a residential within-subject comparison; methadone-maintained participants will undergo spontaneous withdrawal and receive placebo dosing and active cannabidiol. Data collected for this study will establish: (1) the safety of administering two dosing regimens of Epidiolex within the investigators' withdrawal paradigm and (2) the feasibility of the investigators' withdrawal paradigm for demonstrating clinically meaningful increases in withdrawal. Results may be used to support an R01 grant application to more closely examine this hypothesis.
Interventions
DRUGEpidiolex
Epidiolex 100 mg/mL Oral Solution
DRUGPlacebo
Cherry syrup oral solution
Sponsors
Dalio Foundation
Johns Hopkins University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Masking description
Epidiolex is flavor masked with cherry syrup.
Intervention model description
Within subject comparison of Epidiolex to placebo. The order of study drug (active Epidiolex or placebo) is randomized across participants. Epidiolex is flavor masked with cherry syrup.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
* Medically cleared to take study medication * Are not pregnant or breast feeding * Willing to comply with the study protocol * Provides urine that tests positive for methadone * Maintained on 80-120 mg of daily methadone with no dose changes in the past 2 weeks (verified through a medical release with the participant's provider)
Exclusion criteria
* Meet Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 criteria for alcohol/substance use disorder other than opioid use disorder * Previous adverse reaction to a cannabinoid product * Self-report any illicit drug use 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 events * Past year suicidal behavior as assessed via the Columbia Suicide Severity Rating Scale * History of seizure disorder * Past 14 day use of any of the following contraindicated medications: * Clobazam, Valproate * Moderate or strong inhibitors of CYP3A4 or CYPC19 (with the exception of methadone, as outlined in the Protection Against CBD Risks section). * Strong CYP3A4 or CYP2C19 inducers * UGT1A9, UGT2B7, CYP1A2, CYP2C8, CYP2C9 and CYP2C19 substrates (with the exclusion of caffeine). * Central nervous system (CNS) depressants that are contraindicated with Epidiolex * Breathalyzer that tests positive for alcohol prior to session admission * Self-reported consumption of grapefruit juice within 24 hours of session admission * Have a history of clinically significant cardiac arrhythmias or vasospastic disease * Have circumstances that the study investigators believe are contraindicated with study participation and/or would interfere with study participation (e.g., impending jail). * Moderate-severe hepatic impairment as indicated by ALT or AST levels \> 3x ULN and/or Bilirubin levels \>2x ULN as evidenced by a blood test.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety as Assessed by Number of Adverse Events | through completion of the two study sessions, an average of 17 days | Number of Adverse Events reported across sessions with and without study drug. Adverse events were collected for the entire 57 hour session. |
| Number of Participants Whose Aspartate Aminotransferase (AST)/Alanine Aminotransferase (ALT) Levels >3x Upper Limit of Normal | End of residential stay, prior to discharge | Number of participants whose AST/ALT levels \>3x upper limit of normal (ULN) at the end of a study session when they receive Epidiolex and Placebo. This will be used in the assessment of safety. |
| Change in Withdrawal Scores From Baseline AfterReceiving Placebo | Baseline, during residential session up to 57 hours | Change in withdrawal scores during laboratory evaluation of spontaneous withdrawal. Withdrawal is measured with the Subjective Opiate Withdrawal Scale (SOWS). That has a range of 0-64 where a mild score is represented by a score of 1-10, a moderate score is represented by a score of 11-20 and a severe score is considered anything greater than 21. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Initial Efficacy of Study Drug as Assessed by Area Under the Curve for the Subjective Opiate Withdrawal Scale (SOWS) Scores | After first administration of study drug and up to 48 hours | Withdrawal symptom suppression during active and placebo conditions. Area Under the Curve (AUC) analyses will be calculated to characterize withdrawal on the Subjective Opiate Withdrawal Scale (SOWS) scores across time. SOWS AUC will be compared between the two conditions. AUC will range from 0 to 3072 where 0 represents no withdrawal during study drug administration and 3072 represents the most severe withdrawal during study drug administration. |
| Acceptability Assessed by Rating of Medication Acceptance on a 5-point Acceptance Rating Scale | at the end of the 57-hour residential session, prior to discharge | Participant rating of medication acceptance on a 5-point acceptance rating scale. The acceptance rating scale will range from 0-4 where 0 represents no acceptance of the medication and 4 represents complete acceptance of the medication. |
| Acceptability Assessed by Number of Participants Who Would Recommend the Medication to a Family Member or Friend | at the end of the 57-hour residential session, prior to discharge | Number of participants who would recommend the medication to a family member or friend trying to taper down from opioid medications. |
| Acceptability Assessed by Visual Analog Ratings | at the end of the 57-hour residential session, prior to discharge | Visual analog ratings of the degree to which the medication suppressed opioid withdrawal symptoms. The visual analog ratings will be scored on a scale from 0-100 where 0 represents no suppression of withdrawal and 100 represents complete suppression of withdrawal. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Participants Each participant will receive Epidiolex oral solution and Cherry syrup oral solution (placebo) in a randomized fashion.
Epidiolex 100 mg/mL Oral Solution: 8 mL of Epidiolex (800 mg of cannabidiol) + 16 mL of inactive cherry syrup delivered every 12 hours for 48 hours total (4 doses)
Cherry Syrup Oral Solution: 20 mL of inactive cherry syrup delivered every 12 hours for 48 hours total (4 doses) | 3 |
| Total | 3 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Washout - 1 Week | Lost to Follow-up | 1 | 0 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 1 Participants |
| Region of Enrollment United States | 3 Participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 3 |
| other Total, other adverse events | 2 / 3 | 1 / 3 |
| serious Total, serious adverse events | 0 / 3 | 0 / 3 |
Outcome results
Primary
Change in Withdrawal Scores From Baseline AfterReceiving Placebo
Change in withdrawal scores during laboratory evaluation of spontaneous withdrawal. Withdrawal is measured with the Subjective Opiate Withdrawal Scale (SOWS). That has a range of 0-64 where a mild score is represented by a score of 1-10, a moderate score is represented by a score of 11-20 and a severe score is considered anything greater than 21.
Time frame: Baseline, during residential session up to 57 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| All Participants | Change in Withdrawal Scores From Baseline AfterReceiving Placebo | 15.8 score on a scale | Standard Deviation 6.3 |
Primary
Number of Participants Whose Aspartate Aminotransferase (AST)/Alanine Aminotransferase (ALT) Levels >3x Upper Limit of Normal
Number of participants whose AST/ALT levels \>3x upper limit of normal (ULN) at the end of a study session when they receive Epidiolex and Placebo. This will be used in the assessment of safety.
Time frame: End of residential stay, prior to discharge
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| All Participants | Number of Participants Whose Aspartate Aminotransferase (AST)/Alanine Aminotransferase (ALT) Levels >3x Upper Limit of Normal | 0 Participants |
| Placebo | Number of Participants Whose Aspartate Aminotransferase (AST)/Alanine Aminotransferase (ALT) Levels >3x Upper Limit of Normal | 0 Participants |
Primary
Safety as Assessed by Number of Adverse Events
Number of Adverse Events reported across sessions with and without study drug. Adverse events were collected for the entire 57 hour session.
Time frame: through completion of the two study sessions, an average of 17 days
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| All Participants | Safety as Assessed by Number of Adverse Events | Placebo Adverse Events | 4 Adverse Events |
| All Participants | Safety as Assessed by Number of Adverse Events | Epidiolex Adverse Events | 5 Adverse Events |
Secondary
Acceptability Assessed by Number of Participants Who Would Recommend the Medication to a Family Member or Friend
Number of participants who would recommend the medication to a family member or friend trying to taper down from opioid medications.
Time frame: at the end of the 57-hour residential session, prior to discharge
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| All Participants | Acceptability Assessed by Number of Participants Who Would Recommend the Medication to a Family Member or Friend | 3 Participants |
| Placebo | Acceptability Assessed by Number of Participants Who Would Recommend the Medication to a Family Member or Friend | 2 Participants |
Secondary
Acceptability Assessed by Rating of Medication Acceptance on a 5-point Acceptance Rating Scale
Participant rating of medication acceptance on a 5-point acceptance rating scale. The acceptance rating scale will range from 0-4 where 0 represents no acceptance of the medication and 4 represents complete acceptance of the medication.
Time frame: at the end of the 57-hour residential session, prior to discharge
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| All Participants | Acceptability Assessed by Rating of Medication Acceptance on a 5-point Acceptance Rating Scale | 4 score on a scale | Standard Deviation 0 |
| Placebo | Acceptability Assessed by Rating of Medication Acceptance on a 5-point Acceptance Rating Scale | 4 score on a scale | Standard Deviation 0 |
Secondary
Acceptability Assessed by Visual Analog Ratings
Visual analog ratings of the degree to which the medication suppressed opioid withdrawal symptoms. The visual analog ratings will be scored on a scale from 0-100 where 0 represents no suppression of withdrawal and 100 represents complete suppression of withdrawal.
Time frame: at the end of the 57-hour residential session, prior to discharge
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| All Participants | Acceptability Assessed by Visual Analog Ratings | 24.333 units on a scale | Standard Deviation 9 |
| Placebo | Acceptability Assessed by Visual Analog Ratings | 17.5 units on a scale | Standard Deviation 3.5 |
Secondary
Initial Efficacy of Study Drug as Assessed by Area Under the Curve for the Subjective Opiate Withdrawal Scale (SOWS) Scores
Withdrawal symptom suppression during active and placebo conditions. Area Under the Curve (AUC) analyses will be calculated to characterize withdrawal on the Subjective Opiate Withdrawal Scale (SOWS) scores across time. SOWS AUC will be compared between the two conditions. AUC will range from 0 to 3072 where 0 represents no withdrawal during study drug administration and 3072 represents the most severe withdrawal during study drug administration.
Time frame: After first administration of study drug and up to 48 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| All Participants | Initial Efficacy of Study Drug as Assessed by Area Under the Curve for the Subjective Opiate Withdrawal Scale (SOWS) Scores | 1334.7 scores on SOWS scale X hour | Standard Deviation 57.8 |
| Placebo | Initial Efficacy of Study Drug as Assessed by Area Under the Curve for the Subjective Opiate Withdrawal Scale (SOWS) Scores | 1591.5 scores on SOWS scale X hour | Standard Deviation 12 |