Abuse Opioids, Individual Difference, Opioid Sensitivity
Conditions
Keywords
opioid, abuse, genetic, A118G, OPRM1
Brief summary
Within-subject, double-blind, placebo-controlled examination of opioid abuse potential in healthy individuals as a function of A118G SNP on the OPRM1 gene.
Detailed description
Participants completed a 5-day, within-subject, double-blind, placebo-controlled, randomized, human laboratory abuse potential trial. Healthy individuals were admitted to a residential research unit for 5 consecutive days. Blood samples were drawn for genome wide analyses using the Global Screening Array on day 1. Participants were administered an oral dose of the opioid hydromorphone (4mg) on day 2 of the study. Persons who did not evidence strong agonist effects then proceeded into the randomized period wherein they received 0mg, 2mg, and 8mg of oral hydromorphone on the remaining three study days. The order of dosing was randomized, with only 1 dose administered per day and all participants receiving 1 exposure to each dose. Outcomes were standard human abuse potential metrics, including self-reported drug effects and feeling high. Data were analyzed as a function of the A118SNP on the OPRM1 gene that codes for the mu opioid receptor. The overall aim was to determine whether signal for abuse potential among persons with no history of opioid misuse was associated with genotype.
Interventions
Within-subject double-blind, randomized, placebo-controlled, residential human abuse potential study. All participants received 4mg oral hydromorphone on study day 2 and a subset continued into the randomized portion for study days 3-5 wherein they received placebo, 2mg hydromorphone, and 8mg hydromorphone in randomized order. Only one dose was administered per day and following randomized all participants received each dose in random order. Outcomes were collected during 8-hour residential-based sessions and included metrics of FDA human abuse potential testing as well as secondary outcomes of laboratory pain testing, subjective reports of drug effects, and cognitive performance, evaluated as a function of study medication condition. Participants were genotyped for rs-1799971 status and results were analyzed as between-group comparisons based upon genotype.
Sponsors
National Institute on Drug Abuse (NIDA)
Johns Hopkins University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Neither participants nor staff were informed of the class of drugs under investigation. Strict blinding was maintained.
Intervention model description
Within-subject, double-blind, randomized, placebo-controlled, human laboratory design wherein each participant completed each of the study conditions (outlined below as four arms). Participants were genotyped for rs-1799971and data were analyzed using between-group designs based upon rs-1799971 status.
Eligibility
Sex/Gender
ALL
Age
21 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
Inclusion Criterion: 1. Provide a urine sample that tests negative for opioids, methadone, buprenorphine, oxycodone, amphetamine, cocaine, and benzodiazepines 2. Negative ethanol breath test (0.000) 3. Aged 21-50 4. Deemed medically eligible to take hydromorphone Exclusion Criterion: 1. Answer yes to question 1 of the Brief Pain Inventory (89) to assess the presence of chronic pain. 2. Current use of opioids or other medications for pain 3. Meet DSM-5 criteria for current or lifetime alcohol or drug use disorder (excluding nicotine) 4. Self-report any illicit drug use in the past 7 days 5. Self-report opioid use \>5 days in the past 30 6. Evidence of opioid physical dependence at screening or following 1st residential overnight (following confirmed opioid abstinence) 7. Allergy to hydromorphone or other opioid agonists 8. Experience an adverse event that warrants opioid antagonist treatment following 1st hydromorphone dose. 9. If female, not be pregnant or breastfeeding 10. Presence of any clinically significant medical (e.g., chronic renal insufficiency, history of myocardial infarction, seizure disorder) and/or psychiatric illness (e.g., schizophrenia, bipolar disorder) that may interfere with study participation. 11. BMI \>30 (obese category)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Self-report Visual Analog Ratings of HIGH | 30 minutes after study drug administration | Peak visual analog rating scale values of HIGH (rated on 0-100 scale with higher scores indicating higher feeling of being HIGH) collected at 30 minute intervals post-drug administration for 6 hours. |
| Self-report Visual Analog Ratings of DRUG EFFECT | 30 minutes after study drug administration | Peak visual analog rating scale values of DRUG EFFECT (rated on 0-100 scale with higher scores indicating higher drug effect) collected at 30 minute intervals post-drug administration for 6 hours. |
Countries
United States
Participant flow
Recruitment details
100 participants were recruited from the community for participation. Analyses were based upon OPRM1 rs-1799971 allele status (A, G), which was available for 97 participants. All participants completed the same 4 study arms.
Participants by arm
| Arm | Count |
|---|---|
| A118G (rs1799971-G) This is a within-subject study wherein the same 100 participants moved from one treatment arm to the next. | 13 |
| A118A (rs1799971-A) This is a within-subject study wherein the same 100 participants moved from one treatment arm to the next. | 84 |
| Total | 97 |
Baseline characteristics
| Characteristic | A118G (rs1799971-G) | Total | A118A (rs1799971-A) |
|---|---|---|---|
| Age, Continuous | 37.6 years STANDARD_DEVIATION 10 | 33.9 years STANDARD_DEVIATION 9.1 | 33.3 years STANDARD_DEVIATION 8.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 8 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 89 Participants | 79 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 5 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 45 Participants | 43 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 5 Participants | 5 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) White | 9 Participants | 37 Participants | 28 Participants |
| Region of Enrollment United States | 13 participants | 97 participants | 84 participants |
| Sex: Female, Male Female | 4 Participants | 49 Participants | 45 Participants |
| Sex: Female, Male Male | 9 Participants | 48 Participants | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 82 | 0 / 82 | 0 / 97 | 0 / 82 |
| other Total, other adverse events | 19 / 82 | 21 / 82 | 65 / 97 | 49 / 82 |
| serious Total, serious adverse events | 0 / 82 | 0 / 82 | 0 / 97 | 0 / 82 |
Outcome results
Primary
Self-report Visual Analog Ratings of DRUG EFFECT
Peak visual analog rating scale values of DRUG EFFECT (rated on 0-100 scale with higher scores indicating higher drug effect) collected at 30 minute intervals post-drug administration for 6 hours.
Time frame: 30 minutes after study drug administration
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| A118G (rs1799971-G) | Self-report Visual Analog Ratings of DRUG EFFECT | Placebo (oral) | 13.3 score on a scale | Standard Deviation 21.3 |
| A118G (rs1799971-G) | Self-report Visual Analog Ratings of DRUG EFFECT | Hydromorphone (oral) 2mg | 10.8 score on a scale | Standard Deviation 16.5 |
| A118G (rs1799971-G) | Self-report Visual Analog Ratings of DRUG EFFECT | Hydromorphone (oral) 4mg | 23.6 score on a scale | Standard Deviation 27 |
| A118G (rs1799971-G) | Self-report Visual Analog Ratings of DRUG EFFECT | Hydromorphone (oral) 8mg | 39.2 score on a scale | Standard Deviation 37.3 |
| A118A (rs1799971-A) | Self-report Visual Analog Ratings of DRUG EFFECT | Hydromorphone (oral) 8mg | 39.5 score on a scale | Standard Deviation 32.1 |
| A118A (rs1799971-A) | Self-report Visual Analog Ratings of DRUG EFFECT | Placebo (oral) | 11.1 score on a scale | Standard Deviation 20 |
| A118A (rs1799971-A) | Self-report Visual Analog Ratings of DRUG EFFECT | Hydromorphone (oral) 4mg | 31.9 score on a scale | Standard Deviation 29.9 |
| A118A (rs1799971-A) | Self-report Visual Analog Ratings of DRUG EFFECT | Hydromorphone (oral) 2mg | 11.0 score on a scale | Standard Deviation 20.7 |
p-value: 0.805Mixed Model
Primary
Self-report Visual Analog Ratings of HIGH
Peak visual analog rating scale values of HIGH (rated on 0-100 scale with higher scores indicating higher feeling of being HIGH) collected at 30 minute intervals post-drug administration for 6 hours.
Time frame: 30 minutes after study drug administration
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| A118G (rs1799971-G) | Self-report Visual Analog Ratings of HIGH | Placebo (oral) | 7.2 score on a scale | Standard Deviation 13.2 |
| A118G (rs1799971-G) | Self-report Visual Analog Ratings of HIGH | Hydromorphone (oral) 2mg | 4.5 score on a scale | Standard Deviation 5.9 |
| A118G (rs1799971-G) | Self-report Visual Analog Ratings of HIGH | Hydromorphone (oral) 4mg | 12.5 score on a scale | Standard Deviation 19.8 |
| A118G (rs1799971-G) | Self-report Visual Analog Ratings of HIGH | Hydromorphone (oral) 8mg | 25.5 score on a scale | Standard Deviation 29.7 |
| A118A (rs1799971-A) | Self-report Visual Analog Ratings of HIGH | Hydromorphone (oral) 8mg | 22.5 score on a scale | Standard Deviation 27.2 |
| A118A (rs1799971-A) | Self-report Visual Analog Ratings of HIGH | Placebo (oral) | 6.6 score on a scale | Standard Deviation 16.3 |
| A118A (rs1799971-A) | Self-report Visual Analog Ratings of HIGH | Hydromorphone (oral) 4mg | 18.4 score on a scale | Standard Deviation 26.4 |
| A118A (rs1799971-A) | Self-report Visual Analog Ratings of HIGH | Hydromorphone (oral) 2mg | 5.6 score on a scale | Standard Deviation 15.4 |
p-value: 0.567Mixed methods