Alcohol Use Disorder
Conditions
Keywords
alcohol use disorder, naltrexone, Asian American, pharmacogenetics, OPRM1 gene
Brief summary
This study will elucidate the pharmacogenetic effects of the Asn40Asp SNP of the OPRM1 gene on biobehavioral and neural markers of response to naltrexone in individuals of East Asian descent, an ethnic group most likely to express the positive predictive allele.
Detailed description
Recent pharmacogenetic studies have advanced the gene coding for µ-opioid receptors (OPRM1) gene as a potential moderator of responses to naltrexone. The most widely studied polymorphism of the OPRM1 gene is the Asn40Asp single nucleotide polymorphism (SNP), a functional mutation thought to affect receptor activity such that the Asp40 variant binds β-endorphin three times stronger than the Asn40 allele. Recent studies have found that Asp40 carriers have a stronger striatal dopamine response to intravenous alcohol administration and report stronger feelings of alcohol reward. Findings from the COMBINE Study demonstrated that if treated with Medication Management alone and naltrexone, 87.1% of Asp40 carriers had a good clinical outcome, compared with only 54.8% of Asn40 homozygotes. While these findings are promising, studies have also highlighted allele frequency imbalance as a function of ethnicity such that the Asp40 allele frequency is approximately 20% in Caucasians, 5% in individuals of African Ancestry, and as high as 50% among individuals of East Asian descent. Therefore, to the extent to which this SNP moderates behavioral and clinical responses to NTX, ethnicity must be carefully considered in order to extend the findings from primarily Caucasian samples to ethnic minorities, such as Asian Americans. Preliminary work by our team has found that among individuals of East Asian descent, Asp40 carriers show greater NTX-induced blunting of alcohol craving as well as potentiation of the aversive effects of alcohol. This pilot study also found support for a gene dose-response, such that Asp40Asp individuals showed greater NTX responsivity than those with the Asn40Asp genotype. This study seeks to build upon these preliminary findings by testing heavy drinkers of East Asian descent across three OPRM1 genotypes (Asn40Asn, n = 30; Asn40Asp, n = 30, and Asp40Asp, n = 30). Participants will complete two double-blinded, counterbalanced alcohol infusion and self-administration sessions, one after taking NTX (50 mg/day) and one after taking matched placebo for five days. In each medication condition, participants will complete a functional neuroimaging task examining cue-induced craving for alcohol. This study will elucidate the pharmacogenetic effects of the Asn40Asp SNP of the OPRM1 gene on biobehavioral and neural markers of response to naltrexone in individuals of Asian descent, an ethnic group most likely to express the positive predictive allele (Asp40). The long-term objective of this research is to optimize alcoholism pharmacotherapy and to address health disparities by advancing pharmacogenetic studies in ethnic minority groups.
Interventions
DRUGNaltrexone
Naltrexone is an opioid receptor antagonist with highest affinity for mu opioid receptors
DRUGPlacebo
Sugar pill, matched to the active study medication in capsule size and color
Sponsors
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
University of California, Los Angeles
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* current (i.e., past month) alcohol dependence * East Asian ethnicity (i.e., Chinese, Korean, or Japanese) * Prospective genotyping for the A118G SNP of the mu opioid receptor (OPRM1) gene to allow for balanced groups on all three genotypes (AA, AG, GG)
Exclusion criteria
* lifetime DSM-IV of drug dependence (other than alcohol or nicotine) * current use of psychoactive drugs as determined by self-reports and verified using toxicology testing * lifetime diagnosis of bipolar disorder or any psychotic disorder * contraindications to an MRI scan (including left handedness)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Subjective Response - Craving for Alcohol | The AUQ was administered across a period of approximately 1.5 hours. | Alcohol Urge Questionnaire (AUQ) is used to assess subjective experiences of craving for alcohol. It consists of 8 items, each rated on a 7-point Likert scale (1 = strongly disagree, 7 = strongly agree). A summary score is used at each assessment time point. The AUQ was administered at baseline and three levels of breath alcohol concentration: 0.02 g/dl. 0.04, g/dl, and 0.06 g/dl. |
| Subjective Response - Stimulation | The BAES Stimulant Subscale was administered at baseline and three levels of breath alcohol concentration: 0.2 g/dl. 0.04, g/dl, and 0.06 g/dl taking place within approximately 1.5 hours | The Biphasic Alcohol Effects Scale (BAES) Stimulant Subscale consists of 14 items designed to capture the stimulant effects of alcohol, rated on an 11-point scale (0 = not at all. 10 = extremely). Total score for the stimulant subscale ranges from 0-70. |
| Subjective Response - Sedation | The BAES Sedation Subscale was administered at baseline and three levels of breath alcohol concentration: 0.2 g/dl. 0.04, g/dl, and 0.06 g/dl taking place within approximately 1.5 hours | The Biphasic Alcohol Effects Scale (BAES) Sedation Subscale consists of 14 items designed to capture the sedating effects of alcohol, rated on an 11-point scale (0 = not at all. 10 = extremely). Total score for the sedation subscale ranges from 0-70. |
| Neural Response to Alcohol Cues | During the alcohol cue exposure fMRI paradigm which is expected to last 45 minutes | Alcohol taste cues task for functional magnetic resonance imaging (fMRI). Region of Interest (ROI) were atomically defined using the Harvard-Oxford atlas in standard Montreal Neurological Institute (MNI) space, which were transformed into individual participants' native space using Functional Magnetic Resonance Imaging of the Brain Software Library (FSL). Contrast estimates are for Alc \> Water cue, and are arbitrary units. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Alcohol Self-administration - Number of Drinks | Alcohol self-administration period was 1 hour long | Total number of drinks consumed during the alcohol self-administration task |
Countries
United States
Participant flow
Pre-assignment details
A total of 199 individuals were screened in the laboratory, of those 106 completed the physical exam, and of those 87 were eligible and agreed to be randomized. Participants received in random order either Naltrexone (titrated up to 50 mg/day) or Placebo at each Allocation.
Participants by arm
| Arm | Count |
|---|---|
| Asn40Asn Genotype Group that is homozygotes for the Asn40 allele | 29 |
| Asn40asp/Asp40Asp Genotype Group that is a carrier of the Asp40 allele | 48 |
| Total | 77 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Allocation 1 (First Set of Medication) | Investigator Withdrawal | 1 | 0 |
| Allocation 1 (First Set of Medication) | Side Effects | 6 | 0 |
| Allocation 1 (First Set of Medication) | Withdrawal by Subject | 1 | 2 |
| Allocation 2 (Second Set of Medication) | Withdrawal by Subject | 1 | 2 |
Baseline characteristics
| Characteristic | Asn40Asn Genotype | Asn40asp/Asp40Asp Genotype | Total |
|---|---|---|---|
| Age, Continuous | 28.72 years STANDARD_DEVIATION 7.57 | 25.69 years STANDARD_DEVIATION 4.84 | 26.83 years STANDARD_DEVIATION 6.15 |
| Alcohol Use Disorder Identification Test (AUDIT) | 16.14 units on a scale STANDARD_DEVIATION 5.82 | 13.17 units on a scale STANDARD_DEVIATION 4.83 | 14.29 units on a scale STANDARD_DEVIATION 5.39 |
| Race/Ethnicity, Customized Ethnicity Chinese | 12 Participants | 13 Participants | 25 Participants |
| Race/Ethnicity, Customized Ethnicity Japanese | 2 Participants | 6 Participants | 8 Participants |
| Race/Ethnicity, Customized Ethnicity Korean | 11 Participants | 24 Participants | 35 Participants |
| Race/Ethnicity, Customized Ethnicity Taiwanese | 4 Participants | 5 Participants | 9 Participants |
| Region of Enrollment United States | 29 Participants | 48 Participants | 77 Participants |
| Sex: Female, Male Female | 9 Participants | 19 Participants | 28 Participants |
| Sex: Female, Male Male | 20 Participants | 29 Participants | 49 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 75 | 0 / 74 |
| other Total, other adverse events | 35 / 75 | 22 / 74 |
| serious Total, serious adverse events | 0 / 75 | 0 / 74 |
Outcome results
Primary
Neural Response to Alcohol Cues
Alcohol taste cues task for functional magnetic resonance imaging (fMRI). Region of Interest (ROI) were atomically defined using the Harvard-Oxford atlas in standard Montreal Neurological Institute (MNI) space, which were transformed into individual participants' native space using Functional Magnetic Resonance Imaging of the Brain Software Library (FSL). Contrast estimates are for Alc \> Water cue, and are arbitrary units.
Time frame: During the alcohol cue exposure fMRI paradigm which is expected to last 45 minutes
Population: Participants who completed at least one experimental session and whose neuroimaging data was not excluded due to excessive motion (\>2 mm translation) and/or poor registration.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Naltrexone - Asn40Asn | Neural Response to Alcohol Cues | Orbitofrontal cortex | .12 Mean contrast estimate for Alc>Water cue | Standard Deviation 11.75 |
| Naltrexone - Asn40Asn | Neural Response to Alcohol Cues | Ventral Striatum | 1.48 Mean contrast estimate for Alc>Water cue | Standard Deviation 19.94 |
| Naltrexone - Asn40Asn | Neural Response to Alcohol Cues | Anterior Cingulate cortex | 3.31 Mean contrast estimate for Alc>Water cue | Standard Deviation 17.96 |
| Naltrexone - Asn40Asp/Asp40Asp | Neural Response to Alcohol Cues | Ventral Striatum | 8.07 Mean contrast estimate for Alc>Water cue | Standard Deviation 13.95 |
| Naltrexone - Asn40Asp/Asp40Asp | Neural Response to Alcohol Cues | Anterior Cingulate cortex | 7.04 Mean contrast estimate for Alc>Water cue | Standard Deviation 13.9 |
| Naltrexone - Asn40Asp/Asp40Asp | Neural Response to Alcohol Cues | Orbitofrontal cortex | 4.43 Mean contrast estimate for Alc>Water cue | Standard Deviation 9.64 |
| Placebo - Asn40Asn | Neural Response to Alcohol Cues | Orbitofrontal cortex | .45 Mean contrast estimate for Alc>Water cue | Standard Deviation 7.2 |
| Placebo - Asn40Asn | Neural Response to Alcohol Cues | Ventral Striatum | .53 Mean contrast estimate for Alc>Water cue | Standard Deviation 13.47 |
| Placebo - Asn40Asn | Neural Response to Alcohol Cues | Anterior Cingulate cortex | 5.17 Mean contrast estimate for Alc>Water cue | Standard Deviation 14.24 |
| Placebo - Asn40Asp/Asp40Asp | Neural Response to Alcohol Cues | Ventral Striatum | 1.03 Mean contrast estimate for Alc>Water cue | Standard Deviation 13.54 |
| Placebo - Asn40Asp/Asp40Asp | Neural Response to Alcohol Cues | Orbitofrontal cortex | 3.56 Mean contrast estimate for Alc>Water cue | Standard Deviation 6.95 |
| Placebo - Asn40Asp/Asp40Asp | Neural Response to Alcohol Cues | Anterior Cingulate cortex | 9.49 Mean contrast estimate for Alc>Water cue | Standard Deviation 13.07 |
Primary
Subjective Response - Craving for Alcohol
Alcohol Urge Questionnaire (AUQ) is used to assess subjective experiences of craving for alcohol. It consists of 8 items, each rated on a 7-point Likert scale (1 = strongly disagree, 7 = strongly agree). A summary score is used at each assessment time point. The AUQ was administered at baseline and three levels of breath alcohol concentration: 0.02 g/dl. 0.04, g/dl, and 0.06 g/dl.
Time frame: The AUQ was administered across a period of approximately 1.5 hours.
Population: Participants who completed at least one experimental session.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Naltrexone - Asn40Asn | Subjective Response - Craving for Alcohol | BrAc = 0.06 g/dl | 2.0185 score on a scale | Standard Deviation 1.359 |
| Naltrexone - Asn40Asn | Subjective Response - Craving for Alcohol | BrAC = 0.02 g/dl | 1.7037 score on a scale | Standard Deviation 0.9295 |
| Naltrexone - Asn40Asn | Subjective Response - Craving for Alcohol | BrAC = 0.04 g/dl | 1.9198 score on a scale | Standard Deviation 1.126 |
| Naltrexone - Asn40Asp/Asp40Asp | Subjective Response - Craving for Alcohol | BrAC = 0.02 g/dl | 1.9965 score on a scale | Standard Deviation 1.2862 |
| Naltrexone - Asn40Asp/Asp40Asp | Subjective Response - Craving for Alcohol | BrAc = 0.06 g/dl | 2.2014 score on a scale | Standard Deviation 1.343 |
| Naltrexone - Asn40Asp/Asp40Asp | Subjective Response - Craving for Alcohol | BrAC = 0.04 g/dl | 2.1319 score on a scale | Standard Deviation 1.3024 |
| Placebo - Asn40Asn | Subjective Response - Craving for Alcohol | BrAC = 0.04 g/dl | 2.3095 score on a scale | Standard Deviation 1.4499 |
| Placebo - Asn40Asn | Subjective Response - Craving for Alcohol | BrAC = 0.02 g/dl | 2.1012 score on a scale | Standard Deviation 1.2881 |
| Placebo - Asn40Asn | Subjective Response - Craving for Alcohol | BrAc = 0.06 g/dl | 2.3095 score on a scale | Standard Deviation 1.44 |
| Placebo - Asn40Asp/Asp40Asp | Subjective Response - Craving for Alcohol | BrAC = 0.02 g/dl | 1.8478 score on a scale | Standard Deviation 0.9812 |
| Placebo - Asn40Asp/Asp40Asp | Subjective Response - Craving for Alcohol | BrAc = 0.06 g/dl | 2.4891 score on a scale | Standard Deviation 1.4595 |
| Placebo - Asn40Asp/Asp40Asp | Subjective Response - Craving for Alcohol | BrAC = 0.04 g/dl | 2.2645 score on a scale | Standard Deviation 1.2311 |
p-value: 0.39Mixed Models Analysis
p-value: 0.34Mixed Models Analysis
p-value: 0.04Mixed Models Analysis
p-value: 0.47Mixed Models Analysis
p-value: 0.13Mixed Models Analysis
Primary
Subjective Response - Sedation
The Biphasic Alcohol Effects Scale (BAES) Sedation Subscale consists of 14 items designed to capture the sedating effects of alcohol, rated on an 11-point scale (0 = not at all. 10 = extremely). Total score for the sedation subscale ranges from 0-70.
Time frame: The BAES Sedation Subscale was administered at baseline and three levels of breath alcohol concentration: 0.2 g/dl. 0.04, g/dl, and 0.06 g/dl taking place within approximately 1.5 hours
Population: Participants who completed at least one experimental session.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Naltrexone - Asn40Asn | Subjective Response - Sedation | BrAC = 0.02 g/dl | 2.6825 score on a scale | Standard Deviation 2.1146 |
| Naltrexone - Asn40Asn | Subjective Response - Sedation | BrAc = 0.06 g/dl | 3.0688 score on a scale | Standard Deviation 2.4364 |
| Naltrexone - Asn40Asn | Subjective Response - Sedation | BrAC = 0.04 g/dl | 2.8571 score on a scale | Standard Deviation 2.1907 |
| Naltrexone - Asn40Asp/Asp40Asp | Subjective Response - Sedation | BrAC = 0.02 g/dl | 2.3482 score on a scale | Standard Deviation 1.6194 |
| Naltrexone - Asn40Asp/Asp40Asp | Subjective Response - Sedation | BrAc = 0.06 g/dl | 3.1548 score on a scale | Standard Deviation 2.0981 |
| Naltrexone - Asn40Asp/Asp40Asp | Subjective Response - Sedation | BrAC = 0.04 g/dl | 2.8601 score on a scale | Standard Deviation 2.0094 |
| Placebo - Asn40Asn | Subjective Response - Sedation | BrAC = 0.04 g/dl | 2.4949 score on a scale | Standard Deviation 1.7798 |
| Placebo - Asn40Asn | Subjective Response - Sedation | BrAC = 0.02 g/dl | 2.1480 score on a scale | Standard Deviation 1.6452 |
| Placebo - Asn40Asn | Subjective Response - Sedation | BrAc = 0.06 g/dl | 2.6786 score on a scale | Standard Deviation 2.4767 |
| Placebo - Asn40Asp/Asp40Asp | Subjective Response - Sedation | BrAC = 0.02 g/dl | 2.0560 score on a scale | Standard Deviation 1.6726 |
| Placebo - Asn40Asp/Asp40Asp | Subjective Response - Sedation | BrAc = 0.06 g/dl | 2.4627 score on a scale | Standard Deviation 1.8025 |
| Placebo - Asn40Asp/Asp40Asp | Subjective Response - Sedation | BrAC = 0.04 g/dl | 2.6832 score on a scale | Standard Deviation 1.8504 |
p-value: 0.55Mixed Models Analysis
p-value: 0.77Mixed Models Analysis
p-value: 0.04Mixed Models Analysis
p-value: 0.47Mixed Models Analysis
p-value: 0.19Mixed Models Analysis
Primary
Subjective Response - Stimulation
The Biphasic Alcohol Effects Scale (BAES) Stimulant Subscale consists of 14 items designed to capture the stimulant effects of alcohol, rated on an 11-point scale (0 = not at all. 10 = extremely). Total score for the stimulant subscale ranges from 0-70.
Time frame: The BAES Stimulant Subscale was administered at baseline and three levels of breath alcohol concentration: 0.2 g/dl. 0.04, g/dl, and 0.06 g/dl taking place within approximately 1.5 hours
Population: Participants who completed at least one experimental session.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Naltrexone - Asn40Asn | Subjective Response - Stimulation | BrAC = 0.04 g/dl | 2.2963 score on a scale | Standard Deviation 1.886 |
| Naltrexone - Asn40Asn | Subjective Response - Stimulation | BrAc = 0.06 g/dl | 2.8307 score on a scale | Standard Deviation 2.3581 |
| Naltrexone - Asn40Asn | Subjective Response - Stimulation | BrAC = 0.02 g/dl | 2.0423 score on a scale | Standard Deviation 1.7338 |
| Naltrexone - Asn40Asp/Asp40Asp | Subjective Response - Stimulation | BrAC = 0.04 g/dl | 2.7679 score on a scale | Standard Deviation 1.9415 |
| Naltrexone - Asn40Asp/Asp40Asp | Subjective Response - Stimulation | BrAC = 0.02 g/dl | 2.0893 score on a scale | Standard Deviation 1.8291 |
| Naltrexone - Asn40Asp/Asp40Asp | Subjective Response - Stimulation | BrAc = 0.06 g/dl | 3.0149 score on a scale | Standard Deviation 2.1955 |
| Placebo - Asn40Asn | Subjective Response - Stimulation | BrAC = 0.04 g/dl | 2.3316 score on a scale | Standard Deviation 2.0949 |
| Placebo - Asn40Asn | Subjective Response - Stimulation | BrAc = 0.06 g/dl | 2.2347 score on a scale | Standard Deviation 1.9917 |
| Placebo - Asn40Asn | Subjective Response - Stimulation | BrAC = 0.02 g/dl | 2.0102 score on a scale | Standard Deviation 1.9867 |
| Placebo - Asn40Asp/Asp40Asp | Subjective Response - Stimulation | BrAC = 0.02 g/dl | 1.8106 score on a scale | Standard Deviation 1.7512 |
| Placebo - Asn40Asp/Asp40Asp | Subjective Response - Stimulation | BrAc = 0.06 g/dl | 3.0466 score on a scale | Standard Deviation 2.4146 |
| Placebo - Asn40Asp/Asp40Asp | Subjective Response - Stimulation | BrAC = 0.04 g/dl | 2.4658 score on a scale | Standard Deviation 1.9971 |
p-value: 0.23Mixed Models Analysis
p-value: 0.09Mixed Models Analysis
p-value: 0.84Mixed Models Analysis
p-value: 0.05Mixed Models Analysis
Secondary
Alcohol Self-administration - Number of Drinks
Total number of drinks consumed during the alcohol self-administration task
Time frame: Alcohol self-administration period was 1 hour long
Population: Participants who completed at least one experimental session.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Naltrexone - Asn40Asn | Alcohol Self-administration - Number of Drinks | 1.4444 drinks consumed | Standard Deviation 1.5275 |
| Naltrexone - Asn40Asp/Asp40Asp | Alcohol Self-administration - Number of Drinks | 0.6458 drinks consumed | Standard Deviation 1.1576 |
| Placebo - Asn40Asn | Alcohol Self-administration - Number of Drinks | 1.5714 drinks consumed | Standard Deviation 1.4764 |
| Placebo - Asn40Asp/Asp40Asp | Alcohol Self-administration - Number of Drinks | 0.9565 drinks consumed | Standard Deviation 1.3656 |
p-value: 0.14Poisson Regression
p-value: 0.02Poisson
p-value: 0.41Poisson