Alcohol Use Disorder
Conditions
Brief summary
The purpose of this study to evaluate the effects of naltrexone plus lemborexant augmentation compared to naltrexone plus placebo on cue-induced and non-cued alcohol cravings in people with alcohol use disorder and insomnia. Our secondary goals are to evaluate the effects of lemborexant plus naltrexone combination on sleep quality using self-report questionnaires and actigraph data, depression, anxiety, and suicidal ideation.
Detailed description
Alcohol is one of the most popular substances used worldwide for thousands of years. Globally, harmful alcohol use continues to be a major public health and economic burden. The World Health Organization global status report attributed harmful alcohol use to 3 million deaths in 2016.In the United States, alcohol is the most used substance by people over the age of 12, with alcohol use disorder (AUD) affecting 14.5 million people in this age group. Hazardous alcohol use is associated with emergency room visits, overdose, driving fatalities and chronic medical conditions such as liver disease, heart disease, and hypertension. Pharmacological interventions for AUD have expanded over the past few decades, including FDA approved and off-label medications such as naltrexone that have demonstrated efficacy in reducing alcohol cravings, consumption, and likelihood of relapse. However, the significant variability in response to treatment fuels ongoing interest in novel pharmacotherapy for AUD. A common approach involves repurposing readily available medications based on our understanding of AUD pathophysiology. In this study, we focus on the orexin system, which has been implicated in behaviors such as feeding, sleep-wake cycle, motivation, and reward associated with food, sex and substances including alcohol. The brain neuropeptides orexin A and orexin B originate in the hypothalamus and project throughout the central nervous system, activating G-protein-coupled receptors orexin 1 and 2 (OX1R and OX2R). While both orexin receptors are involved in addictive behaviors, OX1R signaling has a stronger association with reward processes whereas OX2R promotes arousal. Chronic alcohol exposure may lead to neuroadaptations in the orexin system, as observed in studies showing a positive correlation between orexin levels and severity of alcohol dependence and distress during alcohol withdrawal. Moreover, multiple animal studies have demonstrated efficacy of orexin antagonists in reducing alcohol craving, self-administration, and reinstatement of alcohol use induced by cues and stress. The orexin antagonist lemborexant is FDA approved for treatment of insomnia. Lemborexant acts on both OX1R and OX2R and has shown efficacy in sleep initiation and maintenance compared to placebo on polysomnography and patient-report. It has demonstrated long-term safety and effectiveness without physical dependence or rebound insomnia. Compared to suvorexant, another orexin antagonist, lemborexant has greater selectivity and stronger binding for orexin receptors. Suvorexant has secondary effects on the adenosine receptor and dopamine transporter whereas lemborexant only has weak binding to melatonin 1. These differences may increase risk of misuse for suvorexant more than lemborexant. In addition, Lemborexant's longer half-life (17-19h) may be advantageous for reduction of cravings during the day. In people with AUD, insomnia is a common problem that is associated with alcohol craving and relapse. Standard treatment for AUD with naltrexone improves cravings and other AUD outcomes, but does not improve sleep. In some cases, naltrexone may have a detrimental effect on sleep. Lemborexant may be able to target both alcohol craving/urges and insomnia when added to standard treatment with naltrexone.
Interventions
10 mg of Lemborexant
DRUGNaltrexone
50 mg of Naltrexone
Sponsors
Baylor College of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Intervention model description
Subjects will be randomized to two different arms: lemborexant plus naltrexone versus placebo plus naltrexone using a computer-generated randomization scheme.
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Admission to The Menninger clinic * Age 18-65 years * diagnosis of alcohol use disorder using the DSM-5 criteria confirmed with SCID-5 and * Diagnosis of insomnia using the DSM 5 criteria, confirmed with SCID-5
Exclusion criteria
* unstable medical conditions (e.g. liver enzymes (ALT and AST) more than 3 times normal) * acute alcohol withdrawal * another drug use disorder other than nicotine and cannabis * use of either of the study medications, naltrexone or lemborexant, within the last 30 days * Use of any opioid medication within the past 10 days * Use of scheduled benzodiazepines and hypnotics * Breathalyzer positive for alcohol * Known sensitivity to naltrexone or lemborexant * Pregnant or breastfeeding * Diagnosis of narcolepsy. The presence of other psychiatric illnesses, use of other psychotropic medications, and stable medical conditions will not be excluded.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cue-induced Alcohol Cravings Using the Alcohol Urge Questionnaire | Baseline to last available post-baseline assessment (2 to 4 weeks after randomization) | Alcohol Urge Questionnaire (AUQ) total score (range 8-56; higher scores indicate greater craving) was assessed following alcohol-related virtual reality cue exposure at baseline and at multiple post-baseline time points during treatment. For this outcome, change from baseline to the last available post-baseline AUQ assessment was calculated and reported as a single summary value. |
| Non-Cued Alcohol Cravings Using the Penn Alcohol Craving Scale | Baseline to study endpoint (2 to 4 weeks after randomization) | Penn Alcohol Craving Scale (PACS): The Penn Alcohol Craving Scale is a 5-item self-report questionnaire assessing alcohol craving over the prior week. Total scores range from 0 to 30, with higher scores indicating greater alcohol craving. PACS assessments were obtained at baseline and weekly during the treatment period. For this outcome, change from baseline to the endpoint PACS assessment was calculated and reported as a single summary value. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Actigraphy to Measure Total Sleep Time | Baseline to study endpoint (2 to 4 weeks after randomization) | The ActiGraph wGT3X-BT will measure daily total sleep time (hours) |
| Actigraphy to Measure Total Awakenings After Sleep Onset During the Study Period | Baseline to study endpoint (2 to 4 weeks after randomization) | The ActiGraph wGT3X-BT will measure total number of awakenings after sleep onset during the study period |
Countries
United States
Participant flow
Recruitment details
Seven participants were randomized, six participants initiated medication.
Pre-assignment details
After enrollment, participants underwent standard inpatient clinical evaluation and screening procedures to confirm eligibility, including diagnostic assessment and review of medical and laboratory data. Participants who did not meet eligibility criteria or did not proceed to initiation of study medication due to loss of follow-up were not assigned to a treatment arm. No washout or run-in period was required prior to randomization.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants |
| Alcohol Dependence Scale | 27.25 Scores on a scale STANDARD_DEVIATION 9.6 |
| 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 | 0 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 | 6 Participants |
| Region of Enrollment United States | 4 Participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 3 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 | 1 / 3 | 1 / 3 |
| serious Total, serious adverse events | 0 / 3 | 0 / 3 |
Outcome results
None listed