Tobacco Dependence
Conditions
Keywords
within-subjects, crossover, laboratory study, Naltrexone vs. Placebo
Brief summary
Despite preclinical evidence supporting the role of the endogenous opioid system in the reinforcing effects of nicotine, the efficacy of the opioid antagonist naltrexone (NTX) as a tobacco dependence treatment remains unresolved. Research is needed to identify those smokers for whom NTX will have the strongest beneficial effects on smoking behavior. The research bridges existing knowledge of genetic, pharmacologic, and behavioral responses to nicotine, and translates this knowledge to treatment for tobacco dependence. The immediate goal was to test whether genetic variation in the mu-opioid receptor gene predicts the effects of naltrexone (NTX) on nicotine reinforcement.
Detailed description
The study was a within-subject double-blind study of the effects of naltrexone versus placebo on the reinforcing value of nicotine, using a validated cigarette choice paradigm. A key question was whether smokers differ in their responses based on the mu opioid receptor gene (OPRM1) Asn40Asp (A118G) variant. Following informed consent, 64 smokers were enrolled in the study. Of these, 60 completed two 4-day study phases interspersed with a 5-7 day washout phase. Baseline statistics are provided for the 64 smokers who enrolled. Each 4-day study phase included a 3-day drug run-up and monitoring phase, then on the 4th day participants came to our Biobehavioral Lab (BBL) where they took their final 50mg of study medication and completed a cigarette choice paradigm. Following a washout phase, the 4-day sequence will be repeated with the alternative study medication. The order of study medication was randomized and counterbalanced between subjects.
Interventions
DRUGNaltrexone
All participants took naltrexone during one of the two 4-day study medication periods. Both 4-day study medication periods were randomized and counterbalanced between naltrexone and placebo; all study medication periods were separated by a 5-7 day washout period. Dosing of the naltrexone was the same for all participants: Day 1: 12.5mg, Day 2: 25mg, Days 3 and 4: 50mg.
DRUGPlacebo
All participants took a placebo (sugar pill) during one of the two 4-day study medication periods. Both 4-day study medication periods were randomized and counterbalanced between naltrexone and placebo. Placebo capsules matched the naltrexone in color, weight and inactive ingredients. The only difference the lack of active naltrexone in each capsule.
Sponsors
National Institute on Drug Abuse (NIDA)
University of Pennsylvania
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Participants must be greater than or equal to 18 years 2. Based on the medical history, physical and laboratory examination, female subjects must: 1. Agree in consent to practice effective contraception during study, be status post-bilateral tubal litigation or be post-menopausal. 2. Not be pregnant, nursing, or planning pregnancy 3. Based upon self-report, subjects must smoke greater than or equal to 10 non-menthol cigarettes per day 4. Because the OPRM1 variant is common (25-30%) in persons of European ancestry, but very rare in other ethnic groups (e.g., 2-9% of African Americans) it is not scientifically justified to include members of other ethnic groups. Therefore, only persons of European ancestry will be recruited. 5. Following orientation by the research staff, subjects must sign written informed consent and HIPAA form.
Exclusion criteria
1. Current diagnosis of kidney disease or history of renal function impairment (unless they have recent kidney function tests (within last 3 months) and approval of their primary physician to participate in the study.) 2. Women who are pregnant, planning a pregnancy, or lactating 3. Current alcohol use \> 25 standard drinks/week (this is because NTX is used to treat alcohol dependence, and effects of NTX on alcohol consumption in alcohol dependent subjects could have indirect effects on cigarette consumption). 4. Current medical problems for which NTX is contraindicated including: active hepatitis (Liver Function Tests 3 times the Upper Limit of Normal). 5. History of opiate dependence (prescription drug or illicit use). 6. History of or current Diagnostic and Statistical Manual of Mental Disorders (Version IV) (DSM IV) substance use disorders (abuse or dependence involving alcohol, cocaine, stimulants, or benzodiazepines) 7. Diagnosis of bulimia and/or anorexia nervosa in the last year 8. Current or past use (with in past 12 months) of any medications containing NTX (e.g., Revia, Trexan), allergy to NTX 9. Concomitant medications (e.g., monoamine oxidase inhibitors or benzodiazepines within past 14 days, antipsychotics, antidepressants, theophylline, systemic steroids, over-the-counter stimulants and anorectics)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Nicotine Cigarette Choices Taken During the Cigarette Choice Procedure. | 2 hours | On day 4 of each study medication period, participants completed a cigarette choice procedure where the subject is asked to take 4 puffs from a nicotinized (nicotine-containing) or a denicotinized (no nicotine) cigarette every 30 minutes for 2 hours (maximum of 24 puffs). The outcome variable is the number of nicotine cigarette choices or puffs out of 24 total puffs during these cigarette choice procedures. Subjects who had the A/A genotype took an average of 18.5 puffs from the nicotine-containing cigarettes. Subjects with the A/G or G/G genotypes took an average of 16.2 puffs from the nicotine-containing cigarettes. |
Countries
United States
Participant flow
Recruitment details
Recruitment occurred from March 2004 to August 2005. All subject sessions occurred at the Tobacco Use Research Center's lab, the Biobehavioral Lab (BBL), at the University of Pennsylvania.
Pre-assignment details
The primary genotype of interest was the functional mu opioid receptor (OPRM1). Smokers with the Asp40 variant (A/G or G/G genotypes; about 27% of smokers) were oversampled, relative to those with the more common Asn40 variant (A/A genotype; 73% of smokers), in order to have an equal number of participants in each genotype group.
Participants by arm
| Arm | Count |
|---|---|
| Entire Study Population Includes subjects with both OPRM1 genotypes (Asp40 (A/G or G/G allele vs. Asn40 (A/A) allele) who started Intervention Period 1. | 64 |
| Total | 64 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention | Lost to Follow-up | 1 | 1 |
| Second Intervention | Lost to Follow-up | 0 | 1 |
| Washout Period | Lost to Follow-up | 1 | 0 |
Baseline characteristics
| Characteristic | Entire Study Population |
|---|---|
| Age, Categorical <=18 years | 1 Participants |
| Age, Categorical >=65 years | 4 Participants |
| Age, Categorical Between 18 and 65 years | 59 Participants |
| Age Continuous | 43.2 years STANDARD_DEVIATION 15 |
| Region of Enrollment United States | 64 participants |
| Sex: Female, Male Female | 26 Participants |
| Sex: Female, Male Male | 38 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 64 | 0 / 64 |
| serious Total, serious adverse events | 0 / 64 | 0 / 64 |
Outcome results
Primary
Number of Nicotine Cigarette Choices Taken During the Cigarette Choice Procedure.
On day 4 of each study medication period, participants completed a cigarette choice procedure where the subject is asked to take 4 puffs from a nicotinized (nicotine-containing) or a denicotinized (no nicotine) cigarette every 30 minutes for 2 hours (maximum of 24 puffs). The outcome variable is the number of nicotine cigarette choices or puffs out of 24 total puffs during these cigarette choice procedures. Subjects who had the A/A genotype took an average of 18.5 puffs from the nicotine-containing cigarettes. Subjects with the A/G or G/G genotypes took an average of 16.2 puffs from the nicotine-containing cigarettes.
Time frame: 2 hours
Population: Participants were analyzed with respect to genotype regardless of intervention.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| OPRM1 Genotype - A/A | Number of Nicotine Cigarette Choices Taken During the Cigarette Choice Procedure. | 18.5 Number of Nicotine Cigarette Puffs Taken | Standard Deviation 4.2 |
| OPRM1 Genotype - A/G or G/G | Number of Nicotine Cigarette Choices Taken During the Cigarette Choice Procedure. | 16.2 Number of Nicotine Cigarette Puffs Taken | Standard Deviation 6.2 |