Effects of Naltrexone on Nicotine Reinforcement

Study Overview
=================
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.

Official Title
-----------------
Pharmacogenetic Investigation of Naltrexone

Conditions
-----------------
Tobacco Dependence

Intervention / Treatment
-----------------
* Drug: Naltrexone
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Participants must be greater than or equal to 18 years Based on the medical history, physical and laboratory examination, female subjects must: Agree in consent to practice effective contraception during study, be status post-bilateral tubal litigation or be post-menopausal. Not be pregnant, nursing, or planning pregnancy Based upon self-report, subjects must smoke greater than or equal to 10 non-menthol cigarettes per day 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. Following orientation by the research staff, subjects must sign written informed consent and HIPAA form. Exclusion Criteria: 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.) Women who are pregnant, planning a pregnancy, or lactating 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). Current medical problems for which NTX is contraindicated including: active hepatitis (Liver Function Tests 3 times the Upper Limit of Normal). History of opiate dependence (prescription drug or illicit use). 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) Diagnosis of bulimia and/or anorexia nervosa in the last year Current or past use (with in past 12 months) of any medications containing NTX (e.g., Revia, Trexan), allergy to NTX Concomitant medications (e.g., monoamine oxidase inhibitors or benzodiazepines within past 14 days, antipsychotics, antidepressants, theophylline, systemic steroids, over-the-counter stimulants and anorectics)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Naltrexone<br>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. | Drug: Naltrexone<br>* 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.<br>* Other names: Revia or Trexan;|
| Placebo Comparator: Placebo<br>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. | Drug: Placebo<br>* 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.<br>* Other names: Sugar pill; inactive medication;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 2 hours | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
within-subjects, crossover, laboratory study, Naltrexone vs. Placebo