Effects of Naltrexone on Nicotine Reinforcement

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 proposed research bridges existing knowledge of genetic, pharmacologic, and behavioral responses to nicotine, and translates this knowledge to treatment for tobacco dependence. Our immediate goal is to test whether genetic variation in the mu-opioid receptor gene predicts the effects of naltrexone (NTX) on nicotine reinforcement.

The current study is a within-subject double-blind study of the effects of NTX versus PLA on the reinforcing value of nicotine, using a validated cigarette choice paradigm. Following informed consent, 40 smokers from each genotype group (n=80) will be asked to complete two 4-day study phases interspersed with a 5-7 day washout phase. Each 4-day study phase will include a 3-day drug run-up and monitoring phase, then on the 4th day participants will come to the Biobehavioral Lab (BBL) where they will take their final 50mg of study medication and complete a cigarette choice paradigm (See table 2). Following a washout phase, the 4-day sequence will be repeated with the alternative study medication. The order of study medication will be counterbalanced between subjects.

Inclusion Criteria:

1. Participants must be >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 >10 non-menthol, cigarettes/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.

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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 (LFT's 3X Upper Limit of Normal).
5. History of opiate dependence (prescription drug or illicit use).
6. History of or current DSM IV substance use disorders (abuse or dependence involving alcohol, cocaine, or stimulants, 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) -