This research study aims to test whether topiramate (a drug that is being used for seizure) will help individuals who have problems with both alcohol and nicotine. The investigators believe that individuals taking topiramate will be more successful at abstaining from both alcohol and nicotine than individuals taking placebo.
We propose a novel pharmacological strategy for treating alcohol and nicotine dependence concomitantly. The reinforcing effects of both alcohol and nicotine are mediated through the cortico-mesolimbic dopamine (CMDA) system, and the concomitant use of both drugs enhances their pharmacological effects. We propose a better approach to control dopamine (DA) effects by contemporaneous indirect modulation of DA release and its functional expression. Both DA release from its cell bodies in the ventral tegmental area and the expression of its reinforcing effects through the cortico-mesolimbic system are modulated by gamma-aminobutyric acid (GABA) efferents under the tonic control of glutamate-mediated excitatory amino acid pathways. Thus, it is reasonable to hypothesize that a medication that facilitates cortico-mesolimbic GABAergic function and inhibits glutamate action should diminish both nicotine's and alcohol's reinforcing effects by inhibiting the release of midbrain DA and its functional expression through pathways projecting from the nucleus accumbens to the cortex. The promise of this novel approach is exemplified by our recent proof-of-concept demonstration that topiramate compared with placebo significantly improved smoking abstinence rates and decreased serum cotinine levels among alcohol dependent smokers. An important clinical effect of topiramate in alcohol-dependent individuals appears to be that its anti-withdrawal effects promote the gradual tapering of drinking. Hence, due to this unique anti-withdrawal effect of topiramate, we propose to adopt the same methodology for treating alcohol-dependent individuals, as is common practice with smokers, of setting a target quit date (TQD) after which relapse to either drug can be measured. We propose an 18-week, double-blind clinical trial with follow-up visits at 1 month and 3 months, in which alcohol-dependent smokers will receive brief behavioral compliance enhancement treatment (BBCET) plus a smoking self-help manual as their psychosocial treatment, and will be randomized to receive placebo,high-dose topiramate (up to 250 mg/day), or low-dose topiramate (up to 125 mg/day) to prevent relapse to heavy drinking and smoking. Each of the 3 treatment arms shall contain 98 individuals, with a total N of 294. The TQD will occur at the beginning of the 6th week of treatment. Our primary objective is to determine whether both low- and high-dose topiramate will be more efficacious than placebo at reducing the percentage of heavy drinking days and increasing the continuous abstinence rate for smoking determined by a combination of self-report and carbon monoxide (CO) monitoring after the TQD and in the last 4 weeks of treatment. We also will be able to determine whether a lower dose of topiramate is as efficacious as the higher dose and, therefore, is associated with a lower adverse profile. Our secondary objectives are to test whether topiramate will be more efficacious than placebo at improving quality of life and reducing craving after the TQD and in the last 4 weeks of treatment and whether this improvement will be sustained in the follow-up phase.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
236
Low-dose topiramate (up to 125 mg/day) with brief behavioral enhancement therapy
Placebo with brief behavioral enhancement therapy
High-dose topiramate (up to 250 mg/day) with brief behavioral enhancement therapy
University of California, San Diego
La Jolla, California, United States
University of Texas MD Anderson Cancer Center
Houston, Texas, United States
University of Virginia Center for Addiction Research & Education
Charlottesville, Virginia, United States
University of Virginia Center for Addiction Research & Education
Richmond, Virginia, United States
Continuous Smoking Abstinence in the Last 4 Weeks of Treatment Continuous Smoking Abstinence in the Last 4 Weeks of Treatment
No smoking in the last 4 weeks of the 18-week treatment with an expired carbon monoxide level of \<10 ppm as the biochemical verification. We used the intent-to-treat assumption, where missing smoking data were considered as smoking.
Time frame: Week 15 - 18 of the 18-week medication treatment
Percentage of Heavy Drinking Days (PHDD) in the Last 4 Weeks of Treatment
A heavy drinking day is defined as \>= 5 standard drinking units for men and \>= 4 standard drinking units for women. We calculated the PHDD used the intent-to-treat assumption, where missing drinking data were considered as heavy drinking.
Time frame: Week 15 - 18 of the 18-week medication treatment
Quality of Life in the Last 4 Weeks of Treatment
We used the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) to measure quality of life in the last 4 weeks of treatment. Scoring involves summing the individual item scores on a 5-point scale, with higher scores indicating greater life satisfaction and enjoyment (better outcome). We report here a percent score of subscales contained within the Q-LES-Q, with higher scores indicating a better outcome. The subscales within the questionnaire have different numbers of items, resulting in different ranges of raw scores, so using a percent score, which used the following formula: (raw\_score - scale\_min\_possible\_score) / (scale\_max\_possible\_score - scale\_min\_possible\_score), helped normalize such differences, improving interpretation using the same range (i.e., 0 - 100) between subscales.
Time frame: Week 15 - 18 of the 18-week medication treatment
Craving for Alcohol and Cigarettes in the Last 4 Weeks of Treatment
We used the Visual Analog Scales (VAS) to assess the craving levels for alcohol and cigarettes, respectively. VAS uses a 100 millimeter line, where 0 mm = no craving (minimum value) and 100 mm = strongest craving ever (maximum value). Participants are asked to make a mark on the line that best represents their current level of craving. Research staff then measure the distance in millimeters from the "No Craving" anchor (0 mm) to the participant's mark, which is their score. A higher score is equal to higher craving (worse outcome). Mean scores of the last 4 weeks of treatment are reported.
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Time frame: Week 15 - 18 of the 18-week medication treatment