Memory Reconsolidation Blockade as a Novel Intervention for Nicotine Dependence

Phase 3

Completed

Conditions: Smoking Cessation

Interventions: Drug: Placebo
Drug: Propranolol

Registration Number: NCT00916721

Lead Sponsor: Massachusetts General Hospital

Brief Summary: Smoking is the leading cause of preventable morbidity and mortality in the US. While approximately 70% of smokers attempt to quit each year, only 5-15% maintain abstinence for 12 months, even with effective pharmacological and psychological interventions. Novel therapies are needed for smoking cessation and relapse prevention. Previous studies show that early post-cessation craving or urge to smoke is a powerful predictor of relapse. A current model of the pathogenesis of addiction maintains that a substance of abuse causes a marked increase release in phasic dopamine release, which in turn strengthens or increases the salience of the memory of the drug experience, leading to a powerful and persistent memory that is easily activated, leading to drug craving and often to drug use. This highly salient memory is also implicated in the physiological arousal associated with craving responses to smoking cues. This process is thought to be implicated in relapse to drug use after even long periods of abstinence. Recent animal research indicates that retrieval returns a consolidated memory such as those associated with drug craving, to a labile state from which it must be restabilized to persist in a process termed reconsolidation. If memories of drug-related experiences are labile when reactivated, this could represent a window of opportunity in which the memory of drug use that underlies drug craving can be influenced pharmacologically. Our hypothesis is that post-reactivation administration of the B-adrenergic blocker, propranolol, following retrieval of drug-associated memories will reduce the strength or salience of the memory by influencing reconsolidation, a process called memory reconsolidation blockade. In this study we will test the hypothesis that a single dose of propranolol given one hour prior to smoking-related cue exposure (post-reactivation treatment) will decrease psychophysiological responses to smoking cues one week later and will predict clinical response to an ensuing series of 6 post-reactivation treatments with script-driven imagery and propranolol. In order to do so, we propose to conduct a randomized, double-blind, placebo-controlled trial of post-reactivation treatment with propranolol in 50 adult smokers. Outcome measures will include in physiological responses to smoking-related cues after one and six post-reactivation treatments and smoking behavior during the treatment and during a 3-month follow-up period.

Detailed Description: SPECIFIC AIMS

1. To evaluate, in current smokers, the efficacy of a single dose of study medication given an hour prior to smoking-related cue exposure (post-reactivation treatment) on psychophysiological response to smoking cues one week later.

2. To evaluate, during the smoking cessation process, the clinical effect of study medication in an ensuing series of 6 post-reactivation treatments on psychophysiologic response to smoking cues measured one week after the last post-reactivation treatment.

3. To evaluate whether medication effect on psychophysiologic response during a single memory reactivation session with script-driven imagery will predict clinical response to an ensuing series of 6 post-reactivation treatments with script-driven imagery and study medication.

4. . To assess whether a single post-reactivation treatment or series of six post-reactivation treatments is associated with reduction in self-reported craving for cigarettes as assessed with the Tiffany QSU.

5. To assess whether a series of six post-reactivation treatments is associated with reduction in smoking as assessed with self-report of cigarettes smoked per day and expired air Carbon monoxide.

To achieve these aims, we will conduct a double-blind, randomized, placebo-controlled trial in a convenience sample of 50 smokers.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 113

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	sugar pill
Propranolol	Propranolol	propranolol

Primary Outcome Measures

Name	Time	Method
Change in the Skin Conductance Level, Caused by Smoking Cues, Measured Using Script Driven Imagery	skin conductance was measured at visit 3, after presentation of two neutral and two smoking scripts	Skin conductance level was obtained through 9-mm (sensor diameter) Ag/AgCl electrodes filled with isotonic paste placed on the non-dominant hypothenar surface using a constant-voltage technique. A Coulbourn Modular Instrument System was used to measure SC during 4 periods; baseline, reading, imagery and recovery.
Change in Heart Rate (Beats Per Minute), Caused by Smoking Cues, Measured Using Script Driven Imagery	Heart rate was measured at visit 3, after presentation of two neutral and two smoking scripts	Heart rate was measured through 9-mm (sensor diameter) Ag/AgCl electrodes filled with electrolytic paste and placed on the medial surface of each forearm. Amplified electrocardiogram signal will input to a tachometer that will provide a voltage output reflecting interbeat interval, which will be transformed to HR. A Coulbourn Modular Instrument System was used to measure HR during 4 periods; baseline, reading, imagery and recovery
Change in the Corrugator Muscle (EMG) Level, Caused by Smoking Cues, Measured Using Script Driven Imagery	Corrugator EMG level was measured at visit 3, after presentation of two neutral and two smoking scripts	Corrugator EMG will be obtained through Ag/AgCl electrodes. The amplified EMG signal will be integrated using a 300-msec. time constant. A Coulbourn Modular Instrument System was used to measure corrugator EMG during 4 periods; baseline, reading, imagery and recovery

Secondary Outcome Measures

Name	Time	Method
Change in Craving Level to Smoking Cues Caused by Smoking Cues, Measured Using Script Driven Imagery	Craving level was measured at visit 3, after presentation of two neutral and two smoking scripts	Craving level will be measured using a 8 point Visual Analogue Scale (VAS) of craving. Participants will be ask "How much do you want a cigarette right now" Participants will answer accordingly: 0=no desire at all; 7=unable to resist craving