A Phase 3 interventional study of Propranolol and Placebo in Smoking Cessation, sponsored by Massachusetts General Hospital. Completed at 1 site in United States. Open to participants aged 18 Years to 65 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2014-09-19.
Sponsored by Massachusetts General Hospital · Phase 3, Interventional, and Treatment
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.
SPECIFIC AIMS
To achieve these aims, we will conduct a double-blind, randomized, placebo-controlled trial in a convenience sample of 50 smokers.
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Exclusion:
propranolol
Drug: Propranolol
sugar pill
Drug: Placebo
Visit 2 (first smoking-related memory reactivation session) the subject will be given 0.67 mg/kg (minimum 40 mg; maximum 80 mg) of short-acting propranolol (or placebo) rounded to the nearest 10 mg. Ninety minutes after this dose, if subject has tolerated the short-acting dose well, and if systolic blood pressure has not fallen by 10 mmHg or more to below 100 mmHg, the subject will be given oral long-acting propranolol 1 mg/kg (minimum 60 mg; maximum 120 mg) or placebo rounded to the nearest 20 mg. . If the subject tolerates the combination dose well, during treatment phase (from visit 7 to 12), both the short- and long-acting doses will be given together immediately prior to memory reactivation.
Also known as: Inderal
Visit 2 (first smoking-related memory reactivation session) the subject will be given 0.67 mg/kg (minimum 40 mg; maximum 80 mg) of short-acting propranolol (or placebo) rounded to the nearest 10 mg. Ninety minutes after this dose, if subject has tolerated the short-acting dose well, and if systolic blood pressure has not fallen by 10 mmHg or more to below 100 mmHg, the subject will be given oral long-acting propranolol 1 mg/kg (minimum 60 mg; maximum 120 mg) or placebo rounded to the nearest 20 mg. . If the subject tolerates the combination dose well, during treatment phase (from visit 7 to 12), both the short- and long-acting doses will be given together immediately prior to memory reactivation.
Change in the Skin Conductance Level, Caused by Smoking Cues, Measured Using Script Driven Imagery
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.
Time frame: skin conductance was measured at visit 3, after presentation of two neutral and two smoking scripts
Change in Heart Rate (Beats Per Minute), Caused by Smoking Cues, Measured Using Script Driven Imagery
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
Time frame: Heart rate was measured at visit 3, after presentation of two neutral and two smoking scripts
Change in the Corrugator Muscle (EMG) Level, Caused by Smoking Cues, Measured Using Script Driven Imagery
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
Time frame: Corrugator EMG level was measured at visit 3, after presentation of two neutral and two smoking scripts
Change in Craving Level to Smoking Cues Caused by Smoking Cues, Measured Using Script Driven Imagery
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
Time frame: Craving level was measured at visit 3, after presentation of two neutral and two smoking scripts
Treatment seeking adults smokers were enrolled from May 2008 to March 2010 at the Center for Addiction Medicine of the Massachusetts General Hospital, in compliance with the Declaration of Helsinki, the U.S. Food and Drug Administration guidelines, and the International Conference on Harmonization Good Clinical Practices Guidelines.
| Milestone | Propranolol | Placebo |
|---|---|---|
| Started | 35 | 39 |
| Completed | 25 | 29 |
| Not completed | 10 | 10 |
| Withdrew: Lost to follow-up | 0 | 1 |
| Withdrew: Adverse event | 6 | 3 |
| Withdrew: Withdrawal by subject | 2 | 2 |
| Withdrew: Protocol violation | 2 | 4 |
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
| units on a scale | Propranolol | Placebo |
|---|---|---|
| Change in Craving Level to Smoking Cues Caused by Smoking Cues, Measured Using Script Driven Imagery | 5.52 ± 1.1 | 4.3 ± 2.1 |
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.
| µS | Propranolol | Placebo |
|---|---|---|
| Change in the Skin Conductance Level, Caused by Smoking Cues, Measured Using Script Driven Imagery | 0.107 ± 0.728 | -0.040 ± 0.337 |
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
| beats per minute | Propranolol | Placebo |
|---|---|---|
| Change in Heart Rate (Beats Per Minute), Caused by Smoking Cues, Measured Using Script Driven Imagery | 0.877 ± 2.285 | 1.162 ± 2.064 |
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
| µV | Propranolol | Placebo |
|---|---|---|
| Change in the Corrugator Muscle (EMG) Level, Caused by Smoking Cues, Measured Using Script Driven Imagery | 0.479 ± 1.309 | 1.464 ± 3.394 |
Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Propranolol | — | 1/35 (2.9%) | 6/35 (17.1%) |
| Placebo | — | 0/39 (0%) | 0/39 (0%) |
| Event | Propranolol | Placebo |
|---|---|---|
| major depressive episode and worsen anxietyPsychiatric disorders | 1/35 | 0/39 |
| Event | Propranolol | Placebo |
|---|---|---|
| bradycardiaVascular disorders | 6/35 | 0/39 |
| Age, Categorical(Participants) | Propranolol | Placebo | Total |
|---|---|---|---|
| <=18 years | 0 | 0 | 0 |
| Between 18 and 65 years | 35 | 39 | 74 |
| >=65 years | 0 | 0 | 0 |
| Age, Continuous(years) | Propranolol | Placebo | Total |
|---|---|---|---|
| Mean | 41.6 ± 10.9 | 42.5 ± 9.84 | 42.1 ± 10.23 |
| Sex: Female, Male(Participants) | Propranolol | Placebo | Total |
|---|---|---|---|
| Female | 8 | 12 | 20 |
| Male | 27 | 27 | 54 |
| Region of Enrollment(participants) | Propranolol | Placebo | Total |
|---|---|---|---|
| United States | 35 | 39 | 74 |
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Massachusetts General Hospital