Memory Reconsolidation Blockade as a Novel Intervention for Nicotine Dependence (SCP)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
A. Eden Evins, Massachusetts General Hospital
ClinicalTrials.gov Identifier:
NCT00916721
First received: June 5, 2009
Last updated: September 16, 2014
Last verified: September 2014
  Purpose

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.


Condition Intervention Phase
Smoking Cessation
Drug: Propranolol
Drug: Placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: Memory Reconsolidation Blockade as a Novel Intervention for Nicotine Dependence

Resource links provided by NLM:


Further study details as provided by Massachusetts General Hospital:

Primary Outcome Measures:
  • Change in the Skin Conductance Level, Caused by Smoking Cues, Measured Using Script Driven Imagery [ Time Frame: skin conductance was measured at visit 3, after presentation of two neutral and two smoking scripts ] [ Designated as safety issue: No ]
    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 [ Time Frame: Heart rate was measured at visit 3, after presentation of two neutral and two smoking scripts ] [ Designated as safety issue: No ]
    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 [ Time Frame: Corrugator EMG level was measured at visit 3, after presentation of two neutral and two smoking scripts ] [ Designated as safety issue: No ]
    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:
  • Change in Craving Level to Smoking Cues Caused by Smoking Cues, Measured Using Script Driven Imagery [ Time Frame: Craving level was measured at visit 3, after presentation of two neutral and two smoking scripts ] [ Designated as safety issue: No ]
    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


Enrollment: 113
Study Start Date: April 2008
Study Completion Date: January 2011
Primary Completion Date: July 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Propranolol
propranolol
Drug: Propranolol
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.
Other Name: Inderal
Placebo Comparator: Placebo
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.
Other Name: placebo

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.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion:

  • Healthy smokers aged 18-65 who have smoked at least 10 cigarettes/day for the past 3 months

Exclusion:

  • Age <18 or >65
  • Systolic blood pressure <100 mm Hg;
  • Medical condition that contraindicates the administration of propranolol, e.g., history of congestive heart failure, heart block, insulin-dependent diabetes, chronic bronchitis, emphysema, or asthma. With regard to asthma, because many persons who say they have had an asthma attack, especially as a child, may only have had hay fever, another allergy, or another non-asthmatic episode, a blanket exclusion criterion may be overly restrictive. Therefore, asthma attacks will only be exclusionary if they a.) occurred within the past ten years, b.) occurred at any time in life if induced by a B-blocker, or c.) are currently being treated, regardless of the date of last occurrence. Cardiological consultation will be obtained as necessary;
  • Previous adverse reaction to, or non-compliance with, a B-blocker;
  • Current use of medication that may involve potentially dangerous interactions with propranolol, including, other B-blockers, antiarrhythmics, or calcium channel blockers.
  • Use of drugs of abuse other than nicotine or caffeine, such as opiates, marijuana, cocaine, or amphetamines, as determined by saliva or urine testing;
  • Pregnancy (in women of child-bearing potential, a pregnancy test will be performed) or breast-feeding;
  • Current PTSD, or psychotic, melancholic, or bipolar disorder
  • Diagnosis of major depressive disorder in the past 6 months or HAM-D score >15 at screening
  • Current participation in any additional nicotine dependence treatment.
  • An urgent need to stop smoking: subjects who receive placebo may not achieve optimal smoking cessation results.
  • Inability to understand the study's procedures, risks, and side effects, or to otherwise give informed consent for participation;
  • Subject candidate does not understand English
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00916721

Locations
United States, Massachusetts
Massachusetts General Hospital - Center For Addiction Medicine
Boston, Massachusetts, United States, 02114
Sponsors and Collaborators
Massachusetts General Hospital
Investigators
Principal Investigator: A. Eden Evins, MD, MPH Massachusetts General Hospital
  More Information

Publications:

Responsible Party: A. Eden Evins, Director Center for Addiction Medicine, Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT00916721     History of Changes
Other Study ID Numbers: 2007P-001903, NIH grant 207610
Study First Received: June 5, 2009
Results First Received: July 9, 2013
Last Updated: September 16, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by Massachusetts General Hospital:
Smoking cessation
propranolol
memory reconsolidation blockade
craving

Additional relevant MeSH terms:
Propranolol
Adrenergic beta-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Anti-Arrhythmia Agents
Cardiovascular Agents
Therapeutic Uses
Antihypertensive Agents
Vasodilator Agents

ClinicalTrials.gov processed this record on October 02, 2014