Memory Reconsolidation Blockade as a Novel Intervention for Nicotine Dependence

NCT00916721 | Completed Phase 3 Results DMC

• 2 other identifiers: 2007P-001903NIH grant 207610
• Study Type: interventional
• Target: 113
• Locations: 1 country
• Sites: 1

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.

Conditions

Smoking Cessation

Keywords

Smoking cessation; propranolol; memory reconsolidation blockade; craving

Outcome Measures

Primary Outcomes (3)

• 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.

  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

  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

  Corrugator EMG level was measured at visit 3, after presentation of two neutral and two smoking scripts

Secondary Outcomes (1)

• 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

Study Arms (2)

Propranolol

ACTIVE COMPARATOR

propranolol

Drug: Propranolol

Placebo

PLACEBO COMPARATOR

sugar pill

Drug: Placebo

Interventions

Propranolol DRUG

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

Propranolol

Placebo DRUG

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.

Placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• Age \<18 or \>65
• Systolic blood pressure \<100 mm Hg;
• 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

Sponsors & Collaborators

• Massachusetts General Hospital: lead

Study Sites (1)

Massachusetts General Hospital - Center For Addiction Medicine

Boston, Massachusetts, 02114, United States

Location

Related Publications (12)

• Lee JL, Everitt BJ, Thomas KL. Independent cellular processes for hippocampal memory consolidation and reconsolidation. Science. 2004 May 7;304(5672):839-43. doi: 10.1126/science.1095760. Epub 2004 Apr 8.

  PMID: 15073322 BACKGROUND

• Alberini CM. Mechanisms of memory stabilization: are consolidation and reconsolidation similar or distinct processes? Trends Neurosci. 2005 Jan;28(1):51-6. doi: 10.1016/j.tins.2004.11.001.

  PMID: 15626497 BACKGROUND

• Suzuki A, Josselyn SA, Frankland PW, Masushige S, Silva AJ, Kida S. Memory reconsolidation and extinction have distinct temporal and biochemical signatures. J Neurosci. 2004 May 19;24(20):4787-95. doi: 10.1523/JNEUROSCI.5491-03.2004.

  PMID: 15152039 BACKGROUND

• McGaugh JL. The amygdala modulates the consolidation of memories of emotionally arousing experiences. Annu Rev Neurosci. 2004;27:1-28. doi: 10.1146/annurev.neuro.27.070203.144157.

  PMID: 15217324 BACKGROUND

• Pitman RK, Sanders KM, Zusman RM, Healy AR, Cheema F, Lasko NB, Cahill L, Orr SP. Pilot study of secondary prevention of posttraumatic stress disorder with propranolol. Biol Psychiatry. 2002 Jan 15;51(2):189-92. doi: 10.1016/s0006-3223(01)01279-3.

  PMID: 11822998 BACKGROUND

• Vaiva G, Ducrocq F, Jezequel K, Averland B, Lestavel P, Brunet A, Marmar CR. Immediate treatment with propranolol decreases posttraumatic stress disorder two months after trauma. Biol Psychiatry. 2003 Nov 1;54(9):947-9. doi: 10.1016/s0006-3223(03)00412-8.

  PMID: 14573324 BACKGROUND

• Przybyslawski J, Roullet P, Sara SJ. Attenuation of emotional and nonemotional memories after their reactivation: role of beta adrenergic receptors. J Neurosci. 1999 Aug 1;19(15):6623-8. doi: 10.1523/JNEUROSCI.19-15-06623.1999.

  PMID: 10414990 BACKGROUND

• Debiec J, Ledoux JE. Disruption of reconsolidation but not consolidation of auditory fear conditioning by noradrenergic blockade in the amygdala. Neuroscience. 2004;129(2):267-72. doi: 10.1016/j.neuroscience.2004.08.018.

  PMID: 15501585 BACKGROUND

• Orr SP, Metzger LJ, Pitman RK. Psychophysiology of post-traumatic stress disorder. Psychiatr Clin North Am. 2002 Jun;25(2):271-93. doi: 10.1016/s0193-953x(01)00007-7.

  PMID: 12136501 BACKGROUND

• Diergaarde L, Schoffelmeer AN, De Vries TJ. Beta-adrenoceptor mediated inhibition of long-term reward-related memory reconsolidation. Behav Brain Res. 2006 Jun 30;170(2):333-6. doi: 10.1016/j.bbr.2006.02.014. Epub 2006 Apr 5.

  PMID: 16600394 BACKGROUND

• Bernardi RE, Lattal KM, Berger SP. Postretrieval propranolol disrupts a cocaine conditioned place preference. Neuroreport. 2006 Sep 18;17(13):1443-7. doi: 10.1097/01.wnr.0000233098.20655.26.

  PMID: 16932155 BACKGROUND

• Robinson MJ, Franklin KB. Central but not peripheral beta-adrenergic antagonism blocks reconsolidation for a morphine place preference. Behav Brain Res. 2007 Aug 22;182(1):129-34. doi: 10.1016/j.bbr.2007.05.023. Epub 2007 May 24.

  PMID: 17604134 BACKGROUND

MeSH Terms

Conditions

Smoking Cessation

Interventions

Propranolol

Condition Hierarchy (Ancestors)

Health Behavior; Behavior

Intervention Hierarchy (Ancestors)

Phenoxypropanolamines; Propanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Propanols; Amines; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Polycyclic Compounds

Limitations and Caveats

Subjects were asked to not smoke for 12 hrs prior propranolol.Then were permitted to smoke throughout the week prior physiologic testing.Possibly each smoking experience presented a potential opportunity for the creation of new smoking memories.

Results Point of Contact

• Title: A. Eden Evins, MD, MPH, Director Center for Addiction Medicine
• Organization: Massachusetts General Hospital

a_eden_evins@hms.harvard.edu

617-643-4679

Study Officials

• A. Eden Evins, MD, MPH

  Massachusetts General Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director Center for Addiction Medicine

Study Record Dates

• First Submitted: June 5, 2009
• First Posted: June 9, 2009
• Study Start: April 1, 2008
• Primary Completion: July 1, 2010
• Study Completion: January 1, 2011
• Last Updated: September 19, 2014
• Results First Posted: September 19, 2014

Record last verified: 2014-09

Locations

US (1)