Nicotine Withdrawal Symptoms and Smoking Relapse

Not Applicable

Completed

Conditions: Nicotine Dependence

Interventions: Device: Transcranial Direct Current Stimulation
Device: sham
Behavioral: Motivational Interviewing
Drug: Nicotine patch
Drug: Placebo patch
Drug: Varenicline Pill
Drug: Placebo pill

Registration Number: NCT01511614

Lead Sponsor: National Institute on Drug Abuse (NIDA)

Brief Summary: Background:

- Smoking is thought to cause changes in the brain that lead to addiction and craving. Smokers who try to quit experience nicotine withdrawal symptoms that include irritability, anxiety, and difficulty concentrating. These symptoms make it difficult for people to stop smoking. Many people say that they continue smoking to help relieve these symptoms, often within the first week after trying to quit. Researchers want to study what is happening in the brain to cause these symptoms, which may help identify new ways to successfully quit smoking.

Objectives:

- To study nicotine withdrawal symptoms and brain function in smokers who stop smoking for 36 hours.

Eligibility:

- Individuals between 18 and 65 years of age who smoke at least 10 cigarettes per day. Participants must be able to stop smoking for 36 hours on two occasions.

Design:

Phase 1

* This study will involve three visits to the National Institute on Drug Abuse.

* NOT be able to smoke for 36 hours before the two imaging visits.

* Wear a nicotine skin patch or a placebo (fake) patch during your 36 hour smoking abstinence period and study visits.

* Have your blood drawn to test for levels of stress-related hormones.

* Complete multiple MRI scanning sessions that last about 1.5 to 2 hours each.

* Undergo EEG (brain waves) recording.

* Answer questionnaires about how you think and feel.

* Complete various tasks and procedures inside and outside of the MRI scanner.

Phase 2

* This study will involve thirteen visits to the National Institute on Drug Abuse.

* Set a quit date and develop a treatment plan with a study therapist.

* Take Chantix (varenicline) every day for a period of 12 weeks.

* Meet for weekly and biweekly counseling sessions with a therapist.

* Answer questionnaires about how you think and feel.

Phase 3

* This study will involve three visits to the National Institute on Drug Abuse.

* Complete an MRI scanning session that will last about 20min each visit

* Meet with a study staff member on each visit who will ask you questions about your smoking behavior and how you think and feel.

Detailed Description: Objective

The primary objective of the current protocol is to gain a greater understanding of the neurobiological mechanisms underlying acute nicotine withdrawal and contributing to the maintenance of, or return to smoking behavior among nicotine-dependent individuals, in the service of developing future smoking cessation treatments. The Nicotine Withdrawal Syndrome is a major cause of failed quit attempts in smokers, and targeting this time period for intervention may help improve smoking cessation outcomes.

Study Population

We will recruit treatment seeking and non-treatment seeking smokers, as well as matched non-smoker control participants.

Design

There are 3 arms included in this protocol, each of which aims to understand the neurobiology of the Nicotine Withdrawal Syndrome during the initial quit period, with the broader goal of increasing quit success rate in the future.

Main Study: To understand (1) the acute neurobiological effects of nicotine withdrawal on treatment-seeking and non-treatment seeking smokers, (2) the long term neurobiological outcomes of varenicline treatment and smoking cessation counseling at 1, 6, and 12 months. We will recruit 85 treatment seeking and 35 non-treatment seeking smokers for a within (nicotine deprivation), between (treatment-seeking status) subjects randomized, double blind, placebo controlled study.

Motivational Interviewing Arm: (1) To increase motivation and preparation for smoking cessation treatment among individuals who express an interest in quitting smoking but are not currently ready to enter treatment, in the service of increasing quit success rate and (2) to understand the neurobiological basis of motivation to quit smoking, and the interaction between motivation to quit and mechanisms that underlie acute nicotine withdrawal. We will recruit 300 current smokers interested in quitting smoking, but not yet ready to set a quit date.

Transcranial Direct Current Stimulation (tDCS) Arm: To understand the acute effect of tDCS on 3 large-scale brain networks dysregulated in nicotine addiction and withdrawal, the Default Mode Network, the Executive Control Network, and the Salience Network. We will enroll 60 non-treatment seeking smokers, with the expectation of 35 completers; and enroll 55 non-smoking controls, with the expectation of 45 completers, for a double blind, sham controlled, randomized crossover study. Smokers will be studied in nicotine abstinence and nicotine sated conditions, as in the Main Study design.

Outcome measures

Primary outcome measures:

1. Change in BOLD signal and FC related to task parameters, between drug (or tDCS) condition.

2. Behavioral performance on each of the tasks assessing inhibitory control processes, reward responsiveness, amygdala, striatal, BNST reactivity, impulsive decision making, cue reactivity and working memory (e.g., reaction time, error rate, hit rate, reward bias).

3. Self-reported craving, withdrawal symptoms and mood/affect

4. Smoking abstinence as determined by self-reported tobacco use, urine cotinine, and breath CO.

Secondary outcome measures:

1. MRS for glutamate concentration.

2. Plasma ACTH and cortisol.

3. Resting state CBF from ASL.

4. ERP and EEG measures.

5. Ratings and scores on self-report characterization measures.

6. Structural MRI and DTI data.

7. Resting state FC at 1, 6 and 12 months post-treatment.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 112

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Main Study - Treatment	Varenicline Pill	Healthy male and female adults who smokers are actively seeking treatment for smoking cessation were asked to complete three study phases: pre-treatment study visits, treatment visits and post-treatment follow-up visits. Pre-treatment (phase 1): 2 MRI sessions: dose-matched nicotine patch or placebo patch during a 36hr smoking abstinence period completed prior to each. Within \~ 2wks of their second scan visit, participants will have 1-3 pre-treatment preparation visits with a therapist. Treatment (Phase 2): 15-18 visits over \~16-19 weeks. First dose of varenicline (0.5 - 1mg/day), 1 week prior to their quit date followed by 12wks of daily varenicline (2mg/day) as well as weekly and biweekly 30min counseling sessions. Follow-up Phase 3: visits at 1, 6, and 12 months after their last treatment visit to assess quit status and smoking abstinence since last visit, complete a series of state measures and complete a 15-20 min scan session.
active tDCS	Transcranial Direct Current Stimulation	(1) anodal left-dlPFC + cathodal right-vmPFC stimulation, with anode over the left dlPFC and cathode over the right-vmPFC; (2) cathodal left-dlPFC + anodal right-vmPFC stimulation, in which polarity is reversed between the two electrodes
sham tDCS	sham	To simulate the experience of tDCS stimulation, current is ramped on and turned off at the beginning and end of the tDCS session. An additional sham option is to have the current ramp up and down only at the beginning of the sham session, and not at the end. This second sham is supported in the literature as an effective blinding technique, which subjects cannot distinguish from active stimulation (Gandiga et al 2006, Brunoni et al 2012) . One of these sham options will be used for data that will be analyzed together, to be determined based on equipment capabilities and preliminary analysis of blinding efficacy in our cross over design. We will assess the efficacy of sham condition by providing participants and the investigator with a questionnaire on the MRI/tDCS session, wherein they will report whether they thought the tDCS session was active or sham. The MRI operator (or other non protocol personnel) will control active/sham conditions.
Main Study - Treatment	Placebo patch	Healthy male and female adults who smokers are actively seeking treatment for smoking cessation were asked to complete three study phases: pre-treatment study visits, treatment visits and post-treatment follow-up visits. Pre-treatment (phase 1): 2 MRI sessions: dose-matched nicotine patch or placebo patch during a 36hr smoking abstinence period completed prior to each. Within \~ 2wks of their second scan visit, participants will have 1-3 pre-treatment preparation visits with a therapist. Treatment (Phase 2): 15-18 visits over \~16-19 weeks. First dose of varenicline (0.5 - 1mg/day), 1 week prior to their quit date followed by 12wks of daily varenicline (2mg/day) as well as weekly and biweekly 30min counseling sessions. Follow-up Phase 3: visits at 1, 6, and 12 months after their last treatment visit to assess quit status and smoking abstinence since last visit, complete a series of state measures and complete a 15-20 min scan session.
Main Study - Treatment	Placebo pill	Healthy male and female adults who smokers are actively seeking treatment for smoking cessation were asked to complete three study phases: pre-treatment study visits, treatment visits and post-treatment follow-up visits. Pre-treatment (phase 1): 2 MRI sessions: dose-matched nicotine patch or placebo patch during a 36hr smoking abstinence period completed prior to each. Within \~ 2wks of their second scan visit, participants will have 1-3 pre-treatment preparation visits with a therapist. Treatment (Phase 2): 15-18 visits over \~16-19 weeks. First dose of varenicline (0.5 - 1mg/day), 1 week prior to their quit date followed by 12wks of daily varenicline (2mg/day) as well as weekly and biweekly 30min counseling sessions. Follow-up Phase 3: visits at 1, 6, and 12 months after their last treatment visit to assess quit status and smoking abstinence since last visit, complete a series of state measures and complete a 15-20 min scan session.
Main Study - Non-Treatment	Placebo patch	Healthy male and female adults who have a history of 1 or more years of consistently smoking cigarettes with a urine cotinine level corresponding to smoker status for the specific test being used, typically corresponding to a urine cotinine above about 200 ng/ml, but who are not currently seeking treatment for smoking cessation. Non-treatment seeking smokers will not set a quit date or make a quit attempt, will not complete a treatment program as part of this study and will not be followed up after they complete the two pre-treatment visits.
Main Study - Motivational Interviewing	Motivational Interviewing	Current smokers who meet criteria for participation but who are not currently ready to enter treatment for smoking cessation. These subjects will receive motivational interviewing to prepare them for a tobacco cigarette quit attempt.
Main Study - Treatment	Nicotine patch	Healthy male and female adults who smokers are actively seeking treatment for smoking cessation were asked to complete three study phases: pre-treatment study visits, treatment visits and post-treatment follow-up visits. Pre-treatment (phase 1): 2 MRI sessions: dose-matched nicotine patch or placebo patch during a 36hr smoking abstinence period completed prior to each. Within \~ 2wks of their second scan visit, participants will have 1-3 pre-treatment preparation visits with a therapist. Treatment (Phase 2): 15-18 visits over \~16-19 weeks. First dose of varenicline (0.5 - 1mg/day), 1 week prior to their quit date followed by 12wks of daily varenicline (2mg/day) as well as weekly and biweekly 30min counseling sessions. Follow-up Phase 3: visits at 1, 6, and 12 months after their last treatment visit to assess quit status and smoking abstinence since last visit, complete a series of state measures and complete a 15-20 min scan session.
Main Study - Non-Treatment	Nicotine patch	Healthy male and female adults who have a history of 1 or more years of consistently smoking cigarettes with a urine cotinine level corresponding to smoker status for the specific test being used, typically corresponding to a urine cotinine above about 200 ng/ml, but who are not currently seeking treatment for smoking cessation. Non-treatment seeking smokers will not set a quit date or make a quit attempt, will not complete a treatment program as part of this study and will not be followed up after they complete the two pre-treatment visits.

Primary Outcome Measures

Name	Time	Method
Behavioral Reaction Speed on the Parametric Flanker Task	During tDCS or sham stimulation. Day 1 for non-smokers. Day 1 or 2 for smokers (counterbalanced for nicotine condition)	Behavioral Reaction speed on Parametric Flanker Task. Task consisted of 3 levels of difficulty: congruent trials (where distractors are the same as the target; e.g. HHHHHHH), incongruent2 trials (where the 2 furthest distractors on each side were incongruent with the target; e.g. HHSSSHH) and incongruent3 trials (where all distractors are incongruent with the target; e.g. HHHSHHH). Table values are reaction time speeds. This table is during 2mA Anodal tDCS at the left Dorsolateral prefrontal cortex (dlPFC), 2mA Cathodal tDCS at left dlPFC, or sham stimulation (i.e. placebo).
Behavioral Accuracy on the Matching Task	During tDCS or sham stimulation. Day 1 for non-smokers. Day 1 or 2 for smokers (counterbalanced for nicotine condition)	Behavioral Performance on the Matching Task. Task consisted of 2 conditions: match faces, where 2 faces appeared at the top of the screen and one at the bottom (target). Participants needed to press a button corresponding to the top row face that matched the target; the control condition was identical, except instead of faces the images consisted of simple shapes (e.g. ovals). Table values are accuracy as a percentage (i.e total times they reponded correctly / total trials). This table is during 2mA Anodal tDCS at the left Dorsolateral prefrontal cortex (dlPFC), 2mA Cathodal tDCS at left dlPFC, or sham stimulation (i.e. placebo).
Behavioral Reaction Speed on the Matching Task	During tDCS or sham stimulation. Day 1 for non-smokers. Day 1 or 2 for smokers (counterbalanced for nicotine condition)	Behavioral Reaction speed on the Matching Task. Task consisted of 2 conditions: match faces, where 2 faces appeared at the top of the screen and one at the bottom (target). Participants needed to press a button corresponding to the top row face that matched the target; the control condition was identical, except instead of faces the images consisted of simple shapes (e.g. ovals).Table values are reaction time speeds. This table is during 2mA Anodal tDCS at the left Dorsolateral prefrontal cortex (dlPFC), 2mA Cathodal tDCS at left dlPFC, or sham stimulation (i.e. placebo).
Nicotine Withdrawal From WSWS	12 hours nicotine abstinent (plus 1-2 hours after patch)	Nicotine withdrawal as measured from the total score on the Wisconsin Smoking Withdrawal Scale (WSWS). The WSWS is a 28-item questionnaire ranging from 0 (strongly disagree) to 4 (strongly agree). The total score ranges from 0 to 112, with higher scores indicating more withdrawal symptoms. Cigarette smokers were 12 hour (overnight) abstinent and had either a nicotine patch or a placebo patch placed 1-2 hours before scanning.
Nicotine Craving From TCQ-SF	12 hours nicotine abstinent (plus 1-2 hours after patch)	Nicotine craving as measured from the total score on the Tobacco Craving Questionnaire-Short Form (TCQ-SF). The TCQ-SF is a 12-item questionnaire designed to measure craving for cigarettes. Each question is answered on a 7-point scale from 1 (Strongly Disagree) to 7 (Strongly Agree). Total scores range from 12 to 84, with higher scores indicating more craving. Cigarette smokers were 12 hour (overnight) abstinent and had either a nicotine patch or a placebo patch placed 1-2 hours before scanning.
BOLD Activation in Right ACC During Parametric Flanker Task tDCS Stimulation	During tDCS or sham stimulation. Day 1 for non-smokers. Day 1 or 2 for smokers (counterbalanced for nicotine condidtion)	BOLD percent signal change in right Anterior Cingulate Cortex (rACC) during parametric flanker task. This table is during 2mA Anodal tDCS at the left Dorsolateral prefrontal cortex (dlPFC), 2mA Cathodal tDCS at left dlPFC, or sham stimulation (i.e. placebo). The 3 task conditions are congruent (i.e. flanker stimuli are identical to target) and medium and high levels of incongruent.
dACC Glutamate	12 hours nicotine abstinent (plus 1-2 hours after patch)	Glutamate measured in the dorsal Anterior Cingulate Cortex (dACC) measured as a ratio to Creatine and Phosphocreatine. Cigarette smokers were 12 hour (overnight) abstinent, and had either a nicotine patch or a placebo patch placed 1-2 hours before scanning.
Behavioral Accuracy on N-Back Working Memory Task	During tDCS or sham stimulation. Day 1 for non-smokers. Day 1 or 2 for smokers (counterbalanced for nicotine condition)	Behavioral Performance on N-Back Working Memory Task. Task consisted of 0-back, 1-back and 3-back. In this task, participants respond with a button when the current stimulus is the same as the previous one (1-back), the one 3 stimuli earlier (3-back) or the letter 'D' (0-back) depending upon task condition. Table values are accuracy as a percentage (i.e total times they reponded correctly / total trials). This table is during 2mA Anodal tDCS at the left Dorsolateral prefrontal cortex (dlPFC), 2mA Cathodal tDCS at left dlPFC, or sham stimulation (i.e. placebo).
Behavioral Reaction Speed on N-Back Working Memory Task	During tDCS or sham stimulation. Day 1 for non-smokers. Day 1 or 2 for smokers (counterbalanced for nicotine condition)	Behavioral Performance on N-Back Working Memory Task. Task consisted of 0-back, 1-back and 3-back. In this task, participants respond with a button when the current stimulus is the same as the previous one (1-back), the one 3 stimuli earlier (3-back) or the letter 'D' (0-back) depending upon task condition. Table values are reaction time speeds. This table is during 2mA Anodal tDCS at the left Dorsolateral prefrontal cortex (dlPFC), 2mA Cathodal tDCS at left dlPFC, or sham stimulation (i.e. placebo).
Behavioral Accuracy on the Parametric Flanker Task	During tDCS or sham stimulation. Day 1 for non-smokers. Day 1 or 2 for smokers (counterbalanced for nicotine condition)	Behavioral Performance on Parametric Flanker Task. Task consisted of 3 levels of difficulty: congruent trials (where distractors are the same as the target; e.g. HHHHHHH), incongruent2 trials (where the 2 furthest distractors on each side were incongruent with the target; e.g. HHSSSHH) and incongruent3 trials (where all distractors are incongruent with the target; e.g. HHHSHHH). Table values are accuracy as a percentage (i.e total times they reponded correctly / total trials). This table is during 2mA Anodal tDCS at the left Dorsolateral prefrontal cortex (dlPFC), 2mA Cathodal tDCS at left dlPFC, or sham stimulation (i.e. placebo).
Affect From PANAS	12 hours nicotine abstinent (plus 1-2 hours after patch)	Positive and Negative mood from the Positive and Negative Affect Schedule (PANAS). The PANAS consists of 20 words related to emotions that participants indicate to what extent they felt this way in the last week. Words are rated from 1 (very slightly or not at all) to 5 (extremely). The PANAS is broken into a Positive and Negative subscale, each consisting of 10 questions and thus ranging from 10 to 50. Higher numbers are indicative of higher levels of positive affect and higher levels of negative affect respectively. Cigarette smokers were 12 hour (overnight) abstinent, and had either a nicotine patch or a placebo patch placed 1-2 hours before scanning.