Nicotine Withdrawal Symptoms and Smoking Relapse

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by:
National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:
NCT01511614
First received: January 13, 2012
Last updated: September 11, 2014
Last verified: August 2014
  Purpose

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 55 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:

  • This study will involve three visits to the National Institute on Drug Abuse.
  • Participants will be screened with a medical history and physical exam. Blood and urine samples will be collected, as well as breath samples to test for recent alcohol use. Participants will also fill out questionnaires and learn about the tests at the next two visits.
  • Before each imaging visit, participants will stop smoking for 36 hours. Before one visit, participants will wear a nicotine skin patch. Before the other visit, participants will wear a placebo (dummy) patch with no nicotine. Participants will not be told which type of patch they are wearing. Participants will measure the level of carbon monoxide in their breath during both of these nonsmoking periods. They will also complete questionnaires about mood and cigarette cravings.
  • Participants will have two study visits with imaging studies to measure brain activity. Each imaging visit will last about 9 to 10 hours. The visit will involve two separate 1.5- to 2-hour scan sessions (a morning scan and an afternoon scan). These scan sessions will involve tests of concentration, memory, and reaction time. Other tests and questionnaires will also be completed outside of the scanner before and after the sessions.

Condition
Nicotine Dependence

Study Type: Observational
Study Design: Time Perspective: Cross-Sectional
Official Title: Identifying Neurobiological Mechanisms That Underlie Acute Nicotine Withdrawal and Drive Early Relapse in Smokers

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Change in BOLD signal and FC related to task parameters, Behavioral performance, and Self-reported craving, withdrawal symptoms and mood/affect. [ Time Frame: Each Scan Visit ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Smoking Abstinence as Determined by Self-Reported Tobacco Use, Urine Cotinine, and Breath CO. [ Time Frame: At Study Visits ] [ Designated as safety issue: No ]
  • MRS for glutamate concentration, Plasma ACTH and cortisol, Resting state CBF, ERP and EEG measures, craving and physiological responses to physical drug cues, self-report characterization measures, & amp; structural MRI and DTI data. [ Time Frame: At Study Visits ] [ Designated as safety issue: No ]

Estimated Enrollment: 462
Study Start Date: December 2011
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. The protocol will focus on the anhedonia, negative affect, inhibitory control deficits and impulsive decision making which accompany acute nicotine withdrawal in humans. The extent to which these acute withdrawal- related processes predict the success of smoking cessation treatment will be assessed. Secondary objectives are to understand the neurobiological basis of responsivity to nicotine replacement with respect to acute nicotine withdrawal symptoms and to examine the neurobiological mechanisms underlying motivation to quit smoking and the interaction between motivation to quit and symptoms which arise during acute withdrawal from nicotine.

Study Population:

We aim to recruit 85 nicotine-dependent individuals aged 18 to 55 years who are currently seeking treatment for smoking cessation (treatment-seeking smokers) and 35 nicotine dependent individuals aged 18-55 years who are not currently seeking treatment for smoking cessation (non-treatment seeking smokers). Nicotine dependency will based on a history of 2 or more years smoking 10 plus cigarettes per day.

Design:

The study will be a within (nicrotine deprivation) between (treatment-seeking status) subjects double blind placebo controlled design. All participants will complete two scanning sessions, each preceded by a 36 hour smoking abstinence period. During one abstinence period and scanning session participants will wear a dose-matched nicotine patch (non-deprived), and during the other abstinence period and scanning session, a placebo-patch (nicotine-deprived). Following participation in both scan sessions treatment-seeking participants will commence 12 weeks of treatment involving daily varenicline administration with weekly counseling. Follow- up assessments will be conducted with treatment-seeking smokers at 1, 6, and 12 months after their last treatment visit.

Outcome Measures:

Primary outcome measures:

  1. Change in BOLD signal and FC related to task parameters, between drug condition.
  2. Behavioral performance on each of the tasks assessing inhibitory control processes, reward responsiveness, amygdala, striatal, BNST reactivity and impulsive decision making (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.
  Eligibility

Ages Eligible for Study:   18 Years to 55 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria
  • INCLUSION CRITERIA:

All Participants must:

  • Be between the ages of 18-55. Be right-handed. Assessment tool(s): Edinburgh Handedness Inventory.
  • Be in good health. Justification: Many illnesses may alter fMRI signals as well as cognitive processes and neural functioning. Assessment tool(s): Participants will provide a brief health history during phone screening, and undergo a medical history and physical examination with a qualified IRP clinician.
  • Be free of active DSM-IV dependence, or dependence in partial remission, on alcohol or any drug except nicotine. Past active dependence is acceptable provided it is at least five years in the past and total time of active dependence did not exceed 4 years. Those with past dependence on any substance other than alcohol or marijuana may not have any current use (past 6 months) of the substance on which they were dependent. For individuals with past alcohol or marijuana dependence, current use of the previously dependent substance will be allowed providing they do not meet any current DSM-IV criteria for substance dependence, with the exception of tolerance. Justification: Dependence on other substances (drugs or alcohol) may result in unique CNS deficits that could confound results and introduce excessive variance. Assessment tool(s): The computerized SCID and clinical substance abuse/dependence assessment. While recreational/intermittent use of alcohol and/or marijuana will be tolerated in all participant groups, individuals will be excluded if they meet current or recent (within 5 years) DSM-IV diagnostic criteria for dependence on any substances. A positive drug test for marijuana will not be exclusionary as long as participants have not used in the 24hrs preceding the imaging visits. In the event of a positive drug test for marijuana, self-reports of current marijuana use will be used to differentiate intermittent/infrequent from chronic/frequent users. Given a possible link between marijuana use and psychosis (Ben Amar and Potvin, 2007) frequent users, defined as those using twice or more per week within the last month, will be excluded from participation.
  • Be able to abstain from alcohol 24hrs before each of the imaging sessions and able to moderate their caffeine intake 12hrs before each session. Justification: Alcohol and caffeine modulate neural functioning in a way that would complicate data interpretation. Assessment tool(s): Self-report and breathalyzer.
  • Must have a urine cotinine (NicAlert) level of 4 or higher and have been smoking consistently for at least one year. For lighter smokers (less than 10 cpd), this is defined as smoking at their current level or more for at least the past year (excluding any quit attempts in the last year). For heavier smokers (more than 10 cpd), they must have been smoking at least an average of 10 cpd for at least the past year (excluding quit attempts).
  • Be able to abstain from smoking for 36hrs on two occasions during the study. Justification: The present protocol will investigate the effect of acute nicotine withdrawal on affective, inhibitory control and decision making processes and their neurobiological correlates. Previous research suggests that a 36hrs deprivation period is appropriate to produce robust effects across these domains (Kozink et al., 2010a; McClernon et al., 2009b; VanderVeen, Cohen, Cukrowicz, & Trotter, 2008). To isolate effects to nicotine-withdrawal (as opposed to tobacco withdrawal), participants will be required to abstain from smoking prior to both scanning session. They will be delivered nicotine during one abstinence period (non-deprived) via a dose-matched transdermal patch, and will wear a placebo patch during the other abstinence period (nicotine-deprived). Assessment tool(s): video recorded measurement of expired CO levels plasma nicotine levels.
  • Agree to also participate in NIDA-IRP protocol 10-DA-N457.

Treatment-seeking smokers will also have to meet the following inclusion criteria:

-Be actively seeking treatment for smoking cessation and willing to engage in 12-weeks of treatment involving daily administration of Varenicline and weekly counseling sessions, as well as follow-up assessments at 1, 6 and 12 months following treatment onset.

EXCLUSION CRITERIA:

All participants will be excluded if they:

  • are not suitable to undergo an fMRI experiment due to certain implanted devices (cardiac pacemaker or neurostimulator, some artificial joints, metal pins, surgical clips or other implanted metal parts), body morphology, or claustrophobia. Justification: MR scanning is one of the primary measurement tools used in the protocol. Assessment tool(s): Prospective participants will fill out an MRI screening questionnaire and undergo an interview with an MR technologist. Questions concerning suitability for scanning will be referred to the MR Medical Safety Officer. Prospective participants will be questioned about symptoms of claustrophobia and placed in the mock scanner during their first visit to assess for possible difficulty tolerating the confinement of the scanner and for ability to fit into the scanner.
  • have coagulopathies, history of, current superficial, or deep vein thrombosis, musculoskeletal abnormalities restricting an individual s ability to lie flat for extended periods of time. Justification: MR scanning sessions require participants to lie flat on their backs and remain perfectly still for approximately two hours. Therefore, conditions that would make that difficult (e.g. chronic back pain, significant scoliosis) or dangerous (e.g. familial hypercoagulability syndrome, history of thrombosis) will be exclusionary. Assessment tool(s): History and physical examination by a qualified IRP clinician, supplemented with a trial of lying in the mock scanner to assess comfort issues.
  • have HIV or Syphilis. Justification: HIV and Syphilis both can have central nervous system (CNS) sequelae, thus introducing unnecessary variability into the data. Assessment tool(s): Oral HIV followed by blood test if oral test is + and STS+ without adequate prior treatment
  • regularly use any prescription (e.g., antidepressants, benzodiazepines, antipsychotics, anticonvulsants, barbiturates), over-the-counter (e.g., cold medicine) or herbal medication (e.g., Kava, Gingko biloba, St. John s wort) that may alter CNS function, cardiovascular function, or neuronal-vascular coupling. Justification: The use of these substances may alter the fMRI signal and/or neural functions of interest in the current study. Assessment tool(s): History and comprehensive urine drug screening to detect antidepressants, benzodiazepines, antipsychotics, anticonvulsants, and barbiturates.
  • have any current neurological illnesses including, but not limited to, seizure disorders, frequent migraines or on prophylaxis, multiple sclerosis, movement disorders, history of significant head trauma, or CNS tumor. Justification: Neurological diseases alter CNS function and, possibly, the neuronal-vascular coupling that forms the basis of the fMRI signal. Assessment tool(s): History and physical examination by a qualified IRP clinician, urine drug screening for anticonvulsants not disclosed by history. History of head trauma with loss of consciousness of more than 30 minutes or with post-concussive sequelae lasting more than two days, regardless of loss of consciousness, will be exclusionary.

The MAI who will also retain discretion to exclude based on a history of neurological illness that may compromise data integrity.

  • have any current major psychiatric disorders to include, but not limited to, mood, anxiety, psychotic disorders, or substance-induced psychiatric disorders, or any current suicidal ideations or history of suicide attempts or currently under antidepressant or antipsychotic medication treatment. The MAI will reserve the right to exclude on the basis of psychiatric history not explicitly described in this criterion Justification: Psychiatric disorders involve the central neural system (CNS) and, therefore, can be expected to alter the fMRI measures being used in this study. A recent FDA communication (2/1/2008) indicates that there may be an association between varenicline and the worsening of current psychiatric illness even if the illness is currently under control. Assessment tool(s): Computerized SCID, Beck Depression Inventory, Beck Anxiety Inventory, Adult ADHD Self-Report Scales and clinical interview confirmation by clinician.
  • are cognitively impaired or learning disabled. Justification: Cognitive impairment and learning disabilities may be associated with altered brain functioning in regions recruited during laboratory task performance. Cognitive impairment may affect one s ability to give informed consent. Assessment tool(s): History of placement in special-education classes as a consequence of serious learning problems and not solely as a consequence of behavioral problems, assessed during the History and Physical screening assessment.
  • have significant cardiovascular or cerebrovascular conditions. Justification: Such conditions may alter blood flow, the fMRI signal and other autonomic signals, and increase risks associated with nicotine patch use. Assessment tool(s): History and physical exam, including 12-lead EKG.
  • have any other major medical condition that in the view of the investigators would compromise the safety of an individual during participation. Justification: Many illness not explicitly covered here may increase risk or alter important outcome measures. Assessment tool(s): History and physical examination by a qualified IRP clinician and CBC, urinalysis, NIDA chemistry panel (liver function tests, electrolytes, kidney function). The following lab values will result in exclusion from the study:

    • Hemoglobin < 10 g/dl
    • White Blood Cell Count < 2400/(micro)l
    • Liver Function Tests > 3X normal
    • Serum glucose > 200 mg/dl
    • Urine protein > 2+
    • Serum creatinine > 2 mg/dl
    • Estimated creatinine clearance < 60ml/min

      • The MAI will retain discretion to exclude based on less extreme lab results. After the screening process has been completed, the MAI will take into account all data collected in order to decide if there is an existing medical illness that would compromise participation in this research.
  • pregnant, planning to become pregnant, or breastfeeding. Females are instructed in the consent to use effective forms of birth control during the study period. Justification: study procedures and drugs used in the current protocol may complicate pregnancy or be transferred to nursing children. Assessment tool(s): Urine and/or serum pregnancy tests, and clinical interview. Urine pregnancy tests will be conducted at the beginning of each imaging visit.

Treatment-seeking smokers will also be excluded if they:

  • have moderate to severe renal impairment. Justification. Given that renal secretion is varenicline s major route of clearance, kidney impairment may result in higher systemic levels of the drug than intended. Per Pfizer s chantix insert, varenicline pharmacokinetics were unchanged in subjects with mild renal impairment in comparison to those with normal renal function, whereas individuals with moderate and severe impairment presented with varenicline levels 1.5 and 2.1-fold higher, respectively. Assessment tool(s): Estimated glomerular filtration rate. Renal insufficiency with estimated creatinine clearance < 60 ml/min calculated by the Cockcroft-Gault equation will be excluded.
  • are diabetic. Justification. A recent case report describes multiple episodes of severe hypoglycemia experienced by a 51 year old Type-I diabetic after beginning varenicline treatment (Kristensen et al., 2008). The discontinuation of varenicline resolved any further hypoglycemic episodes. The safety of varenicline has not been investigated in patients with diabetes. Assessment tool(s): Casual plasma glucose testing. Individuals with glucose levels above 200 mg/dl may be further evaluated for diabetes using a fasting glucose test or be excluded.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01511614

Contacts
Contact: Elliot Stein, Ph.D. (443) 740-2650 estein@mail.nih.gov

Locations
United States, Maryland
National Institute on Drug Abuse Recruiting
Baltimore, Maryland, United States, 21224
Contact: For more information contact Mathew's Media Group Recruiting    800-535-8254    researchstudies@mail.nih.gov   
Sponsors and Collaborators
Investigators
Principal Investigator: Elliot Stein, Ph.D. National Institute on Drug Abuse (NIDA)
  More Information

Publications:
ClinicalTrials.gov Identifier: NCT01511614     History of Changes
Other Study ID Numbers: 999912474, 12-DA-N474
Study First Received: January 13, 2012
Last Updated: September 11, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
fMRI
Nicotine Withdrawal

Additional relevant MeSH terms:
Substance Withdrawal Syndrome
Chemically-Induced Disorders
Mental Disorders
Substance-Related Disorders
Nicotine
Autonomic Agents
Cholinergic Agents
Cholinergic Agonists
Ganglionic Stimulants
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Nicotinic Agonists
Peripheral Nervous System Agents
Pharmacologic Actions
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on October 21, 2014