Smoking Cessation
Conditions
Keywords
therapeutic effects
Brief summary
To examine the effects of varenicline on the subjective, physiological and cognitive responses to intravenous nicotine. Varenicline is a partial nicotine agonist and it is approved as a treatment for smoking cessation. We predict that varenicline treatment will modify subjective, physiological and cognitive responses to IV nicotine.
Detailed description
This will be a 2-4 week double-blind, placebo-controlled study. Twenty four male and female smokers will have two 4-day treatment periods, in which they will be randomized to varenicline (1 mg/day) or placebo. During the first 3 days of each treatment period, smokers will have daily clinic visits and receive their study medication. On Day 4, subjects will come to the laboratory, where they will receive ascending doses of intravenous (IV) nicotine (0.1, 0.4, and 0.7 mg per 70kg). This procedure will allow accurate assessment of varenicline effects on the subjective, physiological and cognitive responses to nicotine. Following a washout period, subjects will be crossed over to the alternative treatment.
Interventions
DRUGVarenicline
Varenicline (1 mg per day) given for 4 days prior to laboratory session
DRUGPlacebo
Sugar Pill
DRUGIV Nic
IV Nicotine given during the laboratory session following 4 days of exposure to the study medication (varenicline or placebo). This nicotine was given during each laboratory session which followed the 4 days of exposure to either placebo then varenicline or varenicline then placebo.
Sponsors
US Department of Veterans Affairs
National Institute on Drug Abuse (NIDA)
Yale University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Female and male smokers, aged 18 to 55 years * History of smoking daily for the past 12 months, at least 15 cigarettes daily * Carbon Monoxide (Alveolar) level \> 10ppm * For women: not pregnant as determined by pregnancy screening, nor breast feeding, and using acceptable birth control methods
Exclusion criteria
* History of heart disease, renal or hepatic diseases * other medical conditions that the physician investigator deems as contraindicated for the subject to be in the study * Regular use of psychotropic medication (antidepressants, antipsychotics, or anxiolytics) * recent psychiatric diagnosis and treatment for Axis I disorders including * major depression, bipolar affective disorder, * schizophrenia and panic disorder within the past year * Current dependence on alcohol * drugs or treatments for drug * alcohol addiction within the past 5 years * Allergy to varenicline
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Subjective Responses to Intravenous Nicotine | 30 minutes after each nicotine infusion | The Drug Effects Questionaire( DEQ) is a 7-item psychometric that measures the following subjective categories: 'drug strength',' high', 'feels stimulated', 'good effects', 'bad effects', 'head rush', and 'like the drug'. Smokers rated each item on a 100 millimeter scale from not at all (a score of 0) to extremely with a maximum score of 100. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Reaction Time (RT) on Modified Stroop Task. | pre-nicotine, and 30 min after last nicotine infusion (Post-Nicotine) | A Modified stroop task was used to assess attentional responses to smoking and negative affect cues. Cues were presented as blue, red or green text. Subjects completed 2 counterbalanced blocks (60 trials per block). One block contained smoking cues and neutral cues. The other block contained negative affect cues and a different set of matched neutral cues. The 2 blocks were administered twice during each experimental session - prior to nicotine infusion, and 30 mins after the last nicotine infusion (2 hrs and 45 mins after medication dosing). The Stroop effect is a differential RT when identifying the colors of words presented as neutral cues vs. emotional cues (i.e. smoking or negative affect cues). |
| Cotinine Levels | Before each laboratory session on day 5 | Subject Cotinine Levels before each laboratory session. |
| Heart Rate | 30 minutes after each nicotine infusion | The average peak change (change score = maximum post dose score minus predose baseline) in heart rate was calculated. |
| Changes in Systolic and Diastolic Blood Pressure | 30 minutes after each nicotine infusion | The average peak change (change score = maximum post dose score minus predose baseline) in systolic and diastolic blood pressure after nicotine infusion. |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited from the New Haven Connecticut area through newspaper advertisements and fliers from the summer of 2007 thru the winter of 2008.
Pre-assignment details
There was no special pre-assignment procedures for this study. Thirty seven smokers signed a consent form with only 17 randomized. 13 smokers never return to clinic after signing a consent form. 2 smokers were excluded secondary to poor IV access. 5 smokers had dropped out due to a scheduling conflict.
Participants by arm
| Arm | Count |
|---|---|
| Entire Study Population Includes all subjects who completed the study. (The total number of subjects who were enrolled in both arms of the study.) | 12 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention | Protocol Violation | 1 | 4 |
Baseline characteristics
| Characteristic | Entire Study Population |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants |
| Age, Continuous | 34.0 years STANDARD_DEVIATION 9.3 |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 9 | 0 / 8 | 0 / 9 | 0 / 8 | 0 / 8 | 0 / 4 |
| serious Total, serious adverse events | 0 / 9 | 0 / 8 | 0 / 9 | 0 / 8 | 0 / 8 | 0 / 4 |
Outcome results
Primary
Subjective Responses to Intravenous Nicotine
The Drug Effects Questionaire( DEQ) is a 7-item psychometric that measures the following subjective categories: 'drug strength',' high', 'feels stimulated', 'good effects', 'bad effects', 'head rush', and 'like the drug'. Smokers rated each item on a 100 millimeter scale from not at all (a score of 0) to extremely with a maximum score of 100.
Time frame: 30 minutes after each nicotine infusion
Population: All participants who complete all interventions.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo, Pre-Nicotine | Subjective Responses to Intravenous Nicotine | Head Rush | 24 millimeters | Standard Error 8 |
| Placebo, Pre-Nicotine | Subjective Responses to Intravenous Nicotine | Drug Strength | 24 millimeters | Standard Error 8 |
| Placebo, Pre-Nicotine | Subjective Responses to Intravenous Nicotine | Feels Stimulated | 25 millimeters | Standard Error 8 |
| Placebo, Pre-Nicotine | Subjective Responses to Intravenous Nicotine | Bad Effects | 7 millimeters | Standard Error 3 |
| Placebo, Pre-Nicotine | Subjective Responses to Intravenous Nicotine | High | 23 millimeters | Standard Error 8 |
| Placebo, Pre-Nicotine | Subjective Responses to Intravenous Nicotine | Like the Drug | 18 millimeters | Standard Error 8 |
| Placebo, Pre-Nicotine | Subjective Responses to Intravenous Nicotine | Good Effects | 19 millimeters | Standard Error 8 |
| Placebo, Post-Nicotine | Subjective Responses to Intravenous Nicotine | High | 38 millimeters | Standard Error 10 |
| Placebo, Post-Nicotine | Subjective Responses to Intravenous Nicotine | Good Effects | 30 millimeters | Standard Error 8 |
| Placebo, Post-Nicotine | Subjective Responses to Intravenous Nicotine | Feels Stimulated | 34 millimeters | Standard Error 10 |
| Placebo, Post-Nicotine | Subjective Responses to Intravenous Nicotine | Drug Strength | 41 millimeters | Standard Error 9 |
| Placebo, Post-Nicotine | Subjective Responses to Intravenous Nicotine | Head Rush | 40 millimeters | Standard Error 9 |
| Placebo, Post-Nicotine | Subjective Responses to Intravenous Nicotine | Like the Drug | 27 millimeters | Standard Error 9 |
| Placebo, Post-Nicotine | Subjective Responses to Intravenous Nicotine | Bad Effects | 15 millimeters | Standard Error 7 |
| Varenicline, Pre-Nicotine | Subjective Responses to Intravenous Nicotine | Good Effects | 45 millimeters | Standard Error 10 |
| Varenicline, Pre-Nicotine | Subjective Responses to Intravenous Nicotine | High | 51 millimeters | Standard Error 10 |
| Varenicline, Pre-Nicotine | Subjective Responses to Intravenous Nicotine | Head Rush | 51 millimeters | Standard Error 9 |
| Varenicline, Pre-Nicotine | Subjective Responses to Intravenous Nicotine | Bad Effects | 23 millimeters | Standard Error 8 |
| Varenicline, Pre-Nicotine | Subjective Responses to Intravenous Nicotine | Feels Stimulated | 38 millimeters | Standard Error 10 |
| Varenicline, Pre-Nicotine | Subjective Responses to Intravenous Nicotine | Drug Strength | 58 millimeters | Standard Error 9 |
| Varenicline, Pre-Nicotine | Subjective Responses to Intravenous Nicotine | Like the Drug | 35 millimeters | Standard Error 10 |
| Varenicline, Post-Nicotine | Subjective Responses to Intravenous Nicotine | Good Effects | 22 millimeters | Standard Error 8 |
| Varenicline, Post-Nicotine | Subjective Responses to Intravenous Nicotine | High | 14 millimeters | Standard Error 4 |
| Varenicline, Post-Nicotine | Subjective Responses to Intravenous Nicotine | Feels Stimulated | 11 millimeters | Standard Error 4 |
| Varenicline, Post-Nicotine | Subjective Responses to Intravenous Nicotine | Head Rush | 11 millimeters | Standard Error 4 |
| Varenicline, Post-Nicotine | Subjective Responses to Intravenous Nicotine | Like the Drug | 14 millimeters | Standard Error 4 |
| Varenicline, Post-Nicotine | Subjective Responses to Intravenous Nicotine | Drug Strength | 16 millimeters | Standard Error 4 |
| Varenicline, Post-Nicotine | Subjective Responses to Intravenous Nicotine | Bad Effects | 8 millimeters | Standard Error 3 |
| Varenicline/ Medium Dose Nicotine | Subjective Responses to Intravenous Nicotine | Like the Drug | 25 millimeters | Standard Error 8 |
| Varenicline/ Medium Dose Nicotine | Subjective Responses to Intravenous Nicotine | Head Rush | 28 millimeters | Standard Error 7 |
| Varenicline/ Medium Dose Nicotine | Subjective Responses to Intravenous Nicotine | High | 27 millimeters | Standard Error 7 |
| Varenicline/ Medium Dose Nicotine | Subjective Responses to Intravenous Nicotine | Drug Strength | 32 millimeters | Standard Error 7 |
| Varenicline/ Medium Dose Nicotine | Subjective Responses to Intravenous Nicotine | Good Effects | 25 millimeters | Standard Error 8 |
| Varenicline/ Medium Dose Nicotine | Subjective Responses to Intravenous Nicotine | Bad Effects | 8 millimeters | Standard Error 3 |
| Varenicline/ Medium Dose Nicotine | Subjective Responses to Intravenous Nicotine | Feels Stimulated | 24 millimeters | Standard Error 8 |
| Varenicline/ High Dose Nicotine | Subjective Responses to Intravenous Nicotine | Bad Effects | 20 millimeters | Standard Error 8 |
| Varenicline/ High Dose Nicotine | Subjective Responses to Intravenous Nicotine | High | 37 millimeters | Standard Error 8 |
| Varenicline/ High Dose Nicotine | Subjective Responses to Intravenous Nicotine | Like the Drug | 35 millimeters | Standard Error 9 |
| Varenicline/ High Dose Nicotine | Subjective Responses to Intravenous Nicotine | Feels Stimulated | 35 millimeters | Standard Error 9 |
| Varenicline/ High Dose Nicotine | Subjective Responses to Intravenous Nicotine | Head Rush | 37 millimeters | Standard Error 8 |
| Varenicline/ High Dose Nicotine | Subjective Responses to Intravenous Nicotine | Drug Strength | 40 millimeters | Standard Error 8 |
| Varenicline/ High Dose Nicotine | Subjective Responses to Intravenous Nicotine | Good Effects | 34 millimeters | Standard Error 9 |
Comparison: A mixed-effect repeated-measures crossover model including fixed main effects for treatment condition (placebo or varenicline), time of measurement and interactions between treatment and time, was utilized. Because multiple measurements were collected before and after each nicotine dose, a change score (maximum post dose score - pre dose baseline) was used in the analysis.p-value: <0.05Mixed Models Analysis
Secondary
Changes in Systolic and Diastolic Blood Pressure
The average peak change (change score = maximum post dose score minus predose baseline) in systolic and diastolic blood pressure after nicotine infusion.
Time frame: 30 minutes after each nicotine infusion
Population: Changes in heart rate, systolic and diastolic blood pressure during the experimental sessions were analyzed on all subjects who completed both experimental sessions (n=12).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo, Pre-Nicotine | Changes in Systolic and Diastolic Blood Pressure | Diastolic Blood Pressure | 7 mm Hg | Standard Error 2 |
| Placebo, Pre-Nicotine | Changes in Systolic and Diastolic Blood Pressure | Systolic Blood Pressure | 12 mm Hg | Standard Error 4 |
| Placebo, Post-Nicotine | Changes in Systolic and Diastolic Blood Pressure | Diastolic Blood Pressure | 6 mm Hg | Standard Error 2 |
| Placebo, Post-Nicotine | Changes in Systolic and Diastolic Blood Pressure | Systolic Blood Pressure | 16 mm Hg | Standard Error 2 |
| Varenicline, Pre-Nicotine | Changes in Systolic and Diastolic Blood Pressure | Diastolic Blood Pressure | 5 mm Hg | Standard Error 1 |
| Varenicline, Pre-Nicotine | Changes in Systolic and Diastolic Blood Pressure | Systolic Blood Pressure | 8 mm Hg | Standard Error 3 |
| Varenicline, Post-Nicotine | Changes in Systolic and Diastolic Blood Pressure | Systolic Blood Pressure | 7 mm Hg | Standard Error 2 |
| Varenicline, Post-Nicotine | Changes in Systolic and Diastolic Blood Pressure | Diastolic Blood Pressure | 5 mm Hg | Standard Error 2 |
| Varenicline/ Medium Dose Nicotine | Changes in Systolic and Diastolic Blood Pressure | Systolic Blood Pressure | 13 mm Hg | Standard Error 3 |
| Varenicline/ Medium Dose Nicotine | Changes in Systolic and Diastolic Blood Pressure | Diastolic Blood Pressure | 6 mm Hg | Standard Error 2 |
| Varenicline/ High Dose Nicotine | Changes in Systolic and Diastolic Blood Pressure | Systolic Blood Pressure | 16 mm Hg | Standard Error 3 |
| Varenicline/ High Dose Nicotine | Changes in Systolic and Diastolic Blood Pressure | Diastolic Blood Pressure | 7 mm Hg | Standard Error 2 |
Secondary
Cotinine Levels
Subject Cotinine Levels before each laboratory session.
Time frame: Before each laboratory session on day 5
Population: Subjects finishing the complete study. (n=12)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo, Pre-Nicotine | Cotinine Levels | 202 ng/mL | Standard Deviation 41 |
| Placebo, Post-Nicotine | Cotinine Levels | 185 ng/mL | Standard Deviation 38 |
p-value: <0.3ANOVA
Secondary
Heart Rate
The average peak change (change score = maximum post dose score minus predose baseline) in heart rate was calculated.
Time frame: 30 minutes after each nicotine infusion
Population: Changes in heart rate, systolic and diastolic blood pressure during the experimental sessions were analyzed on all subjects who completed both experimental sessions (n=12).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo, Pre-Nicotine | Heart Rate | 7 beats per minute | Standard Error 1 |
| Placebo, Post-Nicotine | Heart Rate | 13 beats per minute | Standard Error 2 |
| Varenicline, Pre-Nicotine | Heart Rate | 16 beats per minute | Standard Error 2 |
| Varenicline, Post-Nicotine | Heart Rate | 2 beats per minute | Standard Error 2 |
| Varenicline/ Medium Dose Nicotine | Heart Rate | 5 beats per minute | Standard Error 1 |
| Varenicline/ High Dose Nicotine | Heart Rate | 5 beats per minute | Standard Error 2 |
Comparison: A mixed-effect, repeated-measures, crossover model was used with fixed main effects for treatment (placebo or varenicline), and time after treatment. Interactions between main effects were also analyzed.p-value: <0.05ANOVA
Secondary
Mean Reaction Time (RT) on Modified Stroop Task.
A Modified stroop task was used to assess attentional responses to smoking and negative affect cues. Cues were presented as blue, red or green text. Subjects completed 2 counterbalanced blocks (60 trials per block). One block contained smoking cues and neutral cues. The other block contained negative affect cues and a different set of matched neutral cues. The 2 blocks were administered twice during each experimental session - prior to nicotine infusion, and 30 mins after the last nicotine infusion (2 hrs and 45 mins after medication dosing). The Stroop effect is a differential RT when identifying the colors of words presented as neutral cues vs. emotional cues (i.e. smoking or negative affect cues).
Time frame: pre-nicotine, and 30 min after last nicotine infusion (Post-Nicotine)
Population: Data from all subjects who completed both experimental sessions (nicotine infusion after 4 days of placebo and also 4 days of varneicline, n=12) are presented. RT's \< 100 ms, or \> 1501 ms were excluded from the analysis (\>3 SD's of the mean). The data presented are the mean RT's to identifying word colors under each treatment condition.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo, Pre-Nicotine | Mean Reaction Time (RT) on Modified Stroop Task. | Neutral Block- Smoking Cue | 702.3 milliseconds | Standard Deviation 148.6 |
| Placebo, Pre-Nicotine | Mean Reaction Time (RT) on Modified Stroop Task. | Neutral Block- Negative Affect Cue | 692.5 milliseconds | Standard Deviation 117.5 |
| Placebo, Pre-Nicotine | Mean Reaction Time (RT) on Modified Stroop Task. | Negative Affect block | 679.0 milliseconds | Standard Deviation 104.1 |
| Placebo, Pre-Nicotine | Mean Reaction Time (RT) on Modified Stroop Task. | Smoking Block | 722.3 milliseconds | Standard Deviation 131.3 |
| Placebo, Post-Nicotine | Mean Reaction Time (RT) on Modified Stroop Task. | Neutral Block- Negative Affect Cue | 661.5 milliseconds | Standard Deviation 111.1 |
| Placebo, Post-Nicotine | Mean Reaction Time (RT) on Modified Stroop Task. | Negative Affect block | 641.3 milliseconds | Standard Deviation 114.9 |
| Placebo, Post-Nicotine | Mean Reaction Time (RT) on Modified Stroop Task. | Smoking Block | 693.1 milliseconds | Standard Deviation 129.4 |
| Placebo, Post-Nicotine | Mean Reaction Time (RT) on Modified Stroop Task. | Neutral Block- Smoking Cue | 686.7 milliseconds | Standard Deviation 134.1 |
| Varenicline, Pre-Nicotine | Mean Reaction Time (RT) on Modified Stroop Task. | Neutral Block- Negative Affect Cue | 644.8 milliseconds | Standard Deviation 122.8 |
| Varenicline, Pre-Nicotine | Mean Reaction Time (RT) on Modified Stroop Task. | Neutral Block- Smoking Cue | 652.1 milliseconds | Standard Deviation 115.5 |
| Varenicline, Pre-Nicotine | Mean Reaction Time (RT) on Modified Stroop Task. | Smoking Block | 660.1 milliseconds | Standard Deviation 137.8 |
| Varenicline, Pre-Nicotine | Mean Reaction Time (RT) on Modified Stroop Task. | Negative Affect block | 665.8 milliseconds | Standard Deviation 177.1 |
| Varenicline, Post-Nicotine | Mean Reaction Time (RT) on Modified Stroop Task. | Neutral Block- Negative Affect Cue | 618.6 milliseconds | Standard Deviation 108.5 |
| Varenicline, Post-Nicotine | Mean Reaction Time (RT) on Modified Stroop Task. | Neutral Block- Smoking Cue | 618.6 milliseconds | Standard Deviation 104.7 |
| Varenicline, Post-Nicotine | Mean Reaction Time (RT) on Modified Stroop Task. | Negative Affect block | 631.7 milliseconds | Standard Deviation 128.6 |
| Varenicline, Post-Nicotine | Mean Reaction Time (RT) on Modified Stroop Task. | Smoking Block | 624.2 milliseconds | Standard Deviation 100.1 |
Comparison: A mixed-effect repeated-measures crossover model with fixed main effect terms of treatment (placebo or varenicline) and time of measurement (Pre-Nicotine or Post-Nicotine) was utilized. Interactions between main effect terms were also analyzed.p-value: <0.05Mixed Models Analysis