High-Dose Transdermal Nicotine and Naltrexone: Effects on Nicotine Withdrawal, Urges, Smoking, and Effects of Smoking

Transcription

1 Experimental and Clinical Psychopharmacology In the public domain 2007, Vol. 15, No. 1, DOI: / High-Dose Transdermal Nicotine and Naltrexone: Effects on Nicotine Withdrawal, Urges, Smoking, and Effects of Smoking Damaris J. Rohsenow, Peter M. Monti, Kent E. Hutchison, Robert M. Swift, Selene V. MacKinnon, Alan D. Sirota, and Gary B. Kaplan Providence Veterans Affairs Medical Center and Brown University School of Medicine Although treatment with transdermal nicotine replacement (TNR) has improved smoking abstinence rates, higher doses of TNR could improve effects on urge to smoke, nicotine withdrawal, and reinforcement from smoking, and naltrexone might further reduce reinforcement and urges. A laboratory investigation with 134 smokers using a 3 2 parallel-group design evaluated the effects of TNR (42-mg, 21-mg, or 0-mg patch) as crossed with a single dose of naltrexone (50 mg) versus placebo on urge to smoke, withdrawal, and responses to an opportunity to smoke (intake, subjective effects) after 10 hr of deprivation. Urge and withdrawal were assessed both prior to and after cigarette cue exposure. Only 42 mg TNR, not 21 mg, prevented urge to smoke, heart rate change, and cue-elicited increase in withdrawal. Both 21 and 42 mg TNR blocked cue-elicited drop in heart rate and arterial pressure. Naltrexone reduced cue-elicited withdrawal symptoms but not urges to smoke or deprivationinduced withdrawal prior to cue exposure. Neither medication significantly affected carbon monoxide intake or subjective effects of smoking except that 42 mg TNR resulted in lower subjective physiological activation. No interaction effects were found, and no results differed by gender. Results suggest that starting smokers with 42 mg TNR may increase comfort during initial abstinence, but limited support is seen for naltrexone during smoking abstinence. Keywords: naltrexone, nicotine replacement, smoking, cue reactivity, nicotine withdrawal Medications could assist smokers in general who are trying to quit smoking by means of three clinical mechanisms: by reducing craving or urge to smoke 1 resulting from Damaris J. Rohsenow, Peter M. Monti, Kent E. Hutchison, Robert M. Swift, Selene V. MacKinnon, Alan D. Sirota, and Gary B. Kaplan, Research Service, Providence Veterans Affairs Medical Center, Rhode Island, and Center for Alcohol and Addiction Studies, Brown University School of Medicine. Kent E. Hutchison is now at the Department of Psychology, University of Colorado, Boulder. Selene V. MacKinnon is now at Rhode Island Center for Cognitive Behavioral Therapy, North Kingstown. Gary B. Kaplan is now at the Mental Health Service of Veterans Affairs Boston Healthcare System and in the Departments of Psychiatry and Pharmacology at Boston University School of Medicine. Robert M. Swift is a consultant with Alkermes, the makers of Vivitrol (naltrexone for extended-release injectable suspension), a treatment for alcohol dependence. He is also on the Speakers Bureau for Cephalon, which markets Vivitrol. Portions of this research were presented at the annual meeting of the College on Problems in Drug Dependence in Quebec City, Quebec, Canada, June This research was supported in part by a Merit Review Grant from the Office of Research and Development, Medical Research Service, and by a Research Career Scientist Award and a Senior Research Career Scientist Award from the Department of Veterans Affairs. Correspondence concerning this article should be addressed to Damaris J. Rohsenow, Brown University, Box G-BH, Providence, RI damaris_rohsenow@brown.edu abstinence or smoking cues, by reducing physical withdrawal, and by reducing reinforcement from smoking during a slip or lapse. The efficacy of transdermal nicotine replacement (TNR) has been attributed in part to its ability to decrease craving and withdrawal (Dale et al., 1995; Hurt, Dale, Offord, & Croghan, 1995; Jorenby et al., 1996; Levin et al., 1994). TNR also results in less subjective satisfaction and taste from cigarette smoking (Levin et al., 1994). Deprivation-induced (6 or more hr) craving was blocked by 21 mg TNR in some studies, with or without smoking-related cues (Teneggi et al., 2002; Tiffany, Cox, & Elash, 2000), but 30 mg TNR had no effect on craving after 12 hr of deprivation in another study (Havermans, Debaere, Smulders, Wiers, & Jansen, 2003). Studying the three possible mechanisms of effect in the same study could provide information about the relative effects of these mechanisms. One way to improve smoking outcomes is to modify TNR. One question is whether a higher initial dose of TNR than the dose usually recommended (21 22 mg maximum) may produce greater benefit on these mechanisms of effect. One study comparing 0, 21, 35, and 42 mg TNR found significant main effects for dose-related differences in quit rates at all follow-up points (Hughes et al., 1999), with 42 1 Following the recommendations of Kozlowski, Mann, Wilkinson, and Poulos (1989), we use the term urge rather than craving (except when referring to someone else s measure) because urge is less ambiguous and covers a broader continuum of degree of desire to smoke. 81

2 82 ROHSENOW ET AL. mg compared with 21 mg TNR resulting in 15% more of the patients having quit at 12 weeks and 6% more at 6 and 12 months (Hughes et al., 1999). A second study found that 44 mg compared with 22 mg TNR produced significantly greater abstinence at 4 weeks (23% more quit) but not thereafter (Jorenby et al., 1995). The higher dose also reduced desire to smoke in the first 4 weeks but not withdrawal in the subset who were abstinent when assessed. Studying these mechanisms unconfounded by differences in success in quitting would be informative. A second approach is to determine whether combining TNR with a second agent may increase effects on urge to smoke and withdrawal. Naltrexone is a -opiate antagonist that reduces dopaminergic transmission in the mesolimbic pathways (Kalivas & Stewart, 1991; Wise, 1988) associated with the reinforcing effects of nicotine (e.g., Balfour, 1994). Studies of effects of opiate antagonists without TNR on smoking-related variables show mixed results. Alcoholic smokers who were not trying to quit smoking smoked significantly less on 50 mg naltrexone versus placebo during 2 of the 8 weeks in the study period (Rohsenow et al., 2003). Two small laboratory studies found naloxone (another opiate antagonist) to reduce smoking rates (Gorelick, Rose, & Jarvik, 1989; Karras & Kane, 1980), whereas other studies found no effects on smoking behavior for naloxone (Nemeth-Coslett & Griffiths, 1986) or naltrexone (Sutherland, Stapleton, Russell, & Feyerband, 1995). The very low power of the small sample sizes may account for some of the discrepant results. One laboratory study found that naltrexone reduced the urge to smoke (Houtsmuller, Clemmey, Sigler, & Stitzer, 1997). Another found no effect on craving despite smoking reductions (Epstein & King, 2003), and a third found reduced smoking and lower postsmoking ratings of urge to smoke but no effect on urge to smoke before smoking (King & Meyer, 2000), whereas a fourth found that some doses of naloxone increased urges to smoke (Krishnan-Sarin, Rosen, & O Malley, 1999). Only one controlled smoking treatment trial used naltrexone without TNR; among 69 smokers, higher 4-week quit rates were found for naltrexone versus placebo for women only, with no effect on withdrawal (Covey, Glassman, & Stetner, 1999). The combined effects of TNR with naltrexone (50 mg) have been investigated in five published clinical trials. Our laboratory pilot study found that adding naltrexone versus placebo to 21 mg TNR diminished cue-elicited urge to smoke and withdrawal (Hutchison et al., 1999). In another laboratory study, naltrexone had no effect on ad lib smoking and blocked the beneficial effects of 21 mg TNR on ad lib smoking and smoking reinforcement (Brauer et al., 1999). A treatment trial of naltrexone or placebo crossed with TNR showed no effect of naltrexone on smoking rate or urge (Wong et al., 1999). A second treatment trial of naltrexone or placebo and TNR or placebo found naltrexone to reduce smoking days when n 35 (Mason, Williams, Salvato, Mestre, & Culter, 2004) but not when n 53 (Mason, 2005). A third trial that used naltrexone or placebo plus TNR reported better quit rates, lower craving, and lower smoking pleasure with naltrexone in preliminary analyses with 65 smokers, but only in women (King, Chilton, Hatsukami, & Niaura, 2003). 2 This latter treatment trial suggests that this combination of medications warrants further investigation. Effects may be moderated by gender. No laboratory study has manipulated both naltrexone and TNR for effects on urge, nicotine withdrawal, and smoking topography or intake, nor have the effects of 42 mg TNR on these variables been studied unconfounded by success at quitting. The present study investigated the effects of naltrexone (50 mg) crossed with two doses of TNR (21 mg and 42 mg) in a randomized double-blind, double-placebocontrolled study. Effects on urges to smoke, nicotine withdrawal, and responses to an opportunity to smoke briefly were studied after 10 hr cigarette deprivation. Urges and withdrawal were assessed both before and after cigarette cue exposure because deprivation in the absence of smoking cues reflects a common experience for smokers trying to quit smoking, whereas exposure to smoking cues mimics a common relapse precipitant (Shiffman, 1982). Responses to opportunity to smoke were assessed using an unobtrusive assessment of amount smoked and subjective effects of the smoking. TNR was hypothesized to dose-dependently decrease urge to smoke, nicotine withdrawal, amount smoked, and pleasurable subjective nicotine effects. Naltrexone was hypothesized to decrease urge to smoke, amount smoked, and subjective pleasure from smoking. 3 Participants Method Participants were 134 smokers (72 men, 62 women) recruited through community advertisements. (Six other recruits dropped out because of scheduling, noncompliance, or failure to appear.) All procedures were approved by the Institutional Review Board at the Providence Veterans Affairs Medical Center. Participants needed to smoke at least 15 cigarettes per day for at least 6 months, state an interest in quitting smoking in the next 6 months (to increase generalizability to motivated populations), and not be in a quit attempt or using nicotine replacement. Excluded were people with a history of opioid abuse or dependence; urine positive for opioids; use of medications that contraindicated opiate antagonists; liver function tests greater than three times normal; a medical condition that precluded participation; allergy to adhesives or acetaminophen; use of medications that would interfere with reactivity assessment (including bupropion, anticholinergics, antihistamines, tricyclic antidepressants, anxiolytics, hypnotics, beta blockers or agonists, or alpha blockers); and any women who were pregnant, nursing, or refusing to use reliable birth control. 2 An additional small treatment study (Krishnan-Sarin, Meandzija, & O Malley, 2003) is not reported because results were reported without statistical analyses and are therefore uninterpretable. 3 Although naloxone was shown to increase symptoms resembling opiate withdrawal (Krishnan-Sarin et al., 1999), effects of opiate antagonists on nicotine withdrawal symptoms in nonalcoholics have not been found (Gorelick et al., 1989; Sutherland et al., 1995).

3 HIGH-DOSE TRANSDERMAL NICOTINE WITH NALTREXONE 83 Design A2 3 randomized between-subjects parallel-groups design crossed medication (50 mg naltrexone vs. placebo) with nicotine replacement (42 mg vs. 21 mg vs. placebo). The same randomization table was used within each gender. Randomization resulted in participants per cell of this design. Overview of Procedures Participants provided written informed consent. Payment was $25 for medical screening and $120 for the study in merchandise certificates. Women participated during the first 15 days of their menstrual cycle (on the basis of self-report). Participation took 2 days up to 7 days apart: On the baseline day (DAY1) participants completed questionnaires and nondeprived baseline measures; on the medication day (DAY2) they completed measures after medication and 10 hr of smoking deprivation. On DAY2, cue reactivity assessment occurred, followed by the taste-rating task. Medication Procedures Each participant received one capsule and two patches in double-blind randomized administration. The double-ought opaque capsule contained a 50-mg tablet of generic naltrexone or a 160-mg tablet of unmarked acetaminophen, each packed with 50 mg of powdered riboflavin. Acetaminophen was used to provide a bitter medicine-like taste in case participants tried to break the blind; the child-sized dose was unlikely to relieve withdrawal. Riboflavin allowed assessment of compliance. The two unlabeled patches were either two 21-mg Nicoderm brand TNR patches (with writing removed by means of solvent), one 21-mg and one matching placebo patch, or two matching placebo patches. 4 Baseline Assessment Day (DAY1) Participants were instructed to smoke as usual during the day before coming to the lab at 4:30 p.m. and to smoke a cigarette on arrival. Informed consent was obtained. A baseline carbon monoxide (CO) assessment was collected 30 min after their last cigarette, and then participants completed questionnaires of individual differences, withdrawal, mood, and urge. The blood pressure cuff was then put on the participant s nondominant arm and the Dinamap Compact Monitor (Critikon; Tampa, FL) was started, to accustom the participant to the cycle of automatic inflations and deflations of the cuff. After several minutes of instructions, participants were instructed to sit quietly and relax for the next few minutes. The Dinamap recording was started for a 4-min baseline trial, then restarted for a startle response trial 5 (not reported herein). Afterwards, the instructions for smoking deprivation and medication administration were reviewed, and participants were provided with their medication (sealed in an envelope identified only by subject number) and an emergency card with contact numbers and information for physicians in case of an emergency. Medication Day (DAY2) For DAY2, participants were instructed to smoke their last cigarette at 7 a.m., then apply the patches; eat lunch at noon; and swallow the capsule at 1 p.m. This resulted in 10 hr of smoking deprivation, 10 hr of patch use, and 4 hr with the capsule ingested (to target peak naltrexone levels) prior to the 5 p.m. cue reactivity assessment. Participants reported to the lab at 4:30 p.m. (Some participants completed all steps 1 hr later.) See Figure 1 for an overview of procedures. On arrival, expired CO was assessed. If the CO was greater than 15 ppm, the participant was dismissed and rescheduled. If this occurred a second time, the participant was dismissed from the study. A cutoff of 15 ppm was used for compliance with the smoking restriction because it would allow very heavy smokers to comply. Although some may not have been completely abstinent with this cutoff, this level represents significant deprivation, which was the purpose of the restriction on smoking. A urine sample was collected for riboflavin assessment of capsule compliance. TNR placement was checked. The blood pressure cuff was placed on the nondominant arm. The Dinamap ran while instructions were reviewed to habituate participants to the feeling of the inflations and deflations of the cuff. Cue Reactivity Assessment Procedures were based on those described in Hutchison et al. (1999) and Sayette and Hufford (1994). Neutral and smoking cues were not counterbalanced to prevent carryover effects common with drug cues (Rohsenow & Niaura, 1999), as recommended by a consensus panel (Pickens & Johanson, 1992). During the session, all instructions were presented via audiotape. The Dinamap was restarted at the start of each trial. Participants were instructed to sit quietly and relax for 4 min (hereafter referred to as the relaxation trial), and then they completed self-report ratings. A 4-min startle procedure (not reported here) followed. During a 4-min neutral cue trial, a tray with a pencil, eraser, and small pad of paper were placed on the table, and participants were asked to hold and look at the pencil and eraser throughout the 4 min, following which they covered the cues, and the self-report measures were completed. Three 4-min smoking cue trials followed. A tray containing a pack of the participant s own brand of cigarettes, a clean ashtray, and a lighter was brought in. Participants were asked to take a cigarette out of the pack and hold it for 2 min, then light it without putting it in their mouth, and look at the lit cigarette for the next 2 min. At the end of 4 min, the participant extinguished the cigarette, covered the cues, completed the self-report measures, and had the smoking materials removed. Identical procedures were repeated in two more trials with fresh smoking cue materials. 4 Matching placebo patches were made by a pharmacist at the University of Rhode Island. 5 Headphones delivered a series of bursts of white noise, half of which were preceded by a nearly inaudible tone. Electrodes above and below the eye detected parameters of eye blink response.

4 84 ROHSENOW ET AL. Figure 1. Overview of assessment procedures on medication day after 10 hr of deprivation with transdermal nicotine replacement or placebo and 4 hr after medication or placebo. HR heart rate; MAP mean arterial pressure; CO expired carbon monoxide; MNWS Minnesota Nicotine Withdrawal Scale; BQSU Brief Questionnaire of Smoking Urges; NEQ Nicotine Effects Questionnaire; CERS Cigarette Enjoyment Rating Scale. Cigarette Taste-Rating Task The taste-rating task, which was based on the procedure used in alcohol studies (e.g., Rohsenow, 1982), followed immediately after cue reactivity assessment. The blood pressure cuff was removed. Three of the participant s own cigarettes had their brand markings obscured by tape and were labeled A, B, or C. The participant was presented with the three cigarettes, three clean ashtrays, and two questionnaires per cigarette. They were asked to taste each cigarette sequentially, extinguishing one before starting the next, smoking as much as they wanted from each cigarette, and then immediately rate each cigarette. After the task, participants completed side effects and medication beliefs measures. Measures Individual difference measures. These included demographics and smoking history. The Fagerström Test for Nicotine Dependence (Heatherton, Kozlowski, Frecker, & Fagerström, 1991) is a 6-item measure of degree of dependence on cigarettes (urgency to maintain and restore nicotine levels). Physiological measures. A Bedfont Micro III Smokerlyzer (Bedfont Scientific; Medford, NJ) assessed CO levels. Urine was centrifuged and checked for capsule ingestion using ultraviolet light detection of the riboflavin (Del Boca, Kranzler, Brown, & Korner, 1996). Heart rate in beats per minute and mean arterial pressure were collected using the Dinamap set to STAT mode, which sampled these every 15 s for a total of 16 measures per 4-min trial. During deflection, the Dinamap determines systole, then mean arterial pressure, then diastole and heart rate, using an oscillometric method of determination, with movement artifacts automatically detected and eliminated from the data. We averaged the values over each 4-min trial. Self-report measures of cue reactivity. After each cue reactivity trial, participants completed the following: The Minnesota Nicotine Withdrawal Scale (MNWS; Hughes & Hatsukami, 1986), modified by research findings (Hughes & Hatsukami, 1998) and excluding insomnia, had 6 items rated on 5-point Likert scales. The 10-item Brief Questionnaire of Smoking Urges (BQSU) was given with instructions for participants to rate how they felt right now (Cox, Tiffany, & Christen, 2001). Measure of smoke exposure in the taste-rating task. CO was assessed before and after the taste-rating task to determine the amount of CO inhaled while smoking. Posttask minus pretask CO was the measure of CO boost. Measures of subjective effects of smoking in the tasterating task. After the participant extinguished each cigarette, the following measures were completed: The Cigarette Enjoyment Rating Scale, developed for this study to provide credibility to the taste-rating task (on the basis of Rohsenow, 1982), includes 8 items (satisfying, enjoyable, tasty, strong, harsh, rich, pleasant, like the way it made me feel) rated on 11-point Likert scales from not at all (0) to extremely (10). A single rating of urge to smoke (used for brevity in these repeated measures) used the same Likert scale. The Nicotine Effects Questionnaire (NEQ; Niaura, Hitsman, Abrams, Rohsenow, & Monti, 2003) includes 15 items rated on 11-point Likert scales from not at all (0) to very much (10), with three reliable and valid components: pleasant effects (4 items), unpleasant effects (6 items), and physiological activation effects (5 items). Pleasant effects taps the dimension of liking a cigarette, whereas urge taps the dimension of wanting a cigarette (Robinson & Berridge, 1993). Because the two measures were conceptually redundant, only the NEQ was used in analyses.

5 HIGH-DOSE TRANSDERMAL NICOTINE WITH NALTREXONE 85 Measures of side effects and medication beliefs. A 24- item medication side effects checklist allowed items to be rated for severity (mild, moderate, severe) and cause (caused by medication, patch, neither). At the end, participants indicated which of the following medications they believed they received: nicotine patch, placebo patch, or I can t tell, and naltrexone, placebo, or I can t tell. Data Analysis Plan Variables were checked for assumptions of normality. Any measures repeated across three cue exposure trials or the three cigarettes were checked for reliability across trials or cigarettes using Cronbach s alpha. Credibility of the medication and placebo and differences in side effects were checked using chi-square tests. Effects of the medications and deprivation on baseline (relaxation trial) responses were investigated by comparing the DAY1 baseline measures with the DAY2 relaxation trial measures using Medication Nicotine Replacement Day (2 3 2) analyses of variance (ANOVAs). Effects of the medications on neutral cue trial responses (DAY2 unelicited effects) were investigated by using Medication Nicotine Replacement (2 3) ANOVAs. Effects of the medications on cueelicited responses on DAY2 were investigated using Medication Nicotine Replacement Trial (2 3 2) ANOVAs in which the value for the neutral cue trial was compared with the mean score for the three smoking cue trials for each measure. (The neutral cue trial values could not be used as covariates because they could be affected by the medications.) As is standard practice with these physiological measures, change scores from the relaxation trial baseline on DAY2 were used. For analyses of responses to opportunity to smoke in the taste-rating task, Medication Nicotine Replacement ANOVAs were conducted, entering separately CO boost and the mean across the three cigarettes for self-report measures. Significant nicotine replacement or interaction effects were followed up with planned comparisons. All analyses were repeated with gender as a factor in case gender interacted with medication, on the basis of the results of King et al. (2003). Statistical effect sizes for ANOVAs are reported using Cohen s f (Cohen, 1988), with f.25 being small, f being medium, and f.40 being large. Figures display only the significant effects. Preliminary Analyses Results No significant group differences in demographics and history were seen in Medication Nicotine Replacement ANOVAs and chi-squares. Gender differences were found only for age and past use of nicotine patch (see Table 1). Excellent reliability across the three cue exposure trials was found for heart rate change score (.83), mean arterial pressure change score (.96), urge (BQSU) items (.98), and withdrawal (MNWS) items (.95), so the mean of each measure across the trials was used in analyses. Excellent reliability across the three cigarettes was found for urge ratings (.89), the NEQ (.85), and each subscale of NEQ (.90 for each). NEQ scale scores and urge were averaged across the three cigarettes. Mean ( SD) time since last cigarette before DAY1 assessment started was 55 ( 117.6) min, and mean time before DAY2 assessment started was ( 1.85) hr. The mean ( SD) time lapsed between taking the medication and starting the assessment on DAY2 was 3.51 ( 0.34) hr for naltrexone or placebo and 9.57 ( 1.50) hr for TNR or placebo patch. No differences were significant by condition. Participants receiving active patches versus placebo were more likely to believe they received an active patch: 60% of Table 1 Demographic and Smoking Variables for Participants Men (n 72, 54%) Women (n 62, 46%) Variable n % M SD n % M SD Age * 11.7 Education Non-Caucasian Married or living together Employed Past week mean cigarettes/day FTND score FTND score min to first cigarette Age began daily smoking Number of serious quit attempts Ever used nicotine patch in quit attempt * 45 CO on baseline day CO after 10 hr of deprivation CO before taste test CO after taste test Note. Higher scores on the Fagerström Test for Nicotine Dependence (FTND) indicate greater dependence. CO expired carbon monoxide. * p.05.

6 86 ROHSENOW ET AL. those on the 42-mg patch, 54% on the 21-mg patch, and 30% on the 0-mg patch, 2 (4, N 134) 18.9, p.001. Participants receiving naltrexone or placebo did not differ significantly in their beliefs that they had received naltrexone, 2 (2, N 134) 1.3, ns: Across conditions 40% believed they received naltrexone, 24% believed they received placebo, and 36% had no opinion. The incidence of side effects (percentage of participants reporting the effect) did not differ significantly by group: nervousness (50%), drowsiness (48%), irritability (44%), increased appetite (34%), fatigue (33%), nausea or vomiting (25%), difficulty staying awake (23%), difficulty sleeping (22%), headache (15%), abdominal cramps (15%), low appetite (14%). Effects of Medications on Relaxation Trial Responses on DAY1 Versus DAY2 Urge to smoke. For the BQSU total score, 6 significant effects for day and for Nicotine Replacement Day (see Figure 2) 7 were found, with no other significant main or interaction effects. Urge to smoke was greater on DAY2 than on DAY1, showing that deprivation had its intended effect. Follow-up tests on the interaction showed that urge increased significantly from the nondeprived day to the deprived and medicated day in the 0- and 21-mg conditions only. Nicotine withdrawal. For MNWS, significant effects were found for the Medication Nicotine Replacement interaction, F(2, 128) 6.06, p.005, f.31, and for day, F(1, 128) 81.77, p.001, f.42, with no other significant effects. Withdrawal scores were higher on DAY2 (M SD ) than on DAY1 (M SD ). However, when the analysis was rerun on each day separately, the Medication Nicotine Replacement interaction was significant on only the unmedicated DAY1, not on DAY2, meaning that withdrawal was not significantly affected by either medication. Physiological response. For heart rate, significant effects for day and for Nicotine Replacement Day were found (see Figure 3), with no other significant effects. HR decreased significantly from the nondeprived day to the deprived medicated day only in the placebo patch and 21-mg patch conditions. For arterial pressure, significant effects for day and for Nicotine Replacement Day were found (see Figure 2), with no other significant effects. Arterial pressure decreased from the nondeprived day to the deprived medicated day only in the placebo condition. Nonsignificant effect sizes for all measures were very small (ƒs.10). Effects of Medications on Unelicited Responses to Neutral Cues on DAY2 For the DAY2 neutral cue trial urge to smoke, an effect was found for nicotine replacement, F(2, 127) 5.27, p.01, f.29, with no significant main or interaction effects for medication. Urge was significantly ( p.05) higher in the 0-mg patch condition (M SD ) than in Figure 2. Urge to smoke (Brief Questionnaire of Smoking Urges total score, shown with standard error bars) on baseline day (Day 1) and on medication day (Day 2) prior to cue exposure (collapsed across naltrexone and placebo medication conditions) for the significant day effect, F(1, 127) 15.55, p.001, ƒ.35, and Day Nicotine Replacement interaction effect, F(2, 127) 5.27, p.01, f.29. Urge increased across days only in the 0-mg, F(1, 130) 17.31, and 21-mg, F(1, 130) 8.54, ps.005, patch conditions (indicated by an asterisk). the 42-mg nicotine replacement condition (M SD ), but the 21-mg patch condition (M SD ) did not differ significantly from the 0-mg patch condition. No significant effects were found for 6 Only the BQSU total score was analyzed because there were no differential hypotheses for medication effects on positive versus negative urge scales. For exploratory purposes, all analyses of the BQSU were repeated on the subscales separately, but because the same significant effects found for the total score were also found for both subscales, these analyses were omitted. 7 Although no interactions with gender were significant in any analysis, all figures display results by gender for readers interested in seeing nonsignificant trends or lack of trends.

7 HIGH-DOSE TRANSDERMAL NICOTINE WITH NALTREXONE 87 Figure 3. Heart rate (HR) and mean arterial pressure (MAP) in the relaxation trial on baseline day (Day 1) and prior to cue exposure (collapsed across naltrexone and placebo medication conditions) on medication day (Day 2; with standard error bars) for the day main effect: HR, F(1, 122) 15.64, ƒ.35; MAP, F(1, 122) 13.52, ƒ.33, ps.001; and for the Day Nicotine Replacement interaction effect: HR, F(2, 122) 3.91, ƒ.25; MAP, F(2, 122) 3.72, ƒ.25, ps.03. HR decreased across days only in the 0-mg, F(1, 131) 19.79, p.001, and 21-mg, F(1, 131) 4.51, p.04, patch conditions (indicated by an asterisk), and MAP decreased across days only in the 0-mg condition, F(1, 131) 18.12, p.001. withdrawal, heart rate, and arterial pressure, with very small effect sizes (ƒs.00 for medication, ƒs.10 for nicotine replacement). Effects of Medications on Cue-Elicited Responses on DAY2 Urge to smoke. Across trials on DAY2, significant effects on urge were found only for nicotine replacement and for trial (see Figure 4). Overall, urge was greater in the presence of smoking cues (M SD ) than neutral cues (M SD ). Urge was significantly ( p.05) higher in the placebo (M SD ) and 21-mg (M SD ) patch conditions than in the 42-mg dose (M SD ) nicotine replacement condition. Nicotine withdrawal. Significant effects were found on withdrawal only for nicotine replacement and for the Medication Trial interaction (see Figure 5). The mean ( SD) MNWS scores by nicotine replacement condition were 6.3 ( 5.1) for the 0-mg, 6.0 ( 5.2) for the 21-mg, and 4.2 ( 3.4) for the 42-mg patch, with only placebo differing significantly from 42 mg in planned comparison tests. Withdrawal scores changed significantly from neutral to smoking cues only in the naltrexone condition (see Figure 4). Physiological response. For both heart rate change scores and mean arterial pressure change scores (see Figure 6), significant effects were found only for trial and for Nicotine Replacement Trial. In the placebo patch condition, both scores decreased significantly from neutral to smoking cues. Nonsignificant effect sizes for all measures were small (ƒs.00.15). Effects of Medications on Responses in Smoking Task CO boost from tobacco smoke exposure. For CO boost, a trend for a small effect for medication was found, F(1, 123) 3.52, p.06, f.17, without significant main or interaction effects for nicotine replacement (ƒ.00 for each). Participants given naltrexone tended to smoke less (M SD ppm) than those given a placebo capsule (M SD ppm). Self-report measures. No significant effects were found for urge to smoke or the NEQ pleasant or unpleasant effects scales (all fs.01), but for the physiological activation

8 88 ROHSENOW ET AL. were found on any measure before or during the cue reactivity session. The nonsignificant effect sizes were all very small (ƒ.10) except for two small effects (ƒs.18). Significant main effects for gender in taste-test responses included women reporting lower pleasant effects from smoking (M SD ) than men (M SD ), F(1, 113) 7.86, p.01, f.26, and reporting higher unpleasant effects from smoking (M SD ) on the NEQ than did men (M SD ), F(1, 113) 10.00, p.005, f.30. Discussion Figure 4. Urge to smoke on medication day (Brief Questionnaire of Smoking Urges total score, shown with standard error bars) by cue type (neutral vs. mean of smoking cue trials), F(1, 128) 5.47, ƒ.21, p.02, and nicotine replacement, F(1, 128) 4.99, ƒ.28, p.01, collapsed across naltrexone and placebo medication conditions. Urge was lower ( p.05) in the 42-mg versus 21-mg and 0-mg conditions in planned comparisons (differences indicated with a different letter). scale a significant effect was found for nicotine replacement, F(1, 119) 4.02, p.02, f.26. Lower ( p.05) activation was reported by participants after smoking in the 42-mg condition (M SD ) than in the 21-mg (M SD ) or 0-mg patch (M SD ) conditions. Nonsignificant effects were all very small (medication ƒs.00, nicotine replacement ƒs.10). Effects of Gender in the Analyses of Medication Effects Analyses of hypotheses were repeated adding gender as a factor. No interaction effects of medication or nicotine replacement with gender were significant, so the analyses without gender were retained. No main effects of gender Transdermal nicotine replacement reduced urge to smoke, withdrawal, and some reactions to smoking only at the 42-mg dose in general among these smokers. The 42-mg dose, but not the 21-mg dose, prevented increased urge to smoke and heart rate decrease in response to 10 hr of tobacco deprivation, resulted in lower cue-elicited urge to smoke and withdrawal, and resulted in less of a buzz (subjective physiological activation) after smoking. Finding effects of nicotine on craving regardless of whether cues are present is consistent with other studies (e.g., Tiffany et al., 2000). Possibly, differences in demographics or smoking history across studies may be found to account for the differences seen in effects for mg TNR across studies, with two studies finding helpful effects and one other study finding no effects (Havermans et al., 2003; Teneggi et al., 2002; Tiffany et al., 2000). Because nicotine replacement that is started at 21 mg or less improves smoking cessation rates only by about 10% compared with counseling alone (for meta-analysis see U.S. Department of Health and Human Services, 2000), perhaps characteristics of the successful individuals (e.g., initial weight, greater motivation, or higher tolerance for discomfort) interact in some way with TNR s pharmacologic effects. Because 21 mg TNR replaces only about half of baseline cotinine levels on average, this dose may not be as effective as is needed for many smokers, particularly heavier smokers (Hurt et al., 2003). Hurt et al. (2003) have recommended providing higher TNR so as to match baseline cotinine levels. Neither dose of TNR affected the amount of tobacco smoke exposure participants received when they were permitted to smoke or the amount of pleasure they reported after smoking; this is consistent with wanting and liking being governed by different neurological substrates (Robinson & Berridge, 1993) and suggests that altering reinforcement may not be a clinical mechanism of effect of TNR. However, both the 21- and 42-mg doses blocked the cue-elicited drop in heart rate and arterial pressure. Because heart rate deceleration may reflect an orienting response (Jennings, 1983), both doses of transdermal nicotine may make deprived smokers less likely to attend to smoking cues, a common trigger for relapse (Shiffman, 1982). Implications of these results are that many smokers may find starting with a 42-mg patch to be more comfortable during initial abstinence or helpful in preventing early relapses. It takes several days to obtain the full effects of a 21-mg patch, and most relapses occur rapidly (Garvey,

9 HIGH-DOSE TRANSDERMAL NICOTINE WITH NALTREXONE 89 Figure 5. Withdrawal (Minnesota Nicotine Withdrawal Scale score, shown with standard error bars) averaged across neutral and smoking cues on Day 2 for nicotine replacement (upper panels), F(2, 128) 3.00, ƒ.22, and for Medication (naltrexone vs. placebo medication) Cue Type interaction (lower panels), F(1, 128) 4.74, ƒ.19, ps.05. Withdrawal was lower than the 0-mg condition in the 42-mg condition only, t(131) 2.19, p.05. Withdrawal differed as a function of cue type in the naltrexone condition, F(1, 132) 5.30, ƒ.56, p.03, not the placebo condition (significant planned comparisons indicated by an asterisk). Bliss, Hitchcock, Heinold, & Rosner, 1992; Hughes et al., 1992). The 21-mg patch may have insufficient initial effect on cravings and withdrawal. The improved short-term effect on outcome for 44 mg versus 22 mg TNR seen in a treatment trial (Jorenby et al., 1995) suggests that starting people on a higher dose initially may improve initial abstinence among those able to tolerate it. Naltrexone showed a few effects during deprivation from smoking and no interaction effects with TNR. Naltrexone resulted in reduced nicotine withdrawal in response to smoking cues compared to neutral cues while not affecting withdrawal from deprivation prior to cue exposure. Therefore, naltrexone may have a protective effect in reducing withdrawal responses elicited by a high-risk situation. However, the absolute magnitude of this effect was small and naltrexone did not reduce urge to smoke before cue exposure after 10 hr of deprivation. Naltrexone also tended to result in less smoke exposure as indicated by CO boost in an unobtrusive assessment of smoking, suggesting less reinforcement from smoking, but this effect was statistically small. No interactions of naltrexone with nicotine replacement were evident, consistent with some studies but not with others reviewed earlier. Thus, there is only modest support for a role for naltrexone during early tobacco abstinence, and no clinical mechanism of effect for TNR interacting with naltrexone is apparent. However, complementary and/or additive effects of naltrexone and TNR may account for the treatment effects of the combination seen in two clinical trials (King et al., 2003; Mason et al., 2004). Naltrexone was not observed to reduce urge to smoke or nicotine withdrawal in the absence of smoking-related cues, or subjective reactions to smoking during 10 hr of abstinence. However, participants were smokers not currently trying to quit smoking participating in a laboratory paradigm of initial smoking cessation. Although these smokers were motivated to quit smoking within the next 6 months, naltrexone might be more effective among smokers more highly motivated to quit smoking. However, naltrexone s utility with smokers trying to quit is inconsistent, as reviewed earlier. The present results suggest that any useful effects may be due to dampening cue-elicited withdrawal rather than affecting urge to smoke or withdrawal in the absence of cues. Nonsignificant pharmacological effects did not appear to result from insufficient power. When effects were significant, all but two were at least medium in size (an effect

10 90 ROHSENOW ET AL. Figure 6. Heart rate (HR) and mean arterial pressure (MAP) change scores (change from 1st day resting baseline, shown with standard error bars) by cue type (neutral vs. mean of smoking cue trials): HR, F(1, 121) 5.90, ƒ.22; MAP, F(1, 120) 6.41, ƒ.23, ps.02, and interaction of cues with nicotine replacement: HR, F(2, 121) 4.33, ƒ.27; MAP, F(2, 120) 4.57, ƒ.28, ps.02. Change from neutral to smoking cues was significant only in the placebo patch condition (indicated by asterisk): HR, F(1, 130) 12.94; MAP, F(1, 129) 13.19, ps.001. likely to be visible to the naked eye of a careful observer, according to Cohen, 1992, p. 156). Nonsignificant effects were generally very small, with none in the large end of the small effect size range. Effects of TNR and of naltrexone did not differ by gender, and the nonsignificant effect sizes were all small or very small. Although the lack of gender differences for nicotine replacement are inconsistent with one meta-analysis of treatment effects of TNR (Cepeda-Benito, Reynoso, & Erath, 2004), our results are consistent with lack of gender differences in nicotine self-administration (Perkins, Gerlach, Wilson, Broge, & Fonte, 2001), in large treatment outcome analyses (Shiffman, Sweeney, & Dresler, 2005; Yudkin et al., 2004), and in other meta-analyses of smoking treatments (U.S. Department of Health and Human Services, 2000). Shiffman et al. (2005) pointed out that no treatment trial has found significant gender by TNR differences; the effect has only been seen in one meta-analysis when combining many studies, suggesting that the effect is small enough to require combined data. It is unclear what mechanism was differentially affected by gender in two treatment studies that found naltrexone effects on smoking for women only (Covey et al., 1999; King et al., 2003). Limitations of this study include recruiting only smokers not currently trying to quit smoking, dosing for only 1 day, obtaining a ceiling effect on urge, not including a lower TNR dose, including only one naltrexone dose, not observing medication administration, and not combining medication with a behavioral intervention for smoking cessation. Given the rapid relapse of many smokers, immediate effects of medications are of interest, but longer dosing could have produced different results. Although urge to smoke was significantly increased by smoking cues, the magnitude of effect was quite small so that cue exposure did not have much additional effect, consistent with some other studies (e.g., Tidey, Rohsenow, Kaplan, & Swift, 2005). It may be that the effects of 10 hr of deprivation are so strong that little additional increase can be produced by the presence of smoking cues, or it may be that anticipation of cue exposure resulted in elevated urge to smoke prior to the onset of exposure. In the first case, this same effect is likely to be true in the natural environment as well. In the second case, all trials could be said to reflect elevated urge due to cues plus deprivation. References Balfour, D. J. K. (1994). Neural mechanisms underlying nicotine dependence. Addiction, 89,

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