The transdermal nicotine patch is one of the most widely. Article. Effectiveness of Extended-Duration Transdermal Nicotine Therapy A Randomized Trial

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1 Annals of Internal Medicine Effectiveness of Extended-Duration Transdermal Nicotine Therapy A Randomized Trial Robert A. Schnoll, PhD; Freda Patterson, PhD; E. Paul Wileyto, PhD; Daniel F. Heitjan, PhD; Alexandra E. Shields, PhD; David A. Asch, MD; and Caryn Lerman, PhD Background: Tobacco dependence is a chronic, relapsing condition that may require extended treatment. Objective: To assess whether extended-duration transdermal nicotine therapy increases abstinence from tobacco more than standard-duration therapy in adult smokers. Design: Parallel randomized, placebo-controlled trial from September 2004 to February Participants and all research personnel except the database manager were blinded to randomization. (ClinicalTrials.gov registration number: NCT ) Setting: Academic center. Participants: 568 adult smokers. Intervention: In an unstratified small block randomization scheme, participants were randomly assigned to standard therapy (Nicoderm CQ [GlaxoSmithKline, Research Triangle Park, North Carolina], 21 mg, for 8 weeks and placebo for 16 weeks) or extended therapy (Nicoderm CQ, 21 mg, for 24 weeks). Measurements: The primary outcome was biochemically confirmed point-prevalence abstinence at weeks 24 and 52. Secondary outcomes were continuous and prolonged abstinence, lapse and recovery events, cost per additional quitter, and side effects and adherence. [95% CI, 1.23 to 2.66]; P 0.002), prolonged abstinence (41.5% vs. 26.9%; odds ratio, 1.97 [CI, 1.38 to 2.82]; P 0.001), and continuous abstinence (19.2% vs. 12.6%; odds ratio, 1.64 [CI, 1.04 to 2.60]; P 0.032) versus standard therapy. Extended therapy reduced the risk for lapse (hazard ratio, 0.77 [CI, 0.63 to 0.95]; P 0.013) and increased the chances of recovery from lapses (hazard ratio, 1.47 [CI, 1.17 to 1.84]; P 0.001). Time to relapse was slower with extended versus standard therapy (hazard ratio, 0.50 [CI, 0.35 to 0.73]; P 0.001). At week 52, extended therapy produced higher quit rates for prolonged abstinence only (P 0.027). No differences in side effects and adverse events between groups were found at the extended-treatment assessment. Limitation: The generalizability of the findings may be limited because participants were smokers without medical comorbid conditions who were seeking treatment, and differences in adherence across treatment groups were detected. Conclusion: Transdermal nicotine for 24 weeks increased biochemically confirmed point-prevalence abstinence and continuous abstinence at week 24, reduced the risk for smoking lapses, and increased the likelihood of recovery to abstinence after a lapse compared with 8 weeks of transdermal nicotine therapy. Primary Funding Source: National Institutes of Health. Results: At week 24, extended therapy produced higher rates of point-prevalence abstinence (31.6% vs. 20.3%; odds ratio, 1.81 Ann Intern Med. 2010;152: For author affiliations, see end of text. The transdermal nicotine patch is one of the most widely used tobacco dependence treatments in the United States (1, 2) and Europe (3, 4). Current guidelines for transdermal nicotine recommend 8 weeks of treatment (5). However, the evidence for this recommendation is limited. A meta-analysis comparing nicotine patch trials with 8 weeks or less of treatment versus those with more than 8 weeks of treatment found no difference in quit rates; however, almost all extended-therapy trials were less than 12 weeks in duration (6). Only 1 large randomized, placebo-controlled trial compared standard (8 weeks) with extended (22 weeks) transdermal nicotine therapy (7). Although this trial found no See also: Print Editors Notes Summary for Patients....I-38 Web-Only Appendix Tables Conversion of graphics into slides difference in rates of continuous abstinence between groups, more recent guidelines view continuous abstinence measures as too conservative because smokers who have early lapses but recover are counted as treatment failures (8). This may be particularly important for rescue therapies, such as transdermal nicotine, which increase the likelihood of recovery from smoking lapses (9). Growing recognition indicates that nicotine dependence is a chronic, relapsing condition that may require extended therapy to treat effectively (10 12). Furthermore, the 2008 U.S. Public Health Service Guidelines (5) have called for research on the efficacy of extended therapy for nicotine dependence. We evaluated the relative efficacy of extended (24 weeks) versus standard (8 weeks) transdermal nicotine therapy for promoting biochemically confirmed point-prevalence abstinence at weeks 24 and 52 among adult smokers. METHODS Design We enrolled smokers who sought treatment from October 2004 to March 2008 into a parallel randomized, American College of Physicians

2 Extended Treatment of Tobacco Dependence placebo-controlled trial of standard therapy (transdermal nicotine for 8 weeks and placebo for 16 weeks) versus extended therapy (transdermal nicotine for 24 weeks). Participants and all study personnel, except for the database manager, were blinded to randomization. The primary outcome was biochemically confirmed point-prevalence abstinence at weeks 24 and 52. We completed assessments in March Participants provided informed consent, and the institutional review board at the University of Pennsylvania, Philadelphia, Pennsylvania, approved the procedures. Setting and Participants We conducted our trial at the University of Pennsylvania. We recruited participants through advertisements for a free smoking cessation program. Participants were eligible if they were aged 18 to 65 years and smoked 10 or more cigarettes per day for at least the past year. Exclusions included pregnancy or lactation, uncontrolled hypertension, unstable angina, heart attack or stroke within the previous 6 months, recent diagnosis of cancer or kidney or liver failure, a history of organ transplantation, current diabetes, drug or alcohol dependence, history of an Axis I psychiatric disorder, current use of a concomitant medication, or current treatment of nicotine addiction. Randomization and Interventions Once we confirmed eligibility (by telephone and in person), we randomly assigned participants at week 2 by using a computer-based randomization table provided by a statistician who used Stata, version 8 (StataCorp, College Station, Texas) and a computer program overseen by the database manager. A nonstratified randomization scheme was generated by sampling without replacement and by using small blocks of 20 participants. The 24-week supply of patches was prepackaged and coded with participant identification. The computer program linked the randomization to the patch supply, and only the database manager could link identification with treatment allocation. Behavioral counseling (13) was provided at weeks 2, 0, 1, 4, 8, 12, 16, and 20. Five counselors provided the same counseling to both treatment groups; they were trained by using a manual and were supervised to ensure adherence. At week 2, counseling focused on developing techniques for preparing to quit. At week 0, the quit date, counseling focused on managing withdrawal. The remaining sessions focused on relapse prevention. Participants initiated patch use on the quit date (week 0). Participants received a 21-mg transdermal nicotine patch (Nicoderm CQ, GlaxoSmithKline, Research Triangle Park, North Carolina) for 8 weeks plus a placebo patch for 16 weeks or a 21-mg transdermal nicotine patch for 24 weeks. Outcomes and Measurements Screening and Pretreatment Measures We assessed medication use and history of medical illnesses. We used standard diagnostic criteria from the Diagnostic and Statistical Manual of Mental Disorders, Context Tobacco dependence, a sometimes chronic, relapsing condition, may require extended treatment. Contribution This randomized trial of 568 long-term smokers found higher abstinence rates at 24 weeks for those who received extended nicotine therapy (nicotine patch, 21 mg, for 24 weeks) versus standard nicotine therapy (nicotine patch, 21 mg, for 8 weeks and placebo patch for 16 weeks). However, at 52 weeks, similar numbers in both groups (about 14%) were abstinent. Caution Smokers with comorbid conditions were excluded. Some participants did not provide complete abstinence data. Implication Extended therapy with transdermal nicotine helps some adults quit smoking, but benefits may persist only while treatment is maintained. The Editors fourth edition, to screen for psychiatric illnesses during the structured clinical interview (14). We assessed demographic information (for example, age) and smoking rate, and we used the Fagerström test for nicotine dependence to assess participants degree of nicotine dependence (15). Outcome Measures We assessed daily smoking from the quit date to week 52 by using a timeline follow-back method (16). We asked participants who reported no smoking for the 7 days before weeks 8, 24, and 52 to visit the study site to provide a breath sample for assessment of carbon monoxide levels (17). As recommended (8), the primary outcome was 7-day point-prevalence abstinence at weeks 24 and 52, and we included secondary measures of abstinence to capture different quitting patterns (for example, continuous and prolonged abstinence), including the timing and processes of lapse, relapse, and recovery events (8, 9, 18, 19). Primary Outcome Seven-day point prevalence abstinence is self-reported nonsmoking for 7 days before the assessment, verified by carbon monoxide level ( 10 ppm) (17). We assumed that participants had smoked if they were lost to follow-up, could not provide a carbon monoxide sample, or had carbon monoxide levels greater than 10 ppm (17). Secondary Outcomes Continuous abstinence, a stringent measure of abstinence, refers to self-reported nonsmoking (not even a puff) from the quit date to a follow-up assessment (8). Pro- 2 February 2010 Annals of Internal Medicine Volume 152 Number 3 145

3 Extended Treatment of Tobacco Dependence Figure 1. Study flow diagram. Telephone assessment of eligibility (n = 3276) Attended in-person eligibility screening (n = 623) Allocated to standard therapy (n = 287) Lost to follow-up at 24 wk (n = 74) Declined or missed CO visit: 26 Could not be reached: 48 Lost to follow-up at 52 wk (n = 81) Declined or missed CO visit: 20 Could not be reached: 61 Analyzed (n = 286) Randomly assigned (n = 575) Excluded (n = 2653) Did not meet inclusion criteria: 1977* Declined in-person eligibility screening: 620 Did not attend in-person eligibility screening: 56 Excluded (n = 48) Time: 3 Addiction: 3 Asthma medication: 3 Cancer: 1 Contraindicated medication: 9 Psychiatric medications: 7 Heart diseases: 3 High blood pressure: 16 Steroids: 1 Bupropion: 1 Drug or alcohol treatment: 1 Allocated to extended therapy (n = 288) Lost to follow-up at 24 wk (n = 64) Declined or missed CO visit: 38 Could not be reached: 26 Lost to follow-up at 52 wk (n = 79) Declined or missed CO visit: 30 Could not be reached: 49 Analyzed (n = 282) CO carbon monoxide. * A list of the reasons for participant ineligibility can be provided on request. Inclusion and exclusion criteria listed in the text were identical for telephone and in-person eligibility assessments. Indicates participants included in the intention-to-treat analysis. One participant became ineligible after being randomly assigned and before receiving treatment. Six participants became ineligible after being randomly assigned and before receiving treatment. longed abstinence refers to sustained abstinence from the quit date to a follow-up assessment (8). A key aspect of prolonged abstinence is a grace period, which captures delayed treatment effects (8). For prolonged abstinence, relapse is 7 consecutive days of self-reported smoking from the quit date to weeks 24 and 52 after a 2-week grace period (which means that smoking during the first 14 days after the quit date was not considered a lapse) (8). Time to relapse refers to the time from the quit date until a relapse (7 consecutive days of self-reported smoking). We used this measure in survival models. For lapse and recovery events, a smoking lapse was any day from the quit date to the 24- and 52-week assessments on which participants smoked (even a puff); recovery was any 24-hour period of self-reported abstinence after lapse (19). The outcome of interest was time to transition between runs of smoking days and runs of abstinent days. We asked participants at each assessment if they incurred any direct costs (for example, physician fee or copay or prescription or nonprescription medications) or indirect costs (for example, lost wages to seek medical attention) between the time points as a result of study participation. The primary cost outcome was the incremental cost per additional quitter by treatment group at week 24. Follow-up Procedures and Monitoring Research assistants, blinded to randomization, collected self-reported measures in person at weeks 0, 1, 4, 8, 12, 16, and 20 and by telephone at weeks 24 and 52. Side Effects We assessed side effects by using a 15-item symptom checklist (13) at weeks 0, 1, 4, 8, 12, 16, 20, 24, and 52. This checklist contained symptoms, rated from none to severe (1 to 4), that may occur from nicotine patch use (for example, nausea or skin reaction). Self-reported serious symptoms were those rated severe. We asked participants to contact study personnel if they had any serious medical problems, and research assistants used an open-ended question after the checklist to identify additional serious adverse events. Adverse events were considered serious if the participant considered them debilitating or if they required hospitalization. Serious adverse events were reported to the University of Pennsylvania institutional review board and were classified as related or unrelated to treatment group allocation. Adherence Patch adherence was based on self-report during weeks 0 to 24. We classified participants as adherent if they used 6 or more patches per week (20). We conducted treatment group comparisons of weekly patch adherence for weeks 1, 4, 8, 12, 16, 20, and 24. We also tracked counseling attendance (weeks 2, 0, 1, 4, 8, 12, 16, and 20). At weeks 24 and 52, we queried use of other forms of nicotine replacement therapy or bupropion February 2010 Annals of Internal Medicine Volume 152 Number 3

4 Extended Treatment of Tobacco Dependence A senior data manager oversaw quality control. We used Microsoft Access (Microsoft, Redmond, Washington) for data entry, validation, storage, retrieval, and security and ensured data integrity through range and validity checks during data entry. Data quality assurance reports were generated weekly to summarize production activity and to monitor quality control. Statistical Analysis The target sample size was 600 participants, which provided 80% power to detect an odds ratio for a treatment group effect of We conducted analyses by using Stata, version 8, and included all eligible randomly assigned patients. We used longitudinal logistic regression with generalized estimating equations to analyze 24- and 52-week abstinence rates. We used Cox regression to model time to relapse (stratified by time: weeks 1 to 8, 9 to 24, and 25 to 52). All models included terms for age, Fagerström test for nicotine dependence, and sex because these factors predicted study retention. Multivariate timeto-event models determined whether treatment group predicted transitions from abstinence to lapse and from lapse to recovery (19). This type of alternating-state, multivariate data consists of times to transition between runs of smoking days ( 1 day) and runs of abstinent days ( 1 day) (21). We evaluated up to 8 cycles of lapse and recovery events. Participants could cycle through several events, and we stratified risk sets (those currently abstinent for lapse events and those currently smoking for recovery events) as weeks 1 to 8, weeks 9 to 24, and weeks 25 to 52. We examined Weibull parametric survival models to account for treatment group effects and other covariates (22), and we adjusted SEs for repeated measures by using the clustercorrelated robust variance estimate (23). We used Schoenfeld residuals to test the proportional hazards assumption. Participants lost to follow-up on the timeline follow-back (for time-to-event analyses) were censored at that time (removed from the risk set without registering an event).we used chi-square tests to assess differences between treatment groups in side effects, adherence, and use of other smoking cessation treatments. To capture the periods when symptoms peak (24), analyses of side effects focused on the first week after the quit date (week 1) and 1 month after the transition to placebo versus extended therapy (week 12). Direct and indirect costs incurred up to week 52 across treatment groups were compared, and the incremental cost per additional quitter at week 24 by treatment group was estimated, computing a CI using the Fieller method (25). Treatment cost estimates (from were $120 for counseling (both groups), $140 for standard therapy, and $420 for extended therapy. Role of the Funding Source The National Institutes of Health funded this work. The funding source had no role in the study design, collection and analysis of data, writing of the manuscript, or decision to submit this manuscript for review. RESULTS We randomly assigned 287 persons to standard therapy and 288 to extended therapy. One person in the standard group and 6 in the extended group were ineligible because of medical contraindications after randomization but before treatment began, and we excluded them from the intention-to-treat sample (Figure 1). Participant baseline characteristics were similar across treatment groups (Table 1). No crossover of assignments occurred. We assessed the rate of missing survey data by time and treatment (Appendix Table 1, available at Completion rates at week 24 were higher for extended versus standard therapy (91% vs. 83%; P 0.007), but completion rates at week 52 were similar for extended and standard therapy (83% vs. 79%; P 0.23). Ninety-seven participants (17.1%) had timeline follow-back data that ended before week 52, but this was unrelated to treatment group. The number of missing cost measures per participant ranged from 0 (226 participants) to 10 (7 participants). A greater proportion of participants allocated to standard therapy than those allocated to extended therapy had missing cost measures. We excluded the 7 participants who had no cost measures from the cost analysis. For the remaining 335 participants who had 1 to 9 missing cost measures, we imputed an average for cost per item. Participants who did not respond to the survey at week 24 were younger, had higher Fagerström test for nicotine dependence scores, and reported smoking more cigarettes per day. Participants who Table 1. Participant Characteristics, by Treatment Group Characteristic Standard-Therapy Group (n 286) Extended-Therapy Group (n 282) Overall (n 568) Women, % Mean age (SD), y 44.9 (10.4) 44.8 (10.2) 44.8 (10.3) Education beyond high school, % European ancestry, % Mean FTND score (SD) 5.3 (2.1) 5.2 (2.2) 5.3 (2.1) Mean cigarettes per day (SD), n 21.3 (9.0) 21.1 (9.5) 21.2 (9.2) Mean plasma cotinine level (SD), ng/ml (110.2) (122.9) (116.6) FTND Fagerström test for nicotine dependence. 2 February 2010 Annals of Internal Medicine Volume 152 Number 3 147

5 Extended Treatment of Tobacco Dependence Table 2. Point-Prevalence Abstinence at Weeks 8, 24, and 52 Time Point Standard-Therapy Group (n 286), n (%) Extended-Therapy Group (n 282), n (%) Odds Ratio (95% CI)* Week 8 86 (30.1) 98 (34.8) 1.23 ( ) 0.25 Week (20.3) 89 (31.6) 1.81 ( ) Week (14.3) 41 (14.5) 1.01 ( ) 0.95 Week 24 vs ( ) Week 52 vs ( ) * An odds ratio greater than 1 favors the extended-therapy group. The model controlled for age and sex, which were not related to quit rates, as well as level of nicotine dependence, which was related to quit rates (odds ratio, 0.68 [95% CI, ]; P 0.021). Participants who reported lower nicotine dependence were more likely to maintain abstinence across time points. P Value did not respond to the survey at week 52 were younger. No additional participant characteristic (Table 1) was related to survey completion. Abstinence The odds of point-prevalence abstinence were about 2 times greater for extended versus standard therapy at week 24 (31.6% vs. 20.3%; odds ratio [OR], 1.81 [95% CI, 1.23 to 2.66]; P 0.002) (Table 2). At week 24, extended versus standard therapy had higher rates of prolonged abstinence (41.5% vs. 26.9%; OR, 1.97 [CI, 1.38 to 2.82]; P 0.001) and continuous abstinence (19.2% vs. 12.6%; OR, 1.64 [CI, 1.04 to 2.60]; P 0.032). In contrast, at week 52, extended and standard therapy did not differ in point-prevalence abstinence (14.5% vs. 14.3%; OR, 1.01 [CI, 0.63 to 1.62]; P 0.95) or continuous abstinence (0.7% vs. 1.0%; OR, 0.67 [CI, 0.11 to 4.05]; P 0.67), but prolonged abstinence at week 52 differed (29.1% vs. 21.3%; OR, 1.55 [CI, 1.05 to 2.28]; P 0.027). Time to relapse (any self-reported smoking event) was similar across treatment groups up to week 8, when all participants were receiving active treatment (hazard ratio [HR], 0.79 [CI, 0.58 to 1.07]; P 0.133) (Figure 2). From week 9 to 24, the rate of relapse was slower for those receiving extended versus standard therapy (HR, 0.50 [CI, 0.35 to 0.73]; P 0.001). Time to relapse did not differ across treatment groups from week 25 to 52 (HR, 1.52 [CI, 0.84 to 2.74]; P 0.163). In the analysis of transitions from alternating periods of abstinence and smoking, extended therapy also reduced the speed at which participants lapsed during weeks 9 to 24 (HR, 0.77 [CI, 0.63 to 0.95]; P 0.013) and increased the speed of recovery from a lapse during this interval (HR, 1.47 [CI, 1.17 to 1.84]; P 0.001) (Appendix Table 2, available at Side Effects and Adherence Table 3 shows adverse event data. Three extendedtherapy recipients reported a serious adverse event (myocardial infarction, hypertension, or fainting from blood draw), and 1 standard-therapy recipient reported a serious adverse event (skin redness). All adverse events occurred before week 8, and the myocardial infarction occurred before transdermal nicotine therapy was started; thus, all serious adverse events were not related to extended therapy. Only the participant who had myocardial infarction withdrew from the trial. Extended-therapy recipients had a greater frequency of sleep problems at week 1 versus standard-therapy recipients; no other differences were detected. No differences between treatment groups were found in rates of adherence to the patch at weeks 1, 4, and 8. Compared with standard-therapy participants, extendedtherapy participants reported higher patch adherence at weeks 12 (P 0.001), 16 (P 0.001), 20 (P 0.005), and 24 (P 0.001). Adherence rates were 86% (week 1), 69% (week 4), 56% (week 8), 38% (week 12), 34% (week 16), 32% (week 20), and 25% (week 24) for standard therapy and 85% (week 1), 68% (week 4), 64% (week 8), 53% (week 12), 49% (week 16), 44% (week 20), and 40% (week 24) for extended therapy. Rates of counseling adherence did not differ at weeks 2, 0, 1, and 4 across treatment groups. Compared with standard-therapy participants, extended-therapy participants had higher rates of counseling adherence at weeks 8 (P 0.014), 12 (P 0.001), 16 (P 0.001), and 20 (P 0.001) (Appendix Table 1). We found no differences in use of other nicotine replacement therapies or use of bupropion across treatment groups at week 24. At week 52, 3 participants in the extended-therapy group and no participants in the standard-therapy group reported use of nicotine lozenges (P 0.033). Costs Twenty-four participants (4.2%) reported nonzero outof-pocket costs of treatment. Thirteen participants (2.3%) reported direct costs ranging from $15 to $200 for visiting a health professional (for example, copays); 4 participants (0.7%) reported indirect costs ranging from $10 to $700 for seeing a health professional (for example, lost wages). Seventeen participants (3.0%) reported medication and other health care costs ranging from $3 to $300. After adjustment for session, sex, and treatment group, the average total per-person cost incurred beyond protocol-related counseling and drug treatment was $3.92. We found no difference for costs between treatment groups. Because February 2010 Annals of Internal Medicine Volume 152 Number 3

6 Extended Treatment of Tobacco Dependence these costs were modest and did not differ across groups, we excluded them from subsequent analyses. We estimated the incremental cost per additional quitter for extended versus standard therapy at week 24 as the difference in treatment costs between the treatment groups divided by the difference in point-prevalence quit rates at week 24, or ($420 $140)/( ). The incremental cost of extended versus standard therapy was $2482 per additional quitter (CI, $1519 to $6781). DISCUSSION Smokers who received extended therapy with transdermal nicotine were about twice as likely as those who received standard therapy to achieve abstinence 24 weeks after their quit date. Extended therapy also slowed the time to relapse, reduced the risk for lapse, and increased the chances of recovery from lapses. These benefits with extended therapy cost $2482 per quitter, which compares well with costs of other smoking cessation treatments (26). Benefits of extended therapy with transdermal nicotine were evident only while treatment was maintained. Extended transdermal nicotine therapy produced endof-treatment quit rates similar to those reported for other cessation medications approved by the U.S. Food and Drug Administration, including standard 10-week bupropion treatment (about 19%) (27) and standard 12-week Self-reported Abstinence Figure 2. Time to relapse at week 52, by treatment group HR, 0.79 (CI, ) P = (n = 470)* HR, 0.50 (CI, ) P < (n = 304)* = 6.3 = 6.0 = 13.8 = 11.3 HR, 1.52 (CI, ) P = (n = 191)* = 23.1 = 25.0 Extended therapy Standard therapy Time Point, wk The model controlled for age (HR, 1.00 [95% CI, 0.99 to 1.01]; P 0.65), sex (HR, 0.96 [CI, 0.77 to 1.19]; P 0.69), and level of nicotine dependence. Nicotine dependence level predicted relapse from weeks 0 to 8 (HR, 1.83 [CI, 1.35 to 2.48]; P 0.001) but not from weeks 9 to 24 (HR, 0.91 [CI, 0.61 to 1.36]; P 0.65) or weeks 25 to 52 (HR, 1.04 [CI, 0.60 to 1.70]; P 0.90). The HRs were stable and uniform over the intervals (P 0.80). A residual decline in abstinence after 24 weeks occurred, but the decline was statistically equivalent across treatment groups. HR hazard ratio; R restricted mean number of weeks to relapse (included censored observation times). * Participants at risk for relapse. Table 3. Frequency of Side Effects and Adverse Events* Event Standard-Therapy Group, n/n (%) Extended-Therapy Group, n/n (%) Death 0/286 (0) 0/282 (0) Withdrawal due to adverse event 0/286 (0) 1/282 (0.4) Any self-reported serious symptom 143/286 (50) 142/282 (50.4) Serious adverse event 1/286 (0.4) 3/282 (1.1) Self-reported serious symptoms At1wk Headache 5/252 (2.0) 3/247 (1.2) Nausea 1/252 (0.4) 3/247 (1.2) Alertness 11/252 (4.4) 16/247 (6.5) Coughing 5/252 (2.0) 3/247 (1.2) Pounding heart 3/252 (1.2) 2/247 (0.8) Diarrhea 2/252 (0.8) 0/247 (0) Sleep problems 7/252 (2.8) 19/247 (7.7) Skin irritation or rash 4/252 (1.6) 3/247 (1.2) Calmness 5/252 (2.0) 9/247 (3.6) Dizziness 1/252 (0.4) 1/247 (0.4) Lightheadedness 1/252 (0.4) 2/247 (0.8) Sweating 8/252 (3.2) 3/247 (1.2) Good or high feeling 4/252 (1.6) 7/247 (2.8) Watery eyes 3/252 (1.2) 3/247 (1.2) Coldness of hands or feet 7/252 (2.8) 6/247 (2.4) At 12 wk Headache 2/134 (1.5) 0/182 (0) Nausea 1/134 (0.7) 1/182 (0.5) Alertness 9/134 (6.7) 17/182 (9.3) Coughing 3/134 (2.2) 5/182 (2.7) Pounding heart 2/134 (1.5) 0/182 (0) Diarrhea 0/134 (0) 0/182 (0) Sleep problems 6/134 (4.5) 2/182 (1.1) Skin irritation or rash 1/134 (0.7) 1/182 (0.5) Calmness 4/134 (3.0) 5/182 (2.7) Dizziness 0/134 (0) 1/182 (0.5) Lightheadedness 1/134 (0.7) 1/182 (0.5) Sweating 2/134 (1.5) 4/182 (2.2) Good or high feeling 3/134 (2.2) 4/182 (2.2) Watery eyes 2/134 (1.5) 1/182 (0.5) Coldness of hands or feet 2/134 (1.5) 3/182 (1.6) * Any self-reported serious symptom refers to the total number of participants who reported a severe side effect on the checklist across all time points in which side effects were assessed. Serious adverse event refers to the total number of participants who reported a serious adverse event. Self-reported serious symptoms at 1 wk and 12 wk are those rated 4 (severe) on the side effects checklist. All items were scored such that higher values reflected greater severity of the item, even for positive items, such as good or high feeling, alertness, and calmness. Significant difference between groups (P 0.014). varenicline treatment (33% to 35%) (28, 29). Compared with these medications, transdermal nicotine is accessible over the counter and has fewer contraindications. We searched PubMed for studies published in English to August 2009, and our findings diverged from the only other large trial that reported equivalent efficacy for standard versus extended therapy (7). Of note, the previous trial was done at 37 sites across 17 countries, and quit rates varied from 3% to 30% across sites. That trial compared a 15-mg and a 25-mg dose patch with a 16-hour dosing schedule and tapering, whereas we used a 21-mg dose patch with a 24-hour schedule and no tapering. In addition, the outcome of the previous trial was continuous abstinence 1 year after the quit date. Continuous abstinence is a conservative measure of treatment efficacy be- 2 February 2010 Annals of Internal Medicine Volume 152 Number 3 149

7 Extended Treatment of Tobacco Dependence cause smokers who have early lapses but recover are counted as treatment failures (8). This may be particularly important for rescue therapies, such as transdermal nicotine, that increase the likelihood of recovery from smoking lapses (9, 30). The current data are consistent with a meta-analysis indicating that about 50% of relapses could be averted with extended nicotine patch treatment (31). Improvement in recovery from lapses is one potential mechanism of efficacy for extended treatment. During active treatment (weeks 9 to 24), extended-therapy recipients, if they did lapse, lapsed more slowly and recovered more quickly than those in the standard-therapy group. This is biologically plausible because chronic nicotine, as delivered by the patch, desensitizes 4 2 neuronal nicotinic acetylcholine receptors, which potentially reduces nicotine reward from smoking (32). Extended therapy with transdermal nicotine may also help smokers recover from a lapse by extinguishing the learned reinforcement from smoking, similar to the use of transdermal nicotine before a quit date (33). This may explain why differences in point-prevalence abstinence were no longer evident at week 52. Extended therapy with transdermal nicotine increased costs versus standard therapy, but this cost compares favorably with that of other smoking cessation treatments (26). Although patch use and efficacy increase when costs are covered (3, 4, 34), only 8.6% of U.S. health plans fully cover nicotine patches (35), and only 33 states cover the nicotine patch under Medicaid (36). Longer studies or more comprehensive cost models can address whether the health and economic benefits of enhanced quit rates justify the costs of extended patch therapy. Comparison of the cost per quitter who received extended therapy with the cost per quitter who received precessation treatment with transdermal nicotine (33) is also warranted. In addition, misperceptions about concurrent smoking and nicotine patch use may lead to discontinuing treatment prematurely after lapses (37). Data suggest that smoking while using the patch poses minimal risk (38, 39), and smokers are advised to continue patch use, even after a lapse (40). Participants in our study may not be representative of the general population of smokers, many of whom have comorbid conditions. Because this study evaluated the nicotine patch, carbon monoxide monitoring was used to verify cessation self-reports. Carbon monoxide has a shorter half-life than cotinine; thus, misclassification of participant abstinence reports is possible. Patch adherence was lower than desired; however, we used a conservative definition of adherence, and the adherence rates during the first 8 weeks of treatment were greater than those reported previously (41). The differences in patch adherence between the treatment groups may also indicate incomplete blinding. Finally, 24% of participants at week 24 and 26% at week 52 did not provide abstinence data or a breath sample. We classified these participants as smokers, as others recommend (17). Our study demonstrates the benefits of extendedduration therapy with transdermal nicotine and encourages a reexamination of the recommended duration of tobaccodependence treatment using nicotine patches. Maintaining smokers on transdermal nicotine for 24 weeks improved end-of-treatment abstinence rates compared with standard 8-week treatment and did not increase adverse events or side effects. However, this benefit was lost when therapy was discontinued. Additional research on the optimal duration of therapy and the possible addition of other treatment components (for example, more intensive counseling, precessation use of nicotine patches) from an efficacy, patient acceptance, and cost perspective should be a priority. From University of Pennsylvania, Philadelphia, Pennsylvania, and Massachusetts General Hospital, Boston, Massachusetts. A preliminary report of the study findings was presented at the annual meeting of the Society for Research on Nicotine and Tobacco, 27 February 2008, Portland, Oregon. Acknowledgment: The authors thank Dr. Janet Audrain-McGovern, Dr. Margaret Rukstalis, Angela Pinto, Susan Ware, Kia Kerrin, Janice Biddle, Sean Fleming, Paul Sanborn, and Susan Kerns for assisting with study implementation or manuscript preparation. Grant Support: By a Transdisciplinary Tobacco Use Research Center Grant from the National Cancer Institute and the National Institute on Drug Abuse (P50 CA/DA84718 and P50 CA143187). Potential Conflicts of Interest: Dr. Lerman has served as a consultant to GlaxoSmithKline, one company that manufactures the nicotine patch. She has also served as a consultant or has received research funding from AstraZeneca, Pfizer, and Novartis. Financial support for this study was not provided by an industry sponsor. Dr. Lerman had full access to the data and had full responsibility for the decision to submit for publication. Reproducible Research Statement: Study protocol: Available from Dr. Lerman ( , clerman@mail.med.upenn.edu). Statistical code: Available from Dr. Wiley ( , epw@mail.med.upenn.edu). Data set: Available after 1 January 2011 from Dr. Schnoll ( , schnoll@mail.med.upenn.edu). Corresponding Author: Robert A. Schnoll, PhD, Department of Psychiatry, University of Pennsylvania, 3535 Market Street, Suite 4100, Philadelphia, PA 19104; , schnoll@mail.med.upenn.edu. Current author addresses and author contributions are available at References 1. 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9 Annals of Internal Medicine Current Author Addresses: Drs. Schnoll, Patterson, Wileyto, and Lerman: Department of Psychiatry, University of Pennsylvania, 3535 Market Street, Suite 4100, Philadelphia, PA Dr. Heitjan: Department of Biostatistics and Epidemiology, University of Pennsylvania, 622 Blockley Hall, 423 Guardian Drive, Philadelphia, PA Dr. Shields: Massachusetts General Hospital, 50 Staniford Street, Boston, MA Dr. Asch: Leonard Davis Institute of Health Economics, University of Pennsylvania, 3641 Locust Walk, Philadelphia, PA Author Contributions: Conception and design: E.P. Wileyto, D.F. Heitjan, C. Lerman. Analysis and interpretation of the data: R.A. Schnoll, E.P. Wileyto, D.F. Heitjan, A.E. Shields, D.A. Asch, C. Lerman. Drafting of the article: R.A. Schnoll, F. Patterson, E.P. Wileyto, D.F. Heitjan, A.E. Shields, C. Lerman. Critical revision of the article for important intellectual content: R.A. Schnoll, E.P. Wileyto, D.F. Heitjan, A.E. Shields, D.A. Asch, C. Lerman. Final approval of the article: R.A. Schnoll, F. Patterson, E.P. Wileyto, D.F. Heitjan, A.E. Shields, D.A. Asch, C. Lerman. Statistical expertise: E.P. Wileyto, D.F. Heitjan. Obtaining of funding: C. Lerman. Administrative, technical, or logistic support: F. Patterson. Collection and assembly of data: F. Patterson. Appendix Table 1. Participants Who Completed Assessments or Counseling at Each Time Point Group Time Point 2 wk 0wk 1wk 4wk 8wk 12wk 16wk 20wk 24wk* 52wk* Standard therapy, n (%) 286 (100) 269 (94) 252 (89) 211 (74) 176 (62) 134 (47) 128 (44) 126 (44) Extended therapy, n (%) 282 (100) 269 (95) 247 (86) 213 (76) 200 (71) 182 (64) 165 (58) 166 (58) * Participants provided survey data but missed or declined the carbon monoxide visit. Numbers in parentheses are proportions of the sample that completed counseling at that respective time point. Appendix Table 2. Time to Lapse and Recovery Transition Event, by Week Hazard Ratio (95% CI) P Value Lapse 1 8 wk 0.86 ( ) wk 0.77 ( ) wk 0.96 ( ) 0.77 Recovery 1 8 wk 1.00 ( ) wk 1.47 ( ) wk 0.80 ( ) Participants were allowed a maximum of 8 transition events. The models controlled for age and sex, which were not related to lapse or recovery events. A higher level of nicotine dependence had no effect on lapse but slowed recovery (hazard ratio, 0.71 [95% CI, ]; P 0.001). W-34 2 February 2010 Annals of Internal Medicine Volume 152 Number 3