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I I I I I ffect of Transdermal Nicotine Delivery as an Adjunct to ow Intervention Smoking Cessation Therapy ~ Randomized, Placebo-Controlled, Double-blind Study avid M. Daughton, MS; Scott A. Heatley, MD, PhD; JohnJ. Prendergast, MD; Donna Causey, MD; Mark Knowles, PhD; Clyde N. Rolf, MD; n A. Cheney, PA-C; Kathleen Hatlelid, PA-C; Austin B. Thompson, MD; Stephen I. Rennard, MD 1• To assess the smoking cessation efficacy of trensdermal nicotine patches as an adjunct to low-interventlon therapy, we nducted a double-blind, placebo-controlled trial in 158 smok- ~ . Partlcipants were randomly assigned to one of the following ~~~roe study regimens that required daily application of two 15- cm= patches: (1) 24-hour nicotine deiivery, (2) nicotine delivery ring wakeful hours only, and (3) placebo. The impact of the regimens on smoking cessation rates and tobacco with- I symptoms was examined. During the last 2 weeks of the trial, 39% of the 24-hour nicotine regimen delivery group, 35% of lWas on wakeful hour nicotine regimens, and 13.5% of the place- treatment group achieved abstinence. Self-reported quit rates the two nicotine patch-wearing regimens, as compared with thatforthe placebo group, continued to be significantly higher at &months. Moreover, compared with placebo, the transdermal p ~ne patches significantly reduced tobacco withdrawal toms during the first few weeks of quitting. The differences in quit rates and tobacco withdrawal symptoms between the two groups were not statistically significant. The patches were I tolerated both topically and systemically. We concluded that al nicotine, when used as an adjunct to low-interven- tlon therapy, significantly reduced tobacco withdrawal symp- and enhanced smoking cessation rates. WVch Intern Med.1991;151:749-752) brupt abstinence from cigarettes can produce tobacco ILwithdrawal symptoms that may severely test a smoker's lve to quit "Administration of 2 m of nicotine olacrilex . g p Un reduce tobacco withdrawal symptoms and improve quit for publication September 12,1990. m the University of Nebraska Medical Center, Omaha (Messrs Daughton Cheney, Ms Hatlelid, and Drs Thompson and Rennard), The Pacific ~dical Research Services, Redwood City, Calif (Drs Heatley and Prender- ), the ALZA Corp, Palo Alto, Calif (Drn Causey and Knowles), and the Dow Reaearch Institute, Cincinnati, Ohio (Dr Rol2~M t requests to Pulmonary and Critical Care Medicine Section, Depart- of Internal Medicine, University of Nebraska Medical Center, 600 S 42nd ~. atuha, NE 68195 2465 (Mr Daughton) Item -+ (nMed-Vol 151, April 1991 rates,`6 but there'are some obstacles associated with its use. In particular, many nicotine gum (Polacrilex) users are un- able to master proper chewing techniques. Thus, they have difficulty with extracting sufficient nicotine from the gum without producing unwanted side effects, such as hiccups, oral discomfort, heartburn, nausea, and upset stomach.°•' Continuous, controlled release of nicotine through a trans- dermal patch may resolve some of the problems associated with nicotine gum use. Specifically, transdermal nicotine de- livery should eliminate oral discomfort and minimize gastro- intestinal side effects. Most importantly, transdermal nico- tine administration is easy to master. A single morning application of a transdermal nicotine patch may provide 24 hours of tobacco withdrawal relief. Because of its ease of use, transdermal nicotine delivery may prove to be a very effec- tive adjunct to low-intervention smoking cessation therapy. In a double-blind, placebo-controlled trial, we investigated the smoking cessation efficacy of a new transdermal nicotine system as an adjunct to low-intervention therapy. Three regimens that required daily application of two 15-cm2 patch- es were examined as follows: (1) 24-hour nicotine delivery, (2) nicotine delivery during wakeful hours only, and (3) placebo. The impact of three regimens on ameliorating tobacco with- drawal symptoms and enhancing smoking cessation rates is presented. MATERIALS AND METHODS One hundred fifty-eight smokers (age range, 21 to 64 years) were enrolled at two study centers, hereafter referred to as site A (Univer- sity of Nebraska Medical Center, Omaha) and site B (Pacific Medical Research Services, Redwood City, Calif), after informed consent was obtained. Before study entry, all volunteers underwent a medical history, physical examination, smoking history, 12-lead electrocar- diogram, and laboratory tests that included a complete blood cell count, blood chemistry, and urinalysis. The Fagerstrom Tobacco Dependency Questionnaire,' a measure of tobacco dependency, was Transdermal Nicotine Delivery-Daughtai at al 749

I I I I I I I I I I I I I I I I I I I also administered. To be eligible, participants had to have a history of smoking at ?east one pack of cigarettes daily and have normal health screening results. All 158 study-eligible volunteers were randomly assigned to one of the following three double-blinded treatment regimens that required daily application of two 15-cmZ transdermal therapeutic systems (TTSs): 1. Nicotine administered for 24 hours: the 51 participants assigned to this regimen would apply one TTS (nicotine) and one TTS (placebo) system each morning and remove the'ITS (placebo) patch at bedtime. 2. Nicotine delivery during wakeful hours (approximately 16 h/d): 55 participants applied one TTS (nicotine) and one TTS (placebo) system each morning, removing the TTS (nicotine) at bedtime. 3. Placebo treatment: 52 participants applied two TTS (placebo) systems in the morning and removed one patch at bedtime. The patches to be removed at bedtime were stamped "Remove at Bedtime." All of the patches were physically identical in appearance. The placebo patches included the TTS delivery system without nico- tine, and the patches that contained nicotine were identical for the wakeful and 24-hour treatment applications. Each study site provided smokers with some brief smoking cessa- tion counseling. At the screening visit, site A gave individual counsel- ing, with the use of the American Lung Association's Freedom From Smoking in 20 Days manual.' All participants established an agreed- on quit day to commence patch therapy. At site B, patients attended two group lectures during the first 2 weeks of the trial. Comparable low-intervention counseling/follow-up procedures were performed at both sites during the fina12 weeks of the study. At both sites, participants applied patches daily for 4 weeks, maintained a daily diary of their smoking and any unusual symptoms, and returned once each week for follow-up visits. At each visit, severity of tobacco withdrawal symptoms (craving, irritability, anxi- ety, difficulty with concentrating, restlessness, headache, drowsi- ness, and gastrointestinal effects) were assessed on a five-point scale (0 to 4), with 0 equal to none and 4 being severe. Adverse events, assessed by both patient diaries and by open-ended, general ques- tions, were recorded at each weekly visit. Self-reported cigarette smoking and expired air carbon monoxide values also were recorded. Participants who were smoke-free during the last 2 weeks of the study, as evidenced by self-report, diary records, and expired air carbon monoxide values of 8 ppm or less, were considered as abstinent. At the last study visit, participants rated the overall stop-smoking effectiveness of the patches as excel- lent, good, fair, or poor. Finally, to estimate the degree of nicotine replacement provided by the two nicotine patch regimens, salivary samples from many of the participants were collected at site A at both the screening and the end-of-study visits. All of the procured saliva samples obtained from smoke-free, highly compliant nicotine patch wearers were submitted for cotinine analysis to the American Health Foundation in Valhalla, NY. All of the smokers who achieved abstinence during the study were contacted by telephone 6 to 11 months later to determine current smoking status. In addition, at site A, 15 of the 17 self-reported abstainers had expired air carbon monoxide measured. The determi- nation of overall smoking cessation rates, however, was based on self- reported total abstinence from cigarettes from the end of the study until the time of the telephone interview. DData Analysis Pairwise comparisons of the smoking cessation rates were made by computing the difference between two quit rates and dividing by the estimated SE of the difference. The probability of exceeding this value was computed with the use of the PROBIT function in PC p~p IC .7~aB~7aselin- comparability of the three treatment groups, with respect to the number of cigarettes smoked, years of smoking, and Fager- strom score, was assessed with the use of an analysis of variance 750 Arch Intern Med-Vol 151, April 1991 Table 1.-Mean Demographk: Resuits (N=158)• Measure Mean Range Age, y 41.8 21-64 Cigarettes/d 32.9 20-99 Years of smoking 23.9 3-4g Fagerstrom score 7.0 3-11 Expired air carbon monoxide, ppm 27.4 11-51 'The number (percentage) of subjects by sex was as follows: mafe, 74 (a female, 84 (53). Table 2.-Short-term Smoking Cessation Rates• Treatmentt Treatment Center 24 h Awake Placebo Both sites combined, total 20/51 (39) 19l55 (35) 7/52 (13.5) Site A 11/25 (44) 10/27 (37) 4/25 (16) Site B 9/26 (35) 9/28 (32) 3/27 (11) 'Statistical comparisons were as follows: transdermal therapeutic syst, (nicotine), 24 hours vs placebo: P=.002; transderrnai therapeutic syst, (nicotine), awake vs placebo: P=.008; and transdermal therapeutic syst, (nicotine), 24 hours vs awake: P =.62. tData are given as the number of patients who quit srtrokirx,yCtie total numt of patients (percentage). model that contained main effects for study center and treatme group and a center-by-treatment interaction. Tobacco withdrawal symptom scores were analyzed by computi the mean scores for the eight symptoms and by giving a total wi• drawal severity score for each patient and each study week. repeated-measures analysis of variance was performed on the weel measure. The analysis of variance model contained main effects study center and treatment group and a treatment-by-cerni interaction. RESULTS A logistic regression analysis that contained effects f treatment and study center gave a nonsignificant P vab (P=.37) for the center effect. This provided justification f pooling the data from the two centers. Table 1 presents ti mean demographic profile of the combined study populatior Overall, 39% of the 24-hour TTS (nicotine) treatment grot and 353b of smokers assigned to the wakeful hours regim( achieved abstinence during the last 2 weeks of the trial. comparison, only 13.5% of patients who received placel treatment were successful (P<.01 for both nicotine pat( regimens vs placebo). Differences between the two TTS (ni otine) treatments did not reach significance (P=.62). Despi variability in counseling approaches, the two study cente exhibited remarkably similar findings (Table 2). None of tl measures of cigarette smoking (number of cigarettes smok( per day, number of years of smoking, or Fagerstrom score) ( site assignment were predictive of short-term smoking cess tion (minimum P value for the treatment main effect was -' for years of smoking). Tobacco Withdrawai Relief Both TTS (nicotine) treatment regimens were associatE with lower overall tobacco withdrawal symptoms during tt first 2 study weeks. At the third week, only 24-hour taea ment groups exhibited significantly reduced withdr°w symptoms compared with the placebo treatment group. B the fourth week of the study, many of the placebo treatmer Transdermal Nicotine Delivery-Daughtonet 20463993'78

1.2 1.0 0.8 0.6 0.4 1 2 3 Study Week 4 Fig 1.-Mean withdrawal symptom score. Ordinate shows combined bacco withdrawal symptom score. Abscissa shows study weeks. e total score represents the mean of the scores for the individual rthdrawal symptoms. P values were calculated from pairwise t tests of mean total withdrawal severity scores. Regarding statistical com- ns, P values were as folkrvs: 24-hour administration vs placebo, (week i ), .021 (week 2), .008 (week 3), and .308 (week 4); ~oful hours administration vs placebo,.021 (week 1),.008 (week 2), .162 (week 3}, and .358 (week 4); and 24-hour administration vs wakeful hours administration, .614 (week 1), .700 (week 2), .207 k 3), and.927 (week 4). Open triangles indicate 24-hour adminis- n; open squares, wakeful hours administration; and open circles, acebo. 4roup members had resumed smoking and consequently were no longer experiencing tobacco withdrawal symptoms. No 'gnificant differences in withdrawal symptoms were detect- between the two nicotine treatment regimens at any of the our follow-up periods. The mean overall tobacco withdrawal symptom scores are presented in Fig 1. I Global Rating of Effectiveness Slightly more than two thirds of both the 24-hour (68%) and wakeful hours (69%) nicotine patch-wearing groups rated eir patches as excellent or good smoking cessation aids. By ntrast, less than one third (30%) of placebo treatment group members gave the same rating. Forty-four percent of the ef lacebo treatment group rated their patches as poor smoking ~ssation aids, while only 8% of the 24-hour and 12% of the ul hours nicotine treatment groups provided a similar negative evaluation. I Nicotine Replacement The salivary cotinine data indicated that both nicotine ~ atch regimens were associated with lower nicotine exposure an customary smoking (Fig 2). All of the tested quitters ho received nicotine patch therapy exhibited a decrease in their salivary cotinine. As anticipated, the drop was some- h hat more pronounced in the wakeful hours treatment group ~ean = SEM, 325.4 t 36 to 145.7 t 15 ng/mL) compared with at in the 24-hour treatment group (mean± SEM, 301.2 t 41.4 to 182.6 = 10.2 ng/mL) (P =.14, not significant). might be expected, the wakeful hours treatment group, Itho wore the nicotine patches roughly one third less than the hour treatment group, exhibited a one-third higher mean percentage decrease in their salivary cotinine (52% vs 35%). Vntem Med-Vol 151, April 1991 - - Fig 2.-Salivary cotinine changes in nicotine patch-wearing abstain- ers. Ordinate shows salivary cotinine levels (in nanograms per millili- ter). Abscissa shows nicotine patch-wearing regimens. Pre indicates customary smoking prior to starting the study; post reflects end-of- study values of nicotine patch-wearing abstainers. 6-Month Quit Rates Self-reported 6-month quit rates for both active treatment groups, ie, 229b for the 24-hour and 31% for the wakeful hours, were significantly higher than the 8% placebo treatment group quit rate (for the 24-hour vs placebo treatment compar- ison, P=.046; for the wakeful hours vs placebo treatment comparison, P=.003) (Table 3). The difference between the two active treatment groups was not statistically significant. Relapse rates were similar for both the 24-hour nicotine treatment group (45%) and the placebo treatment group (43%). Of the 19 short-term abstainers on the wakeful hours regimen, 17 (90%) continued to remain smoke-free for more than 6 months. Advene Events Adverse events were generally similar for all three regi- mens. The most frequently reported adverse events are listed in Table 4. Only four patients (two receiving an active drug and two receiving placebo) withdrew from the study due to adverse events. COMMENT The present study suggests that transdermal nicotine ther- apy can enhance both short- and long-term smoking cessation rates when used as an adjunct to low-intervention counseling techniques. Pairwise comparisons of the combined short- term smoking cessation rates showed significant differences between both TTS (nicotine)-wearing treatment regimens and the placebo treatment regimen. Moreover, both TTS (nicotine) treatment groups when compared with the placebo treatment group reported significantly reduced overall tobac- cc, withdrawal symptoms during the first 2 weeks of quitting. While the 24-hour TTS (nicotine) treatment group exhibited slightly higher short-term and somewhat lower long-term quit rates than the wakeful hours treatment group, there were no significant differences in quit rates or tobacco with- Transdermal Nicotine Delivery -Daughton et at 751

I I I I I I I I I I I I I I I I Tabte 3.-6-Montti Setf-reported Smoking Cessation Rates• Treatmentt • TFeatment Center 24 h Awake Placebo Both sites combined, total 11/51 (22) 17/55 (31) 4/52 (8) Site A$ 6/25 (24) 8/27 (30) 3/25 (12) Site B 5/26 (19) 9/28 (32) 1/27 (4) 'Statistical compansons were as follows: transdermal therapeutic system (nicotine), 24 hours vs placebo: P=0.46; transdermal therapeutic system (nicotine), awake vs placebo: P=.003; and transdermal therapeutic system (nicotine), 24 hours vs awake: P =.28. t0ata are given as the number of patients who quit smoking/the total number of patients (percentage). *At site A, all of the self-reported quitters in the awake and placebo treatment groups and four of six members of the 24-hour treatment group were confirmed as abstinent at 6+months based on carbon monoxide levels of 8 ppm or less. Table 4.-Number (Percentage) of Patients Reporting Adverse Effects Inciderce Equal to or Greater Than 5% for Any Treatment Treatment, No. (%) Effect 24 h (n=51) Awake (n=55) Placebo (n=52) Headache 8 (16) 3 (5) 5 (10) Dizziness 7 (14) 4 (7) 6 (12) Fatigue 2 (4) 2 (4) 4 (8) Constipation 1 (2) 4 (7) 0 (0) Taste perversion 2 (4) 4 (7) 0 (0) Muscle pain 2 (4) 3 (5) 0 (0) Rash (face or back) 1 (2) 3 (5) 1 (2) drawal symptoms detected between either of the two TTS (nicotine) treatment regimens. The strikingly similar findings at the two study sites sug- gest that the variations in behavioral intervention methods had little impact on smoking cessation rates. Quite likely, common study techniques, such as establishing quit days, carbon monoxide monitoring, and four weekly follow-ups, contributed to the consistency of the findings and enhanced the efficacy of the TTS (nicotine) patches. The significantly lower quit rates in the placebo treatment group clearly indi- cate that the overwhelming factor associated with successful quitting was nicotine patch therapy. The TTS (nicotine) patches were well tolerated, both sys- temically and topically. The most frequently reported skin reactions were itching or burning after patch application and short-term erythema after patch removal. The vast majority of reported cases of erythema resolved within 24 hours of patch removal. Itching or burning generally persisted for less than 30 minutes after patch application and was more preva- 752 Arch Intern Med-Vol 151, April 1991 lent in the two active treatment groups than the place treatment group. The 6-month follow-up produced some reassuring, but triguing, results. Most importantly, the self-reported q rates remained higher in both the active treatment regime than in the placebo treatment regimen. Clearly, the m( remarkable finding, however, is the low-relapse rate amo the participants on the wakeful hours treatment regimen. The present study does not permit a detailed explanatior the role that patch-wearing treatment regimens may have early and long-term quit rates. A review of the active tre. ment group data, however, suggests that 24-hour nicoti administration may enhance early quit rates, but the wake. hours treatment regimen may have lower relapse ratE Thus, one strategy for nicotine patch use would be to utili the 24-hour treatment regimen early and, once the patier are comfortable on the continuous nicotine regimen, dirE them to remove the system at bedtime. Perhaps a mc effective option, currently under investigation, is to we successful quitters by gradually reducing their nicotine pat dosage. In summary, the study indicates that transdermal nicoti delivery is a safe, convenient, and effective adjunct to lo intervention smoking cessation therapy. This study was funded by ALZA Corp, Palo A1to, Calif through a contr with the Merrell Dow Research Institute, Cincinnati, Ohio. Three of • authors have corporate afFiliationa or contractual agreements with, or o stock in, ALZA or Merrell Dow. The editors have been notified of th, potential conflicts of interest. ReneE Crosby typed the manuscript. Referencef 1. American Psychiatric Association Committee on Nomenclature and S tistics. Nicotine induced organic mental disorder. In: Diagnostic and Stati; cal Manual of Mental Disorders, Revised Third Edition. Washington, L American Psychiatric Aseociation;1989:150-151. 2 Hughes JR, Hatsukami D. Signs and symptoms of tobacco withdraw Arch Gen Paychiatry.1986;43:289-294. 3. Hatsukami DK, Hughes JR, Pickens RW, Svilcia D. Tobacco withdrav symptoms: an experimental analysis. Paychopharnwoologg. 1984;r 231-236. 4. Hjalmarson AIM. Effect of nicotine chewing gum in smoldng cessation randomized, placebacontrolled, double-blind study. JAMA 1984,2521& 233s. 5. Jarvia MJ, Raw M, Russell MAH, Feyerabend C. Randomized, contioll trial of nicotine chewing gum. BMJ. 1982285:537-540. 6. Fortmann SP, Killen JD, 'Ielch MJ, Newman B. Minimal contact t.rn: ment for smoldng cessation: a placebo-controlled trial of nicotine polacrilex a self-directed relapse prevention: initial results of the Stanford Stop Smold: Project. JAMA.1988:260:1575-1580. 7. Physicians' Desk Reference. Oradell, NJ: Medical Economics Bool 1990:1127-1130. 8. Fagerstrom KO. Measuring degree of physical dependence to tobac smoking with reference to individualization of treatment. Addict Behc 1978;3:235-241. 9. American Lung Association. Freedom From Smoking in:'0 Daya Ne York, NY: American Lung Association, 1980. 10. SAS Institute Inc. SAS Userb Guide: Basics. 5th ed. Cary, NC: Sr. Institute Inc;1985:263. ~ t~•l W ~ ~ O Transdermal Nicotine Delivery-Daughton et I