Lowell C. Dale

Nicotine-Replacement Therapy With Use of a Transdermal Nicotine Patch—a Randomized Double-Blind Placebo-Controlled Trial

The rate of smoking was significantly reduced in volunteer subjects by providing effective nicotine replacement, self-help material, and weekly visits with a nurse for 6 weeks. Nicotine-replacement therapy with a transdermal nicotine patch (Nicolan) almost doubled the 6-week smoking-cessation rate in comparison with that in a placebo group (77% versus 39%; P = 0.002) among subjects who were smoking at least 20 cigarettes per day at baseline. Although most subjects who used the active nicotine patches had skin reactions, the reactions were primarily mild. For use of both active and placebo patches, the level of patient compliance was high. Among subjects who continued to smoke, the use of cigarettes was decreased to less than 50% of the baseline smoking level in 7 of 7 with active nicotine patches and in 15 of 19 with placebo patches. Outcomes beyond 6 weeks showed a substantial relapse rate in both groups. Thus, when nicotine-replacement therapy is provided, a need exists for concurrent behavioral intervention and training for prevention of a relapse, neither of which was part of this protocol.

Application of serum nicotine and plasma cotinine concentrations to assessment of nicotine replacement in light, moderate, and heavy smokers undergoing transdermal therapy.

As part of a clinical trial investigating the level of nicotine replacement with different doses of transdermal therapy for smoking cessation, peak and trough serum nicotine and plasma cotinine concentrations were measured in 70 subjects while they were actively smoking (baseline) and daily for 6 consecutive inpatient days while they were receiving transdermal nicotine. Subjects were randomly assigned to a daily 24‐hour patch delivering a transdermal nicotine dose of 0, 11, 22, or 44 mg and stratified by self‐reported smoking rate as either light (10–15 cigarettes per day), moderate (16–30 cigarettes per day), or heavy (>30 cigarettes per day). Steady‐state concentrations of nicotine and cotinine were attained in 1 and 3 days, respectively, at all doses and were independent of baseline smoking rate. Mean percentage replacement of nicotine was calculated by dividing steady‐state peak nicotine or cotinine concentrations by their respective baseline concentrations. Significant underreplacement occurred in subjects receiving the 11 mg/day patch regardless of baseline smoking rate. Underreplacement also occurred in moderate and heavy smokers receiving 22 mg/day and in light smokers at this same dose. Complete replacement occurred only in subjects receiving the 44 mg/day patch. These results have several implications for transdermal nicotine therapy. First, with the higher nicotine and cotinine levels observed with heavier smoking, it is inherent that one size does not fit all, and there is a need to consider more individualization of dosage for nicotine patch therapy. Second, there is substantial underreplacement with the 22 mg/day dose in moderate to heavy smokers and in some light smokers. Third, even with twice the usual dose (i.e., 44 mg/day), there was no accumulation of either nicotine or cotinine. Plasma cotinine levels after achievement of steady state (i.e., after 3 days of patch therapy) can be collected at any time and used to calculate percent replacement using baseline levels.

Nicotine patch therapy for smoking cessation in recovering alcoholics

In a post hoc analysis of prior nicotine patch studies, we analysed findings in 357 subjects (43 recovering alcoholics, 314 non-alcoholics) to determine if recovering alcoholic smokers were more nicotine dependent than non-alcoholics and whether the efficacy of nicotine patch therapy was comparable. The Self-Administered Alcoholism Screening Test was used to identify recovering alcoholics. Recovering alcoholics had significantly higher mean smoking rates (cigarettes per day), Fagerström scores and baseline serum nicotine and cotinine than non-alcoholics. Among a subset of 240 subjects with a comparable treatment protocol, smoking cessation rates at the end of nicotine patch therapy were similar in recovering alcoholics (46%) and non-alcoholics (47%) receiving active 22 mg patches but higher than the respective placebo groups (17% and 19%). The 1-year rate was significantly (p = 0.005) higher in the non-alcoholic group assigned to an active patch (31%) compared to placebo (14%). For recovering alcoholics, the rates were lower and not significantly different (active 0%, placebo 11%). Recovering alcoholic smokers are likely to be more nicotine dependent than non-alcoholic smokers but can achieve comparable short-term cessation rates with nicotine patch therapy. Use of an objective, validated measure of alcohol dependence is indicated in clinical trials when it is desirable to know whether the subjects are active or recovering alcoholics.

Serum nicotine and cotinine levels during nicotine-patch therapy

We related serum nicotine and cotinine levels while subjects were smoking their usual numbers of cigarettes to levels while wearing a nicotine patch under carefully controlled, smoke‐free conditions in a clinical research center. Twenty‐four volunteers who needed intensive treatment for severe nicotine dependence were admitted to the clinical research center and were treated with a 22 mg transdermal nicotine patch each day and an intensive smoking‐cessation program. Serum nicotine and cotinine levels, withdrawal symptoms, and hours and quality of sleep were noted. The steady‐state serum nicotine and cotinine levels produced with the nicotine patch were lower than those observed when the subjects were smoking. Mean nicotine and cotinine levels were inversely related to mean withdrawal scores for the first 6 days. A fixed dose of transdermal nicotine will not be effective for all smokers. Individualization of therapy should be based on objective biologic measures such as serum cotinine and subjective assessment of withdrawal relief.

Cholesterol-Lowering Effect of Stanol Ester in a US Population of Mildly Hypercholesterolemic Men and Women: A Randomized Controlled Trial

OBJECTIVE To determine the efficacy of stanol esters in lowering cholesterol in a US population. SUBJECTS AND METHODS After a run-in phase, 318 subjects were randomized to receive one of the following margarine-like spreads containing stanol ester or placebo for 8 weeks: EU 3 G: 1 g of stanol (ester form) per 8-g serving of a European formula 3 times a day; US 3 G: 1 g of stanol (ester form) per 8-g serving of a US reformulation 3 times a day; US 2 G: 0.67 g of stanol (ester form) per 8-g serving of a US reformulation 3 times a day; or placebo spread. RESULTS Mean +/- SD baseline total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels were 233+/-20 and 153+21 mg+/-dL, respectively. In the US 3 G group, 3 g daily of stanol esters lowered TC and LDL-C levels by 6.4% and 10.1%, respectively. There was a dose-dependent response compared with 2 g daily (US 2 G). Triglyceride and high-density lipoprotein cholesterol levels were unchanged. The incidence of adverse effects was not different from placebo. Serum vitamin A and 25-hydroxyvitamin D levels were not affected. CONCLUSIONS Stanol esters lowered TC and LDL-C levels in a mildly hypercholesterolemic US population without evidence of adverse effects. It may be a useful dietary adjunct to lower cholesterol.

Anesthesiologists, general surgeons, and tobacco interventions in the perioperative period.

Surgery presents an opportunity for interventions in cigarette smokers that will facilitate abstinence from tobacco. However, little attention has been paid to the role of anesthesiologists and surgeons in addressing tobacco use. To determine the practices and attitudes of these physicians regarding this issue, we sent a postal mail survey to a national random sampling of anesthesiologists and general surgeons engaged in active practice within the United States (1000 in each group). Response rates were 33% and 31% for anesthesiologists and surgeons, respectively. More than 90% of both groups almost always ask their patients about tobacco use, and almost all respondents believed that surgical patients should maintain abstinence after surgery. Most believed that it was their responsibility to advise their patients to quit smoking, but only 30% of anesthesiologists and 58% of surgeons routinely do so. Nonetheless, approximately 70% of both groups would be willing to spend an extra 5 min before surgery to help their patients quit. Barriers to intervention included a lack of training regarding intervention techniques, a perceived lack of effective interventions, and insufficient time to intervene. Intervention opportunities are not exploited consistently in the surgical population; educational efforts directed at physicians in surgical specialties are indicated.

Predictors of smoking cessation among elderly smokers treated for nicotine dependence.

OBJECTIVE: To examine outcomes and predictors of smoking cessation among elderly patients treated for nicotine dependence. DESIGN: Retrospective analysis of patients aged 65-82 who received a nicotine dependence consultation at the Mayo Medical Center between 1 April 1988 and 30 May 1992. Patients were contacted by telephone by a trained interviewer six months after the consultation and were sent a follow-up survey in August 1993. SETTING: Mayo Medical Center, Rochester, Minnesota, United States. SUBJECTS: A total of 613 patients (310 men, 303 women) with a mean age of 69.0 (SD 3.5) years were seen during the study period. MAIN OUTCOME MEASURES: Point prevalence self-reported smoking status. Patients were considered abstinent if they self-reported not smoking (not even a puff) during the seven days before contact. RESULTS: At six-month follow up, 24.8% of the 613 patients reported abstinence from smoking. On multivariate analysis, smoking abstinence was more likely if patients were hospitalised at the time of the consultation, married to a non-smoking spouse, very motivated to stop smoking, and reported their longest time of previous abstinence to be less than a day or more than a month. The response rate to the mailed follow-up survey was 69.9% (429 of 613). The mean duration of follow up was 40.0 +/- 13.2 months following the consultation. Of the 429 patients, 103 (24.0%) reported abstinence from smoking and 326 (76.0%) were smoking at six-month follow up. Patients who reported abstinence at six months had a higher cessation rate at the last follow up (76.0%) compared with patients who were smoking at six-month follow up (33.0%, P < 0.001). For patients who were not smoking at six months, no factors were found to significantly predict abstinence at last follow up. For patients who were smoking at six months, factors associated with smoking cessation at last follow up were: more than a year as the longest time off cigarettes before the consultation; counsellor rating of less severe nicotine dependence; and older age at first regular smoking. CONCLUSIONS: Several predictors of smoking cessation were identified in this study which may be useful for tailoring smoking interventions for the elderly.

A randomized controlled trial of adding the nicotine patch to rimonabant for smoking cessation: efficacy, safety and weight gain

AIMS Because smoking cessation rates might be improved by combining drugs and by reducing post-cessation weight gain, we tested the smoking cessation efficacy, safety and effect on body weight of adding the nicotine patch to rimonabant, a cannabanoid type-1 receptor antagonist that reduces body weight. DESIGN Randomized double-blind placebo-controlled trial. SETTING Fifteen US research centers. PARTICIPANTS A total of 755 smokers (> OR = 15 cigarettes/day). Intervention Rimonabant (20 mg daily) was given open-label for 9 weeks. The 735 participants completing week 1 were randomized at day 8 (target quit day) to add a nicotine patch (n = 369) or placebo patch (n = 366) for 10 weeks (21 mg daily for 8 weeks plus a 2-week taper). Participants received weekly smoking counseling and were followed for 24 weeks. MEASUREMENTS Biochemically validated 4-week continuous abstinence at end-of-treatment (weeks 6-9; primary end-point); 7-day point prevalence abstinence at weeks 9 and 24; sustained abstinence (weeks 6-24); change in body weight; and adverse events. FINDINGS Rimonabant plus nicotine patch was superior to rimonabant plus placebo in validated continuous abstinence at weeks 6-9 (39.0% versus 21.3%; odds ratio 2.36, 95% confidence interval: 1.71-2.37; P < 0.01) and in all other efficacy measures. Mean end-of-treatment weight gain among quitters did not differ between groups (0.04 kg for combination versus 0.49 kg for rimonabant only, P = 0.15) and was similar in weight-concerned smokers. Serious adverse event rates did not differ between groups. Depression- and anxiety-related adverse events occurred in 32 (4.2%) and 44 (5.8%) subjects, respectively; eight (1.1%) and nine (1.2%) subjects stopped the drug due to depression and anxiety, respectively. CONCLUSIONS Adding a nicotine patch to rimonabant was well tolerated and increased smoking cessation rates over rimonabant alone. There was little post-cessation weight gain in either group, even among weight-concerned smokers, during drug treatment.

Weight Change After Smoking Cessation Using Variable Doses of Transdermal Nicotine Replacement

OBJECTIVE: Examine weight change in subjects receiving variable doses of transdermal nicotine replacement for smoking cessation.DESIGN: Randomized, double-blind clinical trial.SETTING: One-week inpatient treatment with outpatient follow-up through 1 year.INTERVENTION: This report examines weight change after smoking cessation for 70 subjects randomized to placebo or to 11, 22, or 44 mg/d doses of transdermal nicotine. The study included 1 week of intensive inpatient treatment for nicotine dependence with active patch therapy continuing for another 7 weeks. Counseling sessions were provided weekly for the 8 weeks of patch therapy and with long-term follow-up visits at 3, 6, 9, and 12 months.MEASUREMENTS AND MAIN RESULTS: Forty-two subjects were confirmed biochemically (i.e., by expired carbon monoxide) to be nonsmokers at all weekly visits during patch therapy. Their 8-week weight change from baseline was 3.0±2.0 kg. For these subjects, 8-week weight change was found to be negatively correlated with percentage of cotinine replacement (r=−.38, p=.012) and positively correlated with baseline weight (r=0 .48, p=.001), and age (r=.35, p=.025). Men had higher (p=.003) 8-week weight gain (4.0±1.8 kg) than women (2.1±1.7 kg). Of the 21 subjects who abstained continuously for the entire year, 20 had their weight measured at 1-year follow-up. Among these 20 subjects, 1-year weight change was not found to be associated with gender, baseline weight, baseline smoking rate, total dose of transdermal nicotine, or average percentage of cotinine replacement during the 8 weeks of patch therapy.CONCLUSIONS: This study suggests that higher replacement levels of nicotine may delay postcessation weight gain. This effect is consistent for both men and women. We could not identify any factors that predict weight change with long-term abstinence from smoking.

Inpatient treatment of severe nicotine dependence

The most severely nicotine-dependent patients who have tried traditional treatment programs without success may require maximal intervention to achieve abstinence. In the Clinical Research Center at the Mayo Clinic, we assessed the feasibility of an inpatient treatment program for 24 such subjects, who were hospitalized (in groups of 6) for 2 consecutive weeks. A combination of behavioral, chemical-dependence, and transdermal nicotine-replacement therapy was provided in a smoke-free, protected milieu. Components of the program included group therapy, management of stress, exercise, daily lectures, and supervised activities. The mean age of the 18 women and 6 men was 51.3 years (range, 29 to 69 years). The mean duration of smoking was 33.7 years, and the number of cigarettes smoked per day at the time of admission averaged 33.2. The most frequent tobacco-related medical illnesses were chronic obstructive pulmonary disease, arteriosclerosis obliterans, and coronary artery disease. All subjects but two--each smoked part of a cigarette--remained abstinent from the use of cigarettes while in the Clinical Research Center, and all completed the 2-week inpatient program. The subjects underwent follow-up for 10 weeks after dismissal and were contacted periodically thereafter. At 1 year, 7 of the 24 subjects (29%) had maintained continuous abstinence from smoking, and their self-reported status at 1 year was verified biochemically.