Ivana T. Croghan

Mortality Following Inpatient Addictions Treatment: Role of Tobacco Use in a Community-Based Cohort

OBJECTIVE To determine the impact of tobacco- and alcohol-related deaths on overall mortality following inpatient treatment for alcoholism and other nonnicotine drugs of dependence. DESIGN Population-based retrospective cohort study. SETTING Olmsted County, Minnesota (the Rochester Epidemiology Project), and the Inpatient Addiction Program (IAP) at Mayo Clinic, Rochester. PATIENTS All 845 Olmsted County residents admitted to an inpatient addiction program for treatment of alcoholism and other nonnicotine drugs of dependence during the period 1972 through 1983. METHODS Patients were followed up through the medical record linkage system of the Rochester Epidemiology Project through December 1994 to obtain vital status, and death certificates were obtained for those who died. The underlying cause of death was classified as alcohol related, tobacco related, both, or neither based on the classification from the Centers for Disease Control and Prevention. The observed number of deaths by underlying cause were compared with the expected number using cause-specific 1987 death rates for the white population of the United States. All-cause mortality was also compared with that expected for persons in the West North Central Region of the United States of like age, sex, and year of birth. Univariate and multivariate assessments were made to identify predictors of all-cause mortality from baseline demographic information. RESULTS At admission, the mean (SD) age of the 845 patients was 41.4 (14.5) years, and 35% were women. Altogether, 78% had alcohol as their only nonnicotine drug of dependence and 18% had alcohol and other nonnicotine drugs of dependence, while 4% were classified as having a nonalcohol, nonnicotine drug dependence alone. At admission, 75% were current and 8% former cigarette smokers, 3% were current cigar or pipe smokers, and 2% were current users of smokeless tobacco. Follow-up after the index IAP admission totaled 8913 person-years (mean [SD] of 10.5 [5.6] years per patient). Death certificates were obtained for 96% (214) of the 222 patients who died. Of these 214 deaths, 50.9% (109) had a tobacco-related and 34.1% (73) had an alcohol-related underlying cause (P<.001). The cumulative mortality significantly exceeded that expected (P<.001); at 20 years, the observed mortality was 48.1% vs an expected 18.5%. Multivariate predictors of mortality, even after adjusting for expected mortality, were older age at admission (P<.001) and male sex (P<.001). CONCLUSIONS Patients previously treated for alcoholism and/or other nonnicotine drug dependence had an increased cumulative mortality that was due more to tobacco-related than to alcohol-related causes. Nicotine dependence treatment is imperative in such high-risk patients.

Response to nicotine dependence treatment in smokers with current and past alcohol problems

Smoking prevalence among alcoholics is high, and evidence indicates that smokers with a history of alcohol abuse may have more difficulty quitting cigarette smoking. This study is a post hoc analysis comparing the smoking cessation rates of smokers with active or past alcohol problems to the rates in smokers with no history of alcohol problems who were participants in a randomized, controlled trial of smoking cessation therapy. Subjects received either 44 mg/24 hour or 22 mg/24 hour nicotine patch for 4 or 6 weeks, respectively, followed by a tapering schedule to complete 8 weeks of therapy and a randomly assigned behavioral intervention (minimal, brief individual counseling, group therapy). The Self-Administered Alcoholism Screening Test (SAAST) score was used to determine alcohol group assignment (no alcohol problems <7; active alcohol problems ≥7 and still drinking; past alcohol problems if not drinking due to a past history of alcohol problems). Among 382 subjects (171 men and 211 women), 281 had no alcohol problems (74%), 53 had past alcohol problems (14%), and 48 had active alcohol problems (13%). Smoking cessation rates assessed at both weeks 4 and 8 were significantly different across groups (p=0.026 and 0.002 at weeks 4 and 8, respectively) with lower rates in the groups with past and active alcohol problems when compared to the “no problem” group. At week 26, subjects with past alcohol problems were less likely to be abstinent from smoking than no problem group subjects, but this was not statistically significant (odds ratio =0.49, 95% confidence interval 0.22→1.08). In the short term, smokers with past or active alcohol problems are less likely to quit smoking compared to those with no alcohol problems when treated with nicotine patch therapy for smoking cessation.

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.

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.

Varenicline and bupropion sustained-release combination therapy for smoking cessation

INTRODUCTION Varenicline and bupropion sustained release (SR) are both safe and effective for the treatment of tobacco dependence and have different mechanisms of action. Combination pharmacotherapy with these agents may increase long-term smoking abstinence rates above what is observed with single-agent therapy. METHODS We enrolled cigarettes smokers in an open-label, one-arm, Phase II clinical trial to obtain preliminary data on the potential effectiveness and safety of combination therapy with varenicline and bupropion SR for the treatment of tobacco dependence. Eligible subjects received varenicline titrated to 1.0 mg by mouth twice daily and bupropion SR titrated to 150 mg by mouth twice daily for a total of 12 weeks along with behavioral therapy. Self-reported smoking abstinence was biochemically confirmed with expired carbon monoxide. A total of 38 smokers with a mean age of 49.1 years (SD = 12.4) who smoked an average of 19.9 cigarettes/day (SD = 7.8) for 30 years (SD = 12.3) were enrolled. RESULTS Seven-day point-prevalent smoking abstinence rates were 71% (95% CI = 54%-85%) at 3 months and 58% (95% CI = 41%-74%) at 6 months. Mean weight change during the medication phase among smoking-abstinent subjects was 1.6 kg (SD = 2.4). For both medications, 74% of subjects took at least 90% of the prescribed doses. The most common side effects were sleep disturbance (26%) and nausea (24%). No increase in depressive symptoms was observed, and no subjects reported suicidal ideation. DISCUSSION Combination therapy with varenicline and bupropion SR may be effective for increasing smoking abstinence rates above that observed with monotherapy.

Nicotine Patch Therapy Based on Smoking Rate Followed by Bupropion for Prevention of Relapse to Smoking

PURPOSE To determine whether (1) tailored nicotine patch therapy that is based on smoking rate can be carried out in a multisite oncology investigative group practice setting, (2) long-term use of bupropion reduces the rate of relapse to smoking in smokers who stop smoking with nicotine patch therapy, and (3) bupropion can initiate smoking abstinence among smokers who have failed to stop smoking after nicotine patch therapy. PARTICIPANTS AND METHODS Fourteen North Central Cancer Treatment Group sites recruited generally healthy adult smokers from the general population for nicotine patch therapy and based the patch dosage on smoking rates. At completion of nicotine patch therapy, nonsmoking participants were eligible to be assigned to bupropion or placebo for 6 months (for relapse prevention). and smoking participants were eligible to be assigned to bupropion or placebo for 8 weeks of treatment. RESULTS Of 578 subjects, 31% were abstinent from smoking at the end of nicotine patch therapy. Of those subjects not smoking at the end of nicotine patch therapy who entered the relapse prevention phase, 28% and 25% were not smoking at 6 months (the end of the medication phase) for bupropion and placebo, respectively (P =.73). For those still smoking at the end of nicotine patch therapy, 3.1% and 0.0% stopped smoking with bupropion or placebo, respectively (P =.12). CONCLUSION Tailored nicotine patch therapy for the general population of smokers can be provided in a multisite oncology investigative group setting. Bupropion did not reduce relapse to smoking in smokers who stopped smoking with nicotine patch therapy. Bupropion did not initiate abstinence among smokers who failed to stop smoking with nicotine patch therapy.

Does smoking reduction result in reduction of biomarkers associated with harm? A pilot study using a nicotine inhaler

The aim of the study was to determine if smoking reduction using a nicotine inhaler in heavy cigarette smokers who wanted to reduce but not stop smoking results in decreased levels of known biomarkers of harm. The study design was a one-sample within-subject comparative open-label study of 23 (10 male and 13 female) subjects using a nicotine inhaler to reduce smoking, with follow-up at 24 weeks. A structured protocol was used with a smoking-reduction schedule from 40 or more cigarettes per day to 10 cigarettes per day by week 9. Behavioral counseling was provided by a research assistant and ad lib use of the nicotine inhaler for 12 weeks was permitted. Blood thiocyanate, cotinine, 4-aminobiphenyl hemoglobin adducts; urine NNAL and NNAL-glucuronide; and expired air carbon monoxide were measured. On average, the subjects were able to reduce their smoking by over 50% at week 12, but only two were able to reduce to 10 cigarettes per day. The reported reduction in smoking was not associated with a consistent reduction in the biomarkers. There was no reduction in the NNAL, 4-aminobiphenyl hemoglobin adducts nor carbon monoxide levels of expired air. There was a significant reduction of NNAL-glucuronide and the sum of NNAL and NNAL-glucuronide but only at week 24. Thiocyanate levels increased. Before widely promoting harm reduction as a treatment strategy for heavy smokers, more research needs to be performed to prove conclusively that such smokers who want to reduce but not stop can actually reduce and maintain their smoking rate at a level which is likely to reduce harm. It also needs to be determined whether a reduction in the smoking rate translates into reduction of harm. At the present, for heavy smokers, an abstinence approach seems to be more scientifically sound.

Cost-Effectiveness of Treating Nicotine Dependence: The Mayo Clinic Experience

OBJECTIVE To estimate the cost-effectiveness of treating nicotine dependence, expressed as cost per net year of life gained by smoking cessation. DESIGN A cost-effectiveness analysis was conducted of a cohort of consecutive adult patients treated for nicotine dependence from April 1988 through December 1992 at the Mayo Clinic Nicotine Dependence Center (NDC). MATERIAL AND METHODS The study cohort consisted of 5,544 patients (50.8% female; mean age, 47.8 years) with a mean baseline smoking rate of 25.4 cigarettes per day. After an initial consultation, a nonphysician counselor developed an individual nicotine dependence treatment plan, which could include follow-up counseling, nicotine replacement therapy (patches or gum), group therapy, or an inpatient program. A relapse-prevention program included telephone calls and a series of letters to the patient. We computed the years of life gained for each person specific to age, gender, smoking rate at entry, and 6-month smoking status by using published mortality rates for current and former cigarette smokers. The 6-month smoking status was assumed to be applicable at 1 year. For subsequent determinations, we modeled by computer simulation the year-by-year (to age 100) smoking status by using published relapse and late cessation rates. Coupled with treatment costs, this information allowed the expression of cost per net year of life gained by stopping smoking. Net years of life gained, discounted 0, 3, and 5%, were computed with use of cessation and relapse rates expected for patients not seen in the NDC. Treatment costs were based on 1993 rates for the intervention services but did not include any tobacco product cost savings associated with smoking cessation. RESULTS The 1-year smoking-cessation rate was 22.2%. With all NDC patients included, the estimated net years of life gained, with use of a 5% rate of discount for benefits, was 0.058, and the corresponding cost was

Combination Varenicline and Bupropion SR for Tobacco Dependence Treatment in Cigarette Smokers: A Randomized Trial

6,828 per net year of life gained. CONCLUSION In comparison with the cost-effectiveness of other medical services, the cost of