Bupropion and naltrexone for smoking cessation: A double-blind randomized placebo-controlled clinical trial.

Combination of non-nicotine pharmacotherapies has been underexamined for cigarette smoking cessation. A randomized, double-blind, parallel-group double-dummy study evaluated two medications, bupropion (BUP) and naltrexone (NTX), in treatment-seeking cigarette smokers (N = 121) over a 7-week treatment intervention with 6-month follow-up. Smokers were randomized to either BUP (300 mg/day) + placebo (PBO) or BUP (300 mg/day) + NTX (50 mg/day). The primary outcome was biochemically verified (saliva cotinine, carbon monoxide) 7-day, point-prevalence abstinence. BUP + NTX was associated with significantly higher point-prevalence abstinence rates after 7-weeks of treatment (BUP + NTX, 54.1%; BUP + PBO, 33.3%), P = 0.0210, but not at 6-month follow-up (BUP + NTX, 27.9%; BUP + PBO, 15.0%), P = 0.09. Continuous abstinence rates did not differ, P = 0.0740 (BUP + NTX, 26.2%; BUP + PBO, 13.3%). Those receiving BUP + NTX reported reduced nicotine withdrawal, P = 0.0364. The BUP + NTX combination was associated with elevated rates of some side effects, but with no significant difference in retention between the groups.

Immunogenicity and smoking-cessation outcomes for a novel nicotine immunotherapeutic.

NicVAX, a nicotine vaccine (3'AmNic-rEPA), has been clinically evaluated to determine whether higher antibody (Ab) concentrations are associated with higher smoking abstinence rates and whether dosages and frequency of administration are associated with increased Ab response. This randomized, double-blinded, placebo-controlled multicenter clinical trial (N = 301 smokers) tested the results of 200- and 400-µg doses administered four or five times over a period of 6 months, as compared with placebo. 3'AmNic-rEPA recipients with the highest serum antinicotine Ab response (top 30% by area under the curve (AUC)) were significantly more likely than the placebo recipients (24.6% vs. 12.0%, P = 0.024, odds ratio (OR) = 2.69, 95% confidence interval (CI), 1.14-6.37) to attain 8 weeks of continuous abstinence from weeks 19 through 26. The five-injection, 400-µg dose regimen elicited the greatest Ab response and resulted in significantly higher abstinence rates than placebo. This study demonstrates, as proof of concept, that 3'AmNic-rEPA elicits Abs to nicotine and is associated with higher continuous abstinence rates (CAR). Its further development as a treatment for nicotine dependence is therefore justified.

Exposure to nicotine and a tobacco-specific carcinogen increase with duration of use of smokeless tobacco.

BACKGROUND: Smokeless tobacco is an efficient delivery vehicle for nicotine and can contain significant amounts of carcinogens. However, few studies have examined factors that might moderate levels of nicotine or carcinogen exposure. AIMS: To determine the effect of duration of smokeless tobacco use on the uptake of nicotine and a tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). METHODS: Questionnaires on use of smokeless tobacco were administered, and urine samples from 212 smokeless tobacco users were analysed for biomarkers of uptake of nicotine and NNK. The biomarkers were cotinine and total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL). Male smokeless tobacco users were recruited for studies designed to investigate methods of reducing smokeless tobacco use. The questionnaire and biomarker data were obtained at baseline, prior to reduction. RESULTS: Levels of cotinine (p<0.001) and total NNAL (p<0.001) were significantly correlated with duration (in years) of use of smokeless tobacco products. Median cotinine and total NNAL were 2.4 and 2.1 times higher, respectively, in the > or = 21 years of use than in the 0-5 years of use category. CONCLUSIONS: Smokeless tobacco users adjust their intensity of use with experience in order to increase their nicotine dose, resulting in a corresponding increase in exposure to NNK, a powerful carcinogen. These results indicate the importance of educating smokeless tobacco users about the effects of prolonged use of these products.

Smokeless tobacco brand switching: a means to reduce toxicant exposure?

The purpose of this study was to examine the effects of smokeless tobacco (ST) brand switching on biomarkers of ST exposure and on ST use. Subjects seeking treatment to reduce their use were randomized to ST brand switching with controlled ST topography, brand switching with ad libitum ST use, or a waitlist control with subsequent randomization to one of these two conditions. The waitlist control group was included to assess whether changes were a consequence of time effect. During the intervention, Copenhagen or Kodiak ST users were asked to switch to products that were sequentially lower in nicotine content: Skoal Long Cut Straight or Wintergreen for 4 weeks and then Skoal Bandits for the subsequent 4 weeks. Measures were obtained during the course of treatment and at 12-week follow-up. Significant reductions in total urinary cotinine and 4-(methylnitrosamino)-L-(3-pyridyl)-L-butanol (NNAL) plus its glucuronides (total NNAL) were observed with no significant differences between the controlled topography and ad libitum conditions. Significant reductions were also observed in the amount and duration of dips with a significant intervention effect for durational measures. At 12 weeks, the 7-day biochemically-verified tobacco abstinent rate was 26% in the ad libitum group. ST brand switching may be a feasible alternative intervention for ST users interested in quitting but unwilling to stop ST use completely.

Biomarkers of tobacco exposure or harm: application to clinical and epidemiological studies. 25-26 October 2001, Minneapolis, Minnesota.

Adverse outcomes from tobacco use may take decades to develop. Biomarkers are measures that can be used in the early stages of tobacco use to assess exposure to tobacco toxins or to predict adverse health outcomes with which they are associated. Examples of biomarkers include specific chemical components of tobacco or their metabolites; early biochemical, histological, or physiological effects; and early health effects. Mechanistically relevant and quantitatively valid biomarkers are essential for assessing the ultimate impact of new products, treatments, preventive measures, and public health policies on tobacco-related disease. The tobacco industry's recent introduction of a variety of new tobacco products or devices with implied claims of reduced health risks highlights the need to develop methods for assessing their potential for benefit or harm. A wide variety of biomarkers for tobacco exposure or harm has been studied. Although many questions about their use remain unanswered, substantial data exist regarding their validity and utility. This conference reviewed both the general issues surrounding biomarker use and the current state of knowledge regarding the most widely studied and promising biomarkers.

Progesterone treatment during the early follicular phase of the menstrual cycle: effects on smoking behavior in women.

The goals of this study were (1) to examine the feasibility of administering progesterone to women during the early follicular phase when the endogenous estradiol and progesterone levels are low, and (2) to investigate the effects of oral progesterone treatment on smoking behavior in female smokers. Twelve subjects had two experimental sessions, within 3-9 days after the beginning of their menses. In each experimental session, subjects received a single 200-mg dose of progesterone or placebo, orally. Two and a half hours after the medication treatment, subjects were assessed for subjective response to two puffs of a cigarette and then started the self-administration period in which they had the option to exchange their token for two puffs of cigarette, 15 min apart. Subjects had low levels of estradiol and progesterone before the first and second sessions. Plasma progesterone levels peaked in 2 h following progesterone treatment. Progesterone treatment attenuated the craving for and subjective effects from smoking. Under progesterone treatment, there was a trend for decreased smoking behavior. These preliminary results suggest that the early follicular phase of the menstrual cycle may be a useful interval to investigate the effects of exogenous progesterone in female smokers. The effects of progesterone on nicotine dependence need to be studied further.

Effect of nonnicotine pharmacotherapy on smoking behavior.

Smoking-related disease is the single biggest preventable cause of morbidity and mortality in the United States, yet approximately 25% of Americans continue to smoke. Various dosage forms of nicotine replacement therapy increase smoking quit rates relative to placebo, but they generally do not result in 1-year quit rates of over 20%. To increase these rates, a number of nonnicotine agents have been investigated. Drugs that modulate noradrenergic neurotransmission (bupropion, nortriptyline, moclobemide) are more effective than those affecting serotonin (selective serotonin reuptake inhibitors, buspirone, ondansetron) or other neurotransmitters.

Individual differences in the subjective response to smoked cocaine in humans.

The individual variables that determine the effects of cocaine in humans are not well understood. In this study, we examined the relationship between the subjective response to cocaine and selected individual variables in cocaine-dependent participants. A single 0.4-mg/kg dose of smoked cocaine was received by 75 smoked cocaine users. The variables associated with increased subjective response to cocaine were male sex, presence of alcohol use, higher baseline Beck Depression Inventory (BDI) scores, and duration of cocaine use. The change in heart rate and diastolic blood pressure in response to cocaine delivery were also positively associated with the subjective response to cocaine. In contrast, body weight, years of schooling, and the change in the heart rate with the expectation of cocaine delivery were associated with a diminished subjective response to cocaine. The importance of these variables in maintaining the cocaine use behavior needs to be studied further.

Treatment of spit tobacco users with transdermal nicotine system and mint snuff.

The purpose of this study was to examine the effects of nicotine patch and mint snuff (a nonnicotine product) on craving, withdrawal symptoms, and treatment outcome. This study involved a 2 x 2 factorial design, with Active Nicotine Versus Placebo Patch as one of the factors and Mint Snuff Versus No Mint Snuff as the other factor. Spit tobacco users (N = 402, n = 100-101 in each condition) were randomly assigned to 1 of the 4 treatment conditions for a period of 10 weeks. Treatment outcome was measured up to 62 weeks. The results showed that the nicotine patch was effective in increasing short-term abstinence over the placebo patch and in reducing craving and withdrawal signs and symptoms from spit tobacco. Although mint snuff was not effective in enhancing treatment outcome, it reduced craving and withdrawal symptoms. No interaction effects were observed. At this time, the use of the nicotine patch and mint snuff should be primarily considered for the reduction of craving and withdrawal symptoms.

Sex and menstrual cycle differences in the subjective effects from smoked cocaine in humans.

To investigate sex and menstrual cycle effects in response to cocaine administration, data from existing studies were analyzed. First, responses to a single delivery of 0.4 mg/kg smoked cocaine were investigated. Women reported lower ratings for measures of paranoid/suspicious and heart racing/pounding than did men. In addition, women in the luteal phase reported diminished ratings for a measure of feel high than did both women in the follicular phase of the menstrual cycle and men. Second, responses to up to 6 deliveries of 0.4 mg/kg smoked cocaine were investigated. Women, compared with men, had lower ratings on feel high, heart racing/pounding, and feel stimulated. Results suggest that there are significant sex and menstrual phase differences in the subjective effects of cocaine.

Characteristics of smokeless tobacco users seeking treatment.

Previous studies have described smokeless tobacco (ST) treatment seekers with minimal detail. In the present study, ST users (N = 402), who enrolled in a ST cessation treatment study, were asked to complete an extensive questionnaire that inquired about their ST use patterns, use of other tobacco products, extent of dependence, previous attempts to quit, situations associated with use and support for quitting. The results showed that this population experiences a high level of nicotine exposure and physical dependence on ST. ST use frequently is associated with negative affect situations and times of hunger. A high frequency of users have smoked cigarettes as well as cigars. A supportive social environment for ST cessation exists for these individuals. These results have implications for ST treatment content.

Quantitation of urinary metabolites of a tobacco-specific lung carcinogen after smoking cessation.

We quantified urinary levels of two metabolites of the tobacco-specific lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in people who had stopped smoking: 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its O-glucuronide, 4-[(methylnitrosamino)-1-(3-pyridyl)but-1-yl]-beta-O-D-glucosiduronic acid (NNAL-Gluc). Twenty-seven people completed the study. Thirteen used the nicotine patch starting at the quit date, whereas the others used no patch. Two 24-h urine samples were collected on 2 consecutive days before smoking cessation; blood was also obtained. Beginning at their quit date, subjects provided 24-h urine samples on days 7, 21, 42, 70, 98, and 126, and some subjects also provided samples at later times. The urine was analyzed for NNAL, NNAL-Gluc, nicotine plus nicotine-N-glucuronide, and cotinine plus cotinine-N-glucuronide. Some blood samples were also analyzed for NNAL. The decline of urinary NNAL and NNAL-Gluc after smoking cessation was much slower than expected. This was clearly demonstrated by comparison with cotinine and nicotine levels in urine. One week after smoking cessation, 34.5% of baseline NNAL plus NNAL-Gluc was detected in urine, whereas the corresponding values for cotinine and nicotine were 1.1 and 0.5%, respectively. Even 6 weeks after cessation, 7.6% of the original levels of NNAL plus NNAL-Gluc remained. In some subjects, NNAL plus NNAL-Gluc were detected 281 days after cessation. The distribution half-life for NNAL and NNAL-Gluc was 3-4 days, whereas the elimination half-life was 40-45 days. Total body clearance of NNAL was estimated to be 61.4 +/- 35.4 ml/min, and volume of distribution in the beta-phase was estimated to be 3800 +/- 2100 liters, indicating substantial distribution into the tissues. Parallel studies in rats treated chronically or acutely with NNK in the drinking water support the conclusion that NNAL has a large volume of distribution. There was no effect of the nicotine patch on levels of NNAL plus NNAL-Gluc, indicating that NNK is not formed endogenously from nicotine. The results of this study demonstrate that NNAL and NNAL-Gluc are slowly cleared from the body after smoking cessation, indicating the presence of a high-affinity compartment where NNK, NNAL, and/or NNAL-Gluc are retained or sequestered and slowly released.

The smoking cessation efficacy of varying doses of nicotine patch delivery systems 4 to 5 years post-quit day.

BACKGROUND: This study was undertaken to evaluate the long-term smoking cessation efficacy of varying doses of transdermal nicotine delivery systems 4 to 5 years post-quit day. METHODS: A follow-up study was conducted 48 to 62 months after quit day among patients who were enrolled in the Transdermal Nicotine Study Group investigation. The latter study included group smoking cessation counseling and randomized assignment to 21, 14, or 7 mg nicotine patches or placebo patches. Seven of nine smoking cessation research centers participated in the long term follow-up investigation. RESULTS: The self-reported continuous quit rate among patients originally assigned 21 mg (20.2%) was significantly higher than rates for patients assigned 14 mg (10.4%), 7 mg (11.8%), or placebo patches (7.4%). Log rank survival analysis found no difference in relapse rates after 1 year postcessation. Smokers under age 30 years were significantly less likely to be abstinent at long term follow-up compared to smokers > or = 30 years of age (3 vs 13%, respectively). Mean weight gain in confirmed continuous quitters was 10.1 kg in men and 8.0 kg in women. Of the 63 continuous abstainers surveyed, 30 respondents (48%) reported that they no longer craved cigarettes, and no individual reported daily craving for cigarettes. CONCLUSIONS: Nicotine patch therapy with 21 mg/day patches resulted in a significantly higher long-term continuous abstinence rate compared to lower dose patches and placebo. Relapse rates among the various treatment conditions were similar after 1 year postcessation.

Quantitation of 4-oxo-4-(3-pyridyl)butanoic acid and enantiomers of 4-hydroxy-4-(3-pyridyl)butanoic acid in human urine: A substantial pathway of nicotine metabolism.

A liquid chromatography-atmospheric pressure chemical ionization-tandem mass spectrometry (LC-APCI-MS/MS) method was developed to analyze human urine for 4-oxo-4-(3-pyridyl)butanoic acid (keto acid) and the enantiomers of 4-hydroxy-4-(3-pyridyl)butanoic acid (hydroxy acid) to test our hypothesis that (S)-hydroxy acid could be a biomarker of metabolic activation of the tobacco-specific carcinogens 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN) while (R)-hydroxy acid would be formed predominantly from nicotine, as indicated by studies with rats. Urine was collected from smokers, and from the same individuals after they had stopped smoking and used a nicotine transdermal system (nicotine patch) for 3 weeks. If (S)-hydroxy acid were a biomarker of NNK and NNN metabolic activation, its levels should be higher in the urine of smokers than in nicotine patch users because tobacco smoke, but not the nicotine patch, contains NNK and NNN. Internal standard, [2,2,3,3,4-D5]hydroxy acid, was added to an aliquot of urine, which was then subjected to solid phase extraction. The eluant containing hydroxy acid was esterified with acidic methanol, followed by treatment with (S)-(-)-alpha-methylbenzyl isocyanate, producing methyl-4(S)- or methyl-4(R)-[(S)-alpha-methylbenzylcarbamoyl]-4-(3-pyridyl)buta noate [(S,S)- or (R,S)-MMPB, respectively]. After HPLC purification, the MMPB diastereomers were separated and quantified by LC-APCI-MS/MS. Mean levels of (S)- and (R)-hydroxy acid were 14.1 +/- 8.0 and 1120 +/- 600 ng/mL, respectively, in smokers during ad lib smoking (n = 18), while the corresponding levels during nicotine patch use (n = 18) were 4.1 +/- 3.3 and 363 +/- 228 ng/mL. The amounts of (S)-hydroxy acid were far higher than could be formed from NNK and NNN, and the total amount of hydroxy acid indicated that it was a substantial urinary metabolite of nicotine, in contrast to results with rats. Therefore, the study was extended to quantify keto acid. This was accomplished by NaBH4 treatment of urine, which converted keto acid to hydroxy acid quantitatively, which was in turn analyzed as described above. Levels of keto acid while subjects were smoking and using the nicotine patch were 228 +/- 129 (n = 8) and 97.5 +/- 80.6 ng/mL (n = 8), respectively. These results indicate that conversion of nicotine to keto acid and hydroxy acid is a substantial metabolic pathway in humans, accounting for an estimated 14% of the nicotine dose. Apparently, keto acid is extensively converted to hydroxy acid in humans, in contrast to the results with rats. (S)-Hydroxy acid in human urine cannot be used as a biomarker of NNK and NNN metabolic activation because it is overwhelmed by the (S)-hydroxy acid formed from nicotine, despite the fact that >98% of the urinary hydroxy acid has the (R)-configuration. These results provide new insights about nicotine metabolism in humans.

Targeting treatments to special populations.

The average rate of long-term tobacco abstinence in a general population of treatment-seeking tobacco users is about 25%. Most of these treatments tend to use generic approaches, although the population of tobacco users is quite heterogeneous. It is entirely possible that special populations of smokers have specific treatment needs. If these needs are addressed, then treatment success may be augmented. This paper will review different issues that may surface when treating special populations. The special populations to be examined will be broken down by gender, age and route of tobacco administration. In addition, gaps in the scientific literature and directions for future research will be discussed. Once population-specific treatment needs are identified, then the effects of tailored treatments in augmenting treatment success can be determined.

Oral spit tobacco: addiction, prevention and treatment.

The prevalence of smokeless tobacco is significant and reaches as high as 17% past month use in white males aged 18-25. Smokeless tobacco use is of concern because of the potential for addiction and the associated negative health consequences. This article reviews the basis for addiction to smokeless tobacco, examining the nicotine content in smokeless tobacco products, pharmacokinetics, psychoactive effects, tolerance, and withdrawal. It also explores the negative health consequences which include a number of oral pathologies and increased cardiovascular risk factors. Furthermore, it examines the factors associated with the initiation of smokeless tobacco use, and the current prevention programs that address these factors. Current smokeless tobacco treatment approaches are also discussed as well as predictors for abstinence. Finally, the future directions are discussed in light of the limited amount of research that has been conducted in the smokeless tobacco area, particularly related to prevention and treatment.

Withdrawal and pre-menstrual symptomatology during the menstrual cycle in short-term smoking abstinence: effects of menstrual cycle on smoking abstinence.

This study employs a rigorous inpatient laboratory setting to test the hypothesis that withdrawal symptomatology in short-term smoking cessation in women is increased in the late luteal phase when pre-menstrual symptomatology is the highest. Twenty-one female smokers with clinical, anatomical, and hormonal verification of their menstrual cycle phase were randomized to either a smoking abstinence group (n = 16) or a continued smoking group (n = 5). Participants were admitted to the General Clinical Research Center during alternate phases of their cycle for two 7-day admissions with a 1-month interim period when they resumed smoking. Dependent measures, i.e., Minnesota Nicotine Withdrawal Scale scores, Questionnaire on Smoking Urges scores and Pre-menstrual Assessment Form scores were collected during 2 days of baseline and 5 days of smoking deprivation. Smoking behavior was documented by self-report, breath CO levels and saliva cotinine measurements. Withdrawal symptomatology was not affected by menstrual cycle phase during short-term cessation in spite of increased pre-menstrual changes seen in the late luteal phase. In addition, no phase effect on smoking behavior was detected and cigarette consumption remained stable across the cycle in both groups. These results suggest that for some smoking cessation studies, complex strategies to control for menstrual cycle effects may not be necessary. However, Smoking Urges scores did suggest increased desire to smoke and desire to relieve negative affect in the late luteal phase when women have higher pre-menstrual symptomatology. This suggests women may have greater difficulty quitting smoking in late luteal phase, and it seems prudent to recommend that women quit during the follicular phase of their cycle.