Naltrexone, smoking behaviour and cigarette withdrawal. Effects of naltrexone with nicotine replacement on smoking cue reactivity: preliminary results. Low-dose naltrexone augmentation of nicotine replacement for smoking cessation with reduced weight gain: a randomized trial. Naltrexone alteration of the nicotine-induced EEG and mood activation response in tobacco-deprived cigarette smokers. Association of OPRM1 A118G variant with the relative reinforcing value of nicotine. Pharmacological effects of naltrexone and intravenous alcohol on craving for cigarettes among light smokers: a pilot study. Naloxone does not affect cigarette smoking. Naltrexone alteration of acute smoking response in nicotine-dependent subjects. Effects of naltrexone on smoking cessation outcomes and weight gain in nicotine-dependent men and women. High-dose transdermal nicotine and naltrexone: effects on nicotine withdrawal, urges, smoking, and effects of smoking. Naltrexone treatment for alcoholics: effect on cigarette smoking rates. Naltrexone effects on short-term and long-term smoking cessation. An inpatient study of the effects of buprenorphine on cigarette smoking in men concurrently dependent on cocaine and opioids. A randomized trial of naltrexone for smoking cessation. Naltrexone blockade of nicotine effects in cigarette smokers. Naltrexone reduces the relative reinforcing value of nicotine in a cigarette smoking choice paradigm. Naloxone reduces cigarette smoking. A controlled trial of naltrexone augmentation of nicotine replacement therapy for smoking cessation. Naltrexone administration affects ad libitum smoking behavior. Efficacy of naltrexone in smoking cessation: a preliminary study and an examination of sex differences. [Failure of naloxone to modify the anti-tobacco effect of acupuncture (author's transl)]. Naloxone challenge in smokers. Preliminary evidence of an opioid component in nicotine dependence. Changes of smoking behavior and serum adrenocorticotropic hormone, cortisol, prolactin, and endogenous opioids levels in nicotine dependence after naltrexone treatment. Effects of topiramate or naltrexone on tobacco use among male alcohol-dependent outpatients. Buprenorphine effects on cigarette smoking.
In order to examine the role of endogenous opioids in the reinforcing effects of nicotine, a double-blind, placebo-controlled, cross-over design was used to study the effects of the opiate antagonist, naltrexone, on smoking behaviour and cigarette withdrawal in 12 heavy smokers. Although naltrexone (50 mg) appeared to reduce the perceived difficulty of abstaining during 24-h cigarette withdrawal, other withdrawal symptoms were unaffected. Naltrexone also had no effect on a variety of biochemical and behavioural measures of nicotine intake or on subjective satisfaction and enjoyment from the first cigarette smoked after 24-h abstinence. Similarly naltrexone (100 mg) had no effect on smoking behaviour, nicotine intake or satisfaction from smoking during a 48-h period of ad libitum smoking. However, during the ad libitum smoking period naltrexone caused mood changes of the kind that occur during tobacco withdrawal. Since nicotine intake and smoking behaviour were unaffected, the mood changes are unlikely to have been mediated by blockade or any other form of opioid interaction with nicotinic mechanisms. These findings provide evidence against the notion that the endogenous opioids are involved in mediating the reinforcing properties of nicotine in smokers under normal conditions. Although several studies have examined the effects of opioid antagonists on smoking behavior, there have been no reports of the potentially therapeutic combination of naltrexone and nicotine replacement therapy. The primary objective of the present study was to determine whether naltrexone reduced reactivity to smoking cues among abstinent smokers treated with nicotine replacement. Twenty participants were instructed to abstain from smoking cigarettes for 9 h while using nicotine replacement therapy. Participants were subsequently treated with either naltrexone (50 mg) or placebo before being exposed to smoking cues. Results indicated that the smokers who received the placebo responded to smoking cue exposure with increases in urge to smoke and increases in negative affect. Participants who received naltrexone did not show any increase in urge or negative affect and showed a decrease in withdrawal symptoms after exposure to smoking cues. Although preliminary, the findings suggest that naltrexone may work in combination with nicotine replacement therapies to block the effects of smoking stimuli in abstinent smokers. Fear of weight gain is a significant obstacle to smoking cessation, preventing some smokers from attempting to quit. Several previous studies of naltrexone yielded promising results for minimization of post-quit weight gain. Given these encouraging findings, we endeavored to test whether minimization of weight gain might translate to better quit outcomes for a population that is particularly concerned about gaining weight upon quitting.
                Smokers (N=172) in this investigation were prospectively randomized to receive either 25 mg naltrexone or placebo for 27 weeks (1 week pre-, 26 weeks post-quit) for minimization of post-quit weight gain and smoking cessation. All participants received open label therapy with the nicotine patch for the first 8 weeks post-quit and behavioral counseling over the 27-week treatment. The 2 pre-specified primary outcomes were change in weight for continuously abstinent participants and biologically verified end-of-treatment 7-day point-prevalence abstinence at 26 weeks after the quit date.
                The difference in weight at 26 weeks post-quit between the naltrexone and placebo groups (naltrexone: 6.8 lbs ± 8.94 vs placebo: 9.7 lbs ± 9.19, p = 0.45) was not statistically different. Seven-day point-prevalence smoking abstinence rates at 26 weeks post-quit was not significantly different between the 2 groups (naltrexone: 22% vs placebo: 27%, p = 0.43).
                For smokers high in weight concern, the relatively small reduction in weight gain with low-dose naltrexone is not worth the potential for somewhat lower rates of smoking abstinence.
                Copyright © 2010 Elsevier Ireland Ltd. All rights reserved. The neural mechanisms contributing to the arousal-eliciting actions of smoking and nicotine involve multiple neurotransmitter systems. The current study examined the role of opioid neurotransmission in modulating the neuroelectric- and mood-activating response to acute nicotine administration in overnight tobacco-deprived smokers. In a randomized, double-blind, placebo-controlled design involving 18 (10 male, 8 female) overnight tobacco-abstinent smokers, spectrally analyzed electroencephalographic (EEG) activity and subjective reports of mood, euphoria, and smoking withdrawal were assessed in response to nicotine gum (4 mg) after pretreatment with placebo or with 50 mg of the opioid antagonist naltrexone. In addition to reducing withdrawal symptoms and increasing euphoria ratings, as well as subjective alertness in male participants, nicotine induced an EEG arousal response consisting of diffuse slow wave (delta, theta) amplitude reductions, frontal fast alpha wave amplitude increments, and elevations in beta wave amplitude, which were greater in female than in male smokers. Naltrexone attenuated the alerting and euphoric actions of nicotine but did not affect nicotine's ameliorating effects on withdrawal symptoms. Nicotine-induced frontal reductions in delta and global reductions in theta were prevented by naltrexone pretreatment, as were increases in anterior recordings of relative fast alpha. These findings suggest that the opioid system is involved in nicotine-induced subjective and neuroelectric arousal and implicate opioid-cholinergic interactions in the elicitation of these arousal responses to nicotine. The endogenous opioid system has been implicated in substance abuse and response to pharmacotherapies for nicotine and alcohol addiction. We examined (1) the association of the functional OPRM1 A118G variant with the relative reinforcing value of nicotine and (2) the main and interacting effects of the mu-opioid receptor antagonist naltrexone on nicotine reinforcement.
                In a within-subject, double-blind human laboratory study, 30 smokers of each OPRM1 genotype (A/A vs. A/G or G/G) participated in two experimental sessions following 4 days of orally administered naltrexone 50 mg or placebo. Participants completed a validated assessment of the relative reinforcing value of nicotine. This cigarette choice paradigm assesses self-administration of 0.6 mg nicotine vs. 0.05 mg (denicotinized) cigarettes after a brief period of nicotine abstinence.
                The relative reinforcing value of nicotine (number of nicotine cigarette puffs) was predicted by a significant OPRM1 by gender interaction. Among women, the low-activity G allele (A/G and G/G) was associated with a reduced reinforcing value of nicotine; among male smokers, there was no association with genotype. Smokers carrying a G allele were also significantly less likely to differentiate the nicotine vs. denicotinized cigarettes by subjective ratings of satisfaction and strength. No evidence for an effect of naltrexone on nicotine reinforcement was found in the overall sample or in the genotype or gender subgroups.
                This study provides initial evidence for an association of the OPRM1 A118G variant with nicotine reinforcement in women. Although naltrexone has been widely researched in the context of drinking and smoking behaviors, with each substance studied separately, little is known about the effects of naltrexone on craving for cigarettes during alcohol intoxication.
                The present study used a within-subjects double-blind placebo-controlled design to (1) examine the effects of alcohol, administered intravenously, on craving for cigarettes; (2) test the effects of naltrexone on cigarette craving during alcohol intoxication; and (3) examine the relationship between craving for alcohol and cigarettes across rising breath alcohol concentrations (BrACs).
                Heavy drinking light smokers completed two counterbalanced intravenous alcohol challenge sessions, one after taking naltrexone (50 mg) for 3 days and one after taking a placebo for 3 days. During each session, participants reported on their craving for alcohol and cigarettes.
                Analyses revealed a significant positive effect of BrAC on urge to smoke as well as a BrAC x Medication interaction. Specifically, the linear relationship between BrAC and urge to smoke was significantly weaker in the naltrexone condition, as compared to placebo. There was also a positive association between urge to drink and urge to smoke, and this relationship was moderated by BrAC.
                These findings demonstrate that the pharmacological effects of alcohol alone induce craving for cigarettes and that naltrexone blunts the progression of craving for cigarettes during alcohol intoxication. These results highlight the potential clinical utility of naltrexone for heavy drinkers trying to quit smoking. In order to provide information about the hypothesis that endogenous opioids mediate the reinforcing properties of cigarette smoking, the present study examined the effects of naloxone, an opioid antagonist, on cigarette smoking in seven normal volunteers. The study used experimental procedures that had previously been shown sensitive for detecting the effects of other drugs, (including a nicotine antagonist) on smoking. Isolated subjects smoked their regular brand of cigarettes freely in a naturalistic laboratory environment while watching television or reading. Sixty minutes before each 2 h smoking session subjects received an IM injection of naloxone HCl (0.0625, 0.25, 1.0, or 4.0 mg/kg) or placebo. Each subject received each treatment three times in a mixed order across days. Naloxone did not significantly affect any measure of cigarette smoking including number of cigarettes, number of puffs, or expired air carbon monoxide level. Naloxone did, however, produce significant dose-related increases in subject ratings of yawning, stretching, and relaxation. The results of the present study provide no support for the endogenous opioid theory of smoking reinforcement. There are mixed results on the effects of opioid antagonists on acute nicotine response in humans. The present study examined the effects of a single dose of 50 mg oral naltrexone relative to placebo on smoking response in 22 chronic smokers during short-term nicotine abstinence, after acute smoking and subsequent smoking deprivation, and on smoking behavior in a choice paradigm. The results showed that naltrexone significantly reduced immediate postcigarette ratings of smoking craving and desire to smoke and increased light-headedness, dizziness, and head rush (ps < 0.05). Reductions in craving and smoking desire persisted during a subsequent 1 h nonsmoking interval. Naltrexone also was found to significantly reduce the total number of cigarettes smoked in the choice interval, which was supported by objective measures of both reduced CO and plasma nicotine levels (ps < 0.01). Exploratory analyses on potential individual difference factors revealed that smokers with the highest levels of craving during abstinence showed the most pronounced naltrexone attenuation of smoking response. The results support the continued exploration of naltrexone as an adjunct to smoking cessation, especially in identified smoker subgroups most sensitive to the effects of opioid antagonism. This study examined whether the opioid receptor antagonist naltrexone is efficacious in smoking cessation and whether sex moderates the response. We assessed smoking quit rates and weight gain in a double-blind randomized trial comparing oral naltrexone (n = 162) with placebo (n = 154) in nicotine-dependent participants who wanted to quit smoking. The medication was gradually titrated up to 50 mg during the week before the quit date and then maintained at this dose for 12 weeks. For the first 4 weeks after the quit date, all participants received a nicotine patch to mitigate tobacco withdrawal and attended weekly individual cognitive-behavioral smoking cessation counseling sessions. After this time, participants continued with naltrexone or placebo through 12 weeks. Follow-up assessments were conducted at 26 and 52 weeks. During treatment, naltrexone (vs placebo) increased quit rates, attenuated smoking urge, and reduced weight gain. At follow-up, after medication discontinuation, the effect of naltrexone on improving quit rates was no longer evident. Men and women experienced different benefits from naltrexone; men showed greater reductions in smoking, whereas women showed greater reductions in weight gain. In sum, naltrexone showed acute efficacy in treating nicotine dependence, but after the medication was discontinued, the effect on quit rate was not maintained. Further study of naltrexone in smoking cessation treatment and reduction of cessation-related weight gain, as well as preclinical investigation of mechanisms underlying sex differences, is warranted. Although treatment with transdermal nicotine replacement (TNR) has improved smoking abstinence rates, higher doses of TNR could improve effects on urge to smoke, nicotine withdrawal, and reinforcement from smoking, and naltrexone might further reduce reinforcement and urges. A laboratory investigation with 134 smokers using a 3 x 2 parallel-group design evaluated the effects of TNR (42-mg, 21-mg, or 0-mg patch) as crossed with a single dose of naltrexone (50 mg) versus placebo on urge to smoke, withdrawal, and responses to an opportunity to smoke (intake, subjective effects) after 10 hr of deprivation. Urge and withdrawal were assessed both prior to and after cigarette cue exposure. Only 42 mg TNR, not 21 mg, prevented urge to smoke, heart rate change, and cue-elicited increase in withdrawal. Both 21 and 42 mg TNR blocked cue-elicited drop in heart rate and arterial pressure. Naltrexone reduced cue-elicited withdrawal symptoms but not urges to smoke or deprivation-induced withdrawal prior to cue exposure. Neither medication significantly affected carbon monoxide intake or subjective effects of smoking except that 42 mg TNR resulted in lower subjective physiological activation. No interaction effects were found, and no results differed by gender. Results suggest that starting smokers with 42 mg TNR may increase comfort during initial abstinence, but limited support is seen for naltrexone during smoking abstinence. Naltrexone (NTX), by its pharmacological action in the mesolimbic pathways, should decrease reinforcement from nicotine as well as from alcohol. By means of this mechanism, NTX could result in temporary increases in smoking followed by decreased smoking rates among alcoholics not motivated to quit smoking. The change from pretreatment in smoking rates of 73 recently abstinent alcoholics in a 12-week clinical trial of NTX vs. placebo during alcoholism treatment was compared during 8 of the 12 weeks. Only smokers compliant with NTX were included in the analyses. NTX was associated with decreased smoking at every time point, but the effect was significant at only one time point. When alcohol relapsers were excluded, NTX patients showed decreased smoking at every time point, but the effect was significant at only two time points, a reduction of about five cigarettes per day. When smoking stage of change was included in the analyses, NTX showed no significant main or interaction effects on smoking rate. Precontemplators showed significantly less change in smoking rate than all other patients at the first and last four time points. Therefore, NTX alone currently does not show promise for promoting smoking reduction among recently abstinent alcoholics who have not sought or been given smoking cessation treatment. Further research is needed on possible effects with smokers motivated to quit smoking and on other methods of promoting smoking cessation among alcoholics. This study examined the efficacy of naltrexone, a long-acting opiate antagonist, as a smoking cessation aid in a double-blind placebo-controlled randomized trial. It was hypothesized that naltrexone would result in higher quit rates at the end of treatment and six months later.
                Subjects were 68 smokers aged 18 to 65 who smoked at least 20 cigarettes daily and wished to stop smoking. They took naltrexone or placebo daily for four weeks and were seen weekly for individual smoking cessation therapy.
                A statistical trend towards a higher overall cessation rate (cotinine < 15 ng/mL) at end-of-treatment was observed among subjects treated with naltrexone than placebo (46.7% vs. 26.3%, respectively, odds ratio = 2.5, p < .10); however, this difference was attenuated at six months (27% vs. 15%, respectively, odds ratio = 1.9, p = ns). Stratified analysis indicated the usefulness of naltrexone primarily for female smokers and those with a history of major depression. These effects remained six months later.
                These results provide, at best, mild promise for naltrexone as a smoking cessation drug and provide another instance of a differential response to nicotine dependence treatment according to gender and depression history. The effect of sublingual buprenorphine on cigarette smoking was examined in 23 adult men with DSM III-R diagnosis of concurrent opiate and cocaine dependence. After admission to a clinical research ward, subjects were detoxified with methadone (10-50 mg/day), then were drug-free for 6 days before random assignment to either 4 or 8 mg/day of buprenorphine. Gradually increasing daily sublingual doses of buprenorphine were administered for 5 days, then subjects were maintained on 4 or 8 mg/day of buprenorphine for 12 days. Each subject's preferred brand of cigarettes was available ad libitum throughout the study. Five responses (FR 5) on a key were required to earn each cigarette. The time and number of cigarettes were recorded by an automated cigarette dispenser. Subjects acquired significantly more cigarettes during the buprenorphine induction and maintenance phases (25.5+/-2.0) than during the drug-free phase (18.5+/-1.8; p<0.0002). During buprenorphine induction, the number of cigarettes acquired was positively correlated with increasing doses of buprenorphine (p<0.001) and the inter-cigarette interval was significantly shorter during buprenorphine maintenance than during drug-free conditions (p<0.001). These data showed that daily administration of the partial mu opioid agonist buprenorphine was associated with increased smoking in men concurrently dependent on opiates and cocaine. These findings are consistent with previous reports of opioid-cigarette interactions. To evaluate the efficacy and safety of orally administered naltrexone, alone or in combination with nicotine patches, as a treatment for cigarette smoking.
                Randomized, partially-blinded, 2 x 2 factorial trial using naltrexone (active vs. placebo) and nicotine patches (active vs. none).
                One hundred cigarette smokers.
                Twelve weeks of either placebo-only, naltrexone-only, placebo with nicotine patches or naltrexone with nicotine patches. The naltrexone dose was 50 mg taken once daily, and the nicotine patch dose was 21 mg/24-hour for the first 8 weeks and 14 mg/24-hour for the remaining 4 weeks. Brief behavioral intervention was provided at each visit.
                One-week point-prevalence smoking abstinence rates confirmed by an expired air carbon monoxide level of 8 parts per million (ppm) or less, daily cigarette smoking and cigarette craving.
                At the end of treatment, there was no effect of naltrexone on smoking abstinence. The smoking abstinence rates were 19% and 22% for the placebo only and naltrexone only treatment groups, respectively, and 48% and 46% for the placebo with nicotine patch and naltrexone with nicotine patch groups, respectively. However, the effect of the nicotine patch at this time was significant (p = 0.006), but not at the 6-month follow-up. No significant effect of naltrexone was observed on daily cigarette smoking on cigarette craving during the study.
                The opioid antagonist naltrexone was not found to be effective for smoking cessation and had no significant effect on daily cigarette consumption or craving. The results of the present study provide no support for the use of naltrexone, alone or in combination with nicotine patches, as a therapeutic treatment for smoking cessation. The role of endogenous opiate systems in cigarette smoking remains unclear. In laboratory animals, opiate antagonists block many of the effects of nicotine, but in humans they do not consistently alter smoking behavior.
                This study explored the effects of naltrexone, alone and in combination with nicotine, on smoking behavior.
                In a double-blind, double-dummy, within-subjects design, 19 regular smokers received four treatments of 1 week duration: naltrexone tablet (50 mg) plus placebo skin patch, placebo tablet plus nicotine skin patch (21 mg/24 h), naltrexone tablet plus nicotine skin patch, and placebo tablet plus placebo skin patch. During each treatment, subjects rated their responses to nicotine-containing and denicotinized cigarettes in the laboratory, and to their own brand of cigarette smoked ad libitum outside the laboratory.
                Pretreatment with the nicotine patch attenuated smoking-induced decreases in craving, negative affect, and rates of ad lib smoking, and potentiated the aversiveness of a cigarette. Naltrexone reversed these effects of the nicotine patch, and produced negative effects on mood.
                The blockade of nicotine's effects by naltrexone supports a role for opioid mechanisms in cigarette smoking. Human behavioral pharmacology studies can examine how medications that target different neurotransmitter systems influence different aspects of smoking. Naltrexone and bupropion have been shown to alter ad lib smoking behavior; however, medication effects on nicotine reward in a cigarette choice paradigm have yet to be investigated.
                This study explored the effects of an acute dose of naltrexone, bupropion, or placebo on the relative reinforcing value of nicotine from cigarette smoking using new nicotine and de-nicotinized (Quest, 0.6 and 0.05 mg = "denicotinized") cigarettes.
                In a double-blind, within-subjects design, 26 dependent smokers participated in three experimental cigarette smoking sessions following pretreatment with either naltrexone (50 mg), bupropion (300 mg), or placebo. After medication administration and 2 h of monitored deprivation from cigarettes and food, participants rated their responses to the initial exposure to the cigarettes and then participated in four choice sessions over a 2-h period during which they could take four puffs from either cigarette.
                The relative reinforcing value of nicotine, as measured by the number of nicotine puffs chosen out of 16, was significantly lower following naltrexone compared to placebo. There were no effects of an acute dose of bupropion on nicotine choices.
                These results suggest that naltrexone may reduce the relative reinforcing effects of nicotine via cigarette smoking and support ongoing investigation of opioid antagonists as potential smoking cessation pharmacotherapies. nan Many smokers remain refractory to current therapies, which only partially address weight gain after smoking cessation. Thus, this study evaluated whether naltrexone hydrochloride augmentation of nicotine patch therapy improves smoking abstinence and reduces postcessation weight gain more than nicotine patch therapy alone and at what dose.
                Six-week double-blind placebo-controlled trial with follow-up in an outpatient research center. Four hundred individuals who smoked 20 or more cigarettes daily were randomly assigned to treatment for 6 weeks with a 21-mg nicotine patch and oral naltrexone hydrochloride (0, 25, 50, or 100 mg/d) after equal random treatment assignment and followed up for 1 year after randomization. The a priori specified primary end points were prolonged 4-week cigarette abstinence after a 2-week grace period in the intent-to-treat sample and weight gain in these abstainers.
                We found no significant differences in prolonged 4-week abstinence (P = .49) or 6-week continuous abstinence after the quit date (P = .12) during treatment in the intent-to-treat analysis. Among 295 treatment completers, the 100-mg dose was associated with higher continuous abstinence rates (71.6%) compared with placebo (48%) (odds ratio, 2.73; 95% confidence interval, 1.39-5.39; P<.01). Among continuous abstainers, the 25-mg naltrexone hydrochloride group gained significantly less weight (mean +/- SEM, 0.7 +/- 0.31 kg) than the placebo group (mean +/- SEM, 1.9 +/- 0.33 kg; P<.01). Similar naltrexone dose effects on weight were found for those with prolonged abstinence and treatment completers, irrespective of abstinence.
                The 100-mg dose of naltrexone hydrochloride appears the most promising for augmenting the efficacy of the nicotine patch on smoking cessation outcomes but requires further study. The significant weight reduction with low-dose naltrexone therapy suggests that it may be useful as a second-line treatment for weight-concerned smokers. Endogenous opioid peptides have been implicated in the reinforcement of smoking and opioid antagonists have been examined to determine their role in smoking behavior. To date, the relationship between smoking behavior and chronic opiate antagonist administration during ad libitum smoking has not been investigated. The purpose of this study was to examine the relationships between naltrexone, an opiate antagonist administered orally, and smoking behavior and mood states during ad libitum smoking. A repeated measures experimental design was used. Normal adult male and female volunteers, admitted to the Clinical Research Center, were randomly assigned to naltrexone-treated (n = 22) or placebo-control (n = 21) groups in a double-blind manner. Day 1 was considered acclimation to the unit and day 2 was baseline, or pre-drug administration. On days 3, 4, and 5, subjects received 50 mg naltrexone or a placebo at 0700 and 1600 hours. Plasma nicotine and expired air carbon monoxide levels were measured daily at 1900 hours. Number of cigarettes smoked, mood states, withdrawal symptomatology and self-reported satisfaction with smoking were also quantified daily. Results indicated that plasma nicotine levels (P = 0.005), number of cigarettes smoked daily (P = 0.003) and self-reported satisfaction with smoking (P = 0.043) were significantly lower among those treated with naltrexone, compared to the placebo-control group. Expired air carbon monoxide levels did not differ between the two groups. In addition, mood states and withdrawal symptoms did not differ between groups. These findings suggest that endogenous opioid peptides influence specific smoking behavior variables. This double-blinded, placebo-controlled trial evaluated the efficacy of naltrexone as an adjunct to standard smoking cessation treatment. Participants (N = 110) were adult male and female nicotine-dependent smokers who expressed interest in quitting smoking. All subjects received six sessions of behavioral counseling (1 hr/session for 6 weeks), and 1 month of the nicotine patch (21 mg for the first 2 weeks, 14 mg the third week, 7 mg the fourth week). Subjects were randomly assigned to the naltrexone or placebo group. The naltrexone group started at 25 mg daily for 3 days prior to the quit date, and increased to 50 mg/day on the quit date and following 8 weeks. At the end of medication treatment, the naltrexone group had better quit rates versus the placebo group (48% quit on naltrexone vs. 41% on placebo), but this difference was not statistically significant. However, men and women differed on several measures: in the placebo group, women had significantly lower quit rates than men (39% vs. 67%, p<.05), but in the naltrexone group, women had quit rates comparable with those of men (58% vs. 62%, p = ns). Further examination revealed that naltrexone significantly reduced men's and women's cessation-related weight gain and selectively reduced women's urge to smoke to relieve negative affect and withdrawal. The results suggest continued examination of naltrexone as an adjunct in smoking cessation, particularly in female smokers, who have historically shown worse outcomes with traditional treatment methods. nan This study used an opioid antagonist challenge procedure to evaluate the responsivity of the endogenous opioid system in nicotine-dependent individuals, as evidenced by naloxone-induced alterations in both behavioral (withdrawal, craving) and neuroendocrine (cortisol levels) parameters.
                Twenty subjects (9 smokers and 11 nonsmokers) participated in 4 laboratory sessions during which they were challenged with 0, 0.8, 1.6, or 3.2 mg/70 kg of naloxone and then monitored for 1 hour for subjective signs and symptoms of opiate-like withdrawal, nicotine craving, and alterations in cortisol levels.
                Nicotine-dependent subjects evidenced naloxone dose-dependent increases in withdrawal signs and symptoms. Lower doses of naloxone also produced increases in urges to smoke (craving) and tiredness in smokers. Smokers, when compared with nonsmokers, had lower prenaloxone baseline levels of cortisol and attenuated cortisol release in response to challenge with naloxone.
                These results provide preliminary evidence to suggest that long-term exposure to cigarette smoke is associated with alterations in the responsivity of the endogenous opioid system and the hypothalamic-pituitary-adrenal axis that may contribute to the development of nicotine dependence. This study was done to evaluate the therapeutic effects of naltrexone on smoking behaviors and to measure the changing of brain substances for elucidating the mode of action by naltrexone. Twenty-five voluntarily participated healthy male smokers were randomly assigned to naltrexone group or placebo group for 2 weeks. In this study, naltrexone group showed significant reduction in daily cigarette consumption amount, the expiratory CO levels, brief questionnaire for smoking urge (B-QSU) score, and FTQ score. However, only 2 subjects in naltrexone group quitted smoking completely at 4th week. Plasma levels of pituitary hormones (ACTH, cortisol, and prolactin) and endogenous opioids (beta-endorphin and dynorphin A) were checked weekly before and after the 'provocation and smoking coupled' stimulus once in a week for 3 weeks. In naltrexone group, pituitary hormones showed upward tendencies even though only the prolactin had statistical significance. However, beta-endorphin and dynorphin A were not significantly different between the two groups. It was suggested that naltrexone made effects on hypothalamo-pituitary-adrenocortical axis activity as well as smoking behavior. However, the meaning of these endocrinal changes by naltrexone is not conclusive, whether it is beneficial or aversive. A high smoking prevalence has been registered among alcoholics. It has been pointed out that alcoholic smokers may have a more severe course and greater severity of alcoholism. This study aims at comparing smoking and non-smoking alcoholics in terms of treatment outcomes and verifying the efficacy of topiramate and naltrexone to decrease the use of cigarettes among alcoholic smokers.
                The investigation was a double-blind, placebo-controlled, 12-week study carried out at the University of São Paulo, Brazil. The sample comprised 155 male alcohol-dependent outpatients (52 non-smokers and 103 smokers), 18-60 years of age, with an International Classification of Diseases (ICD-10) diagnosis of alcohol dependence. After a 1-week detoxification period, the patients randomly received placebo, naltrexone (50mg/day) or topiramate (up to 300 mg/day). Only the alcoholic smokers who adhered to the treatment were evaluated with reference to the smoking reduction.
                Cox regression analysis revealed that the smoking status among alcoholics increased the odds of relapse into drinking by 65%, independently of the medications prescribed, using the intention-to-treat method. Topiramate showed effectiveness to reduce the number of cigarettes smoked when compared to placebo among adherent patients (mean difference=7.91, p<0.01). There were no significant differences between the naltrexone group and the placebo group.
                The results of this study confirm that the treatment is more challenging for smoking alcoholics than for non-smoking ones and support the efficacy of topiramate in the smoking reduction among male alcoholic smokers who adhered to the treatment. Cigarette smoking increased during administration of buprenorphine, an opioid mixed agonist-antagonist, in comparison to drug-free baseline in seven heroin addicts maintained on buprenorphine for 24 days (P less than 0.01-0.001). Ascending buprenorphine doses (0.5 - 8.0 mg/day) were associated with significant increases in cigarette smoking at doses of 2.0 mg/day sc and above. Cigarette smoking during 10 days of buprenorphine maintenance at 8 mg/day was significantly higher than during the buprenorphine induction phase (P less than 0.01). Six subjects given placebo buprenorphine over 14 days showed no change in cigarette smoking. The placebo group self-administered heroin for 10 days, and cigarette smoking increased significantly during heroin use (P less than 0.001). The rate of cigarette smoking defined by intercigarette intervals was highest during the 10 days of high-dose buprenorphine maintenance or placebo plus heroin self-administration. Both groups requested significantly more cigarettes at intervals of 0-10, 11-20, and 21-30 min than during the drug-free baseline. These data confirmed previous findings that opioid agonist administration is associated with increased cigarette smoking and suggest that buprenorphine has primarily agonist effects on cigarette smoking.
Based on data from eight trials and over 1200 individuals, there was no evidence of an effect of naltrexone alone or as an adjunct to NRT on long-term smoking abstinence, with a point estimate strongly suggesting no effect and confidence intervals that make a clinically important effect of treatment unlikely. Although further trials might narrow the confidence intervals they are unlikely to be a good use of resources.