Effects of naltrexone on alcohol self-administration in heavy drinkers

The mechanisms underlying the suppressant effects of naltrexone (NTX) on ad libitum alcohol drinking in a bar/restaurant setting were investigated in heavy beer drinkers. Fifty-one male and female heavy drinkers (mean age = 22) received 50 mg of NTX or placebo (PBO), p.o., on two separate occasions in a randomized, double-blind crossover protocol. After 7 days of taking medication, subjects were provided with the opportunity to consume beer ad libitum during two, 90-min test sessions that were held 1 to 2 weeks apart. Blood samples were collected on test days to ensure medication compliance and to measure blood levels of NTX and the active beta-naltrexol. Less beer was consumed during NTX treatment. NTX decreased urges to consume alcohol. NTX-treated subjects also took significantly longer to finish each glass of beer and were more likely to terminate beer drinking early. Self-report stimulation and ratings of positive mood states were lower during NTX treatment. Negative side effects of NTX, such as nausea and headache, were reported more frequently with NTX. Not all of the subjects decreased their beer intake on NTX, and some subjects drank more beer. Nonresponders to NTX were not related to blood levels of the active metabolite beta-naltrexol or to a family history of alcoholism. Overall, the results of this study suggest that NTX affects a number of the components of alcohol drinking sequence, including lowering cravings, decreasing the positive reinforcing effects of alcohol, and increasing headache and nausea, each of which may contribute to reducing alcohol intake.     

Effects of topiramate on cue-induced cigarette craving and the response to a smoked cigarette in briefly abstinent smokers

Rationale Clinical studies have shown that topiramate, an anticonvulsant medication, may be effective as a treatment for smoking cessation. However, less is known about topiramate effects on nicotine withdrawal and craving and its interactions with a smoked cigarette. Objectives The objective of this study was to investigate the effects of topiramate treatment on abstinence-related nicotine withdrawal, cue-induced cigarette craving, and the acute effects of a smoked cigarette. Materials and methods Fifteen female and 25 male cigarette smokers were randomly assigned to 9-day treatment with topiramate (final titration dose, 75 mg/day) or placebo. On the last day of treatment, after a 3-h smoke-free abstinence period, participants were evaluated for symptoms of nicotine withdrawal and then underwent cigarette and neutral cue reactivity testing. Thirty minutes after completing cue exposure testing, participants were then evaluated for the acute effects of a smoked cigarette. Cue reactivity and acute smoking measures included subjective ratings of cigarette craving and withdrawal and physiological measures of skin conductance and temperature, heart rate, and blood pressure. In addition, smoking topography was measured using a puff volume apparatus. Results Topiramate treatment enhanced subjective ratings of withdrawal after the 3-h abstinence period and reduced pre-cue skin conductance levels. Cigarette cue exposure resulted in a moderate increase in craving, which was unaffected by treatment. Topiramate treatment enhanced the rewarding effects of a smoked cigarette, even while participants smoked less per puff and achieved lower plasma nicotine levels. Conclusion Results suggest that topiramate enhances both nicotine withdrawal and reward. These findings question the utility of topiramate treatment for smoking cessation.     

Brain opioid receptor binding in early abstinence from alcohol dependence and relationship to craving: An [C]diprenorphine PET study

The importance of the opioid receptor system in substance dependence is increasingly recognised. We used PET with the non-selective tracer [¹¹C]diprenorphine to examine opioid receptor binding in early abstinence from alcohol dependence and the relationship to craving. We recruited 11 alcohol dependent patients and 13 controls. Subjects underwent one [¹¹C]diprenorphine PET scan in early abstinence from dependent alcohol use ( 2 weeks) and 2 months later if continuously abstinent. Global and regional [¹¹C]diprenorphine volumes of distribution (VD) were increased in alcohol dependent patients compared with controls but did not reach significance. We demonstrated a correlation between global and regional [¹¹C]diprenorphine VD and craving in alcohol dependent patients which persisted in the anterior cingulate cortex into extended abstinence. This confirms previous work showing increased opioid receptor availability in early abstinence from substances of abuse and correlation with craving suggesting that the opioid system plays a fundamental role in this phase of addiction.     

24-h smoking abstinence potentiates fMRI-BOLD activation to smoking cues in cerebral cortex and dorsal striatum

Rationale  Exposure to smoking-related cues can trigger relapse in smokers attempting to maintain abstinence. Objectives  In the present study, we evaluated the effect of 24-h smoking abstinence on brain responses to smoking-related cues using functional magnetic resonance imaging (fMRI). Materials and methods  Eighteen adult smokers underwent fMRI scanning following smoking as usual (satiated condition) and following 24-h abstinence (abstinent condition). During scanning, they viewed blocks of photographic smoking and control cues. Results  Following abstinence, greater activation was found in response to smoking cues compared to control cues in parietal (BA 7/31), frontal (BA 8/9), occipital (BA 19), and central (BA 4) cortical regions and in dorsal striatum (putamen) and thalamus. In contrast, no smoking cue greater than control cue activations were observed following smoking as usual. Direct comparisons between conditions (satiated vs. abstinent) showed greater brain reactivity in response to smoking cues following abstinence. In addition, positive correlations between pre-scan craving in the abstinent condition and smoking cue activation were observed in right dorsomedial prefrontal cortex (dmPFC) including superior frontal gyrus (BA 6/10), anterior cingulate gyrus (BA 32), and supplementary motor area (BA 6). Conclusions  The present findings indicate that smoking abstinence significantly potentiates neural responses to smoking-related cues in brain regions subserving visual sensory processing, attention, and action planning. Moreover, greater abstinence-induced craving was significantly correlated with increased smoking cue activation in dmPFC areas involved in action planning and decision making. These findings suggest that drug abstinence can increase the salience of conditioned cues, which is consistent with incentive-motivation models of addiction. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Diurnal variation in cue-induced responses among protracted abstinent heroin users

Objectives

The physiological and psychological responses to drug cue exposure have been assessed in substance abusers. However, there is no study to demonstrate whether the responses to drug cue exposure are diurnal dependence. The present study was to examine whether there was a variation in drug-related cue reactivity across the diurnal cycle among recently abstinent opiate addicts.

Methods

Four groups of 20 abstinent heroin dependent patients (n = 80) were exposed to both neutral and drug-related videos at four separate times during the day: 8:00, 12:00, 16:00, and 20:00 h. Physiological and psychological responses, including heart rate, blood pressure, heroin craving, and subjective anxiety were assessed before and after each cue exposure.

Results

Drug cue significantly increased craving ratings compared to neutral cues across all the four separate times of day. Drug cue-induced craving was greater in the morning (8:00 am) than noon (12:00 pm), but was similar to evening assessments (8 pm). Drug cues also significantly increased anxiety, which positively correlated with cue-induced craving. Drug cues increased heart rate, systolic and diastolic blood pressures, which were not correlated with cue-induced craving or anxiety. However, no time effects were found on the three physiological measures.

Conclusions

Cue-induced craving could be profoundly affected by the time points of cue exposure, using cue-reactivity paradigm. The relative sensitivity of morning and evening assessments of drug craving suggests a need for replication and further research on mechanisms contributing to these diurnal variations.     

Tetrodotoxin reduces cue-induced drug craving and anxiety in abstinent heroin addicts

Background

Tetrodotoxin (TTX) is a neurotoxin found in puffer fish and other marine animals. New clinical studies suggest that low-dose TTX can safely relieve severe, treatment-resistant cancer pain. The therapeutic potential of TTX in addiction is supported by studies in laboratory animals. The purpose of this double-blind, placebo-controlled study was to assess the effect of a single intramuscular dose of TTX on cue-induced craving and anxiety in abstinent heroin addicts.

Methods

Forty-five abstinent heroin addicts were randomly assigned to three treatment groups: placebo, 5 µg TTX, or 10 µg TTX. Participants were exposed to a neutral video or a heroin-related video. Craving, anxiety, blood pressure, and heart rate were measured pre- and post-exposure.

Results

Heroin-related cues increased both craving and anxiety and had no effect on blood pressure and heart rate. A single dose of TTX dose-dependently attenuated the increases in craving and anxiety while having no effect on blood pressure or heart rate.

Conclusion

The results suggest that low-dose TTX is acutely effective in reducing cue-induced increases in heroin craving and associated anxiety.     

Clinical and laboratory assessment of the subjective experience of drug craving

Measures of subjective drug craving — often defined as the experience of an intense or compelling urge or desire — may be used to predict relapse, evaluate psychological and pharmacological treatments, and test theories of addiction and craving. This review summarizes both direct self-report questionnaires and indirect behavioral, physiological and reaction time measures designed to assess craving for alcohol, amphetamines, cocaine, heroin, marijuana, and tobacco. Multi-item questionnaires have typically been based on one of four underlying conceptualizations of addiction or craving (obsessive–compulsive, approach-avoidance, multi-dimensional, intensity–frequency–duration). Most multi-item self-report questionnaires have high internal consistency, correlate significantly with single-item craving ratings, and demonstrate several aspects of construct validity. Proposed indirect or proxy measures of craving include drug dreams, speed of drug consumption, willingness to work for drug access, selection of monetary rewards over drug access, psychophysiological reactivity, and attentional bias to drug cues. These proxy measures of craving are presumed to obviate self-report biases, to be less subject to conscious self-control, and to reflect craving which the person may not be able to articulate; however, there have been too few demonstrations of their validity and they have too many practical limitations to supplant self-report measures of craving at this time.     

Promoter specific methylation of the dopamine transporter gene is altered in alcohol dependence and associated with craving

Dopaminergic neurotransmission plays a crucial role in the genesis and maintenance of alcohol dependence. Epigenetic regulation via promoter specific DNA methylation of the dopamine transporter gene (DAT) may influence altered dopaminergic neurotransmission in alcoholism. Aim of the present study was to investigate DNA promoter methylation of DAT in early alcohol withdrawal and in relation to alcohol craving. We analyzed blood samples of 76 patients admitted for detoxification treatment and compared them to 35 healthy controls. Methylation specific quantitative real-time PCR was used to measure the promoter specific DNA methylation of the dopamine transporter. We assessed the extent of alcohol craving using the obsessive compulsive drinking scale (OCDS). Compared to healthy controls we found a significant hypermethylation of the DAT-promoter (Mann-Whitney U-test: p = 0.001). Ln-transformed methylation of the DAT-promoter was negatively associated with the OCDS (linear regression: Beta = −0.275, p = 0.016), particularly with the obsessive subscale (Beta = −0.300, p = 0.008). Findings of the present study show that the epigenetic regulation of the DAT-promoter is altered in patients undergoing alcohol withdrawal. Furthermore, hypermethylation of the DAT-promoter may play an important role in dopaminergic neurotransmission and is associated with decreased alcohol craving.     

A qualitative and quantitative review of cocaine-induced craving: the phenomenon of priming

Drug-induced craving is thought to play an important role in relapse occasioned by a "slip", or an isolated use of a previously abused drug after a period of abstinence. Clinical experience suggests that acute exposure to cocaine elicits craving (hereafter referred to as "priming"); however, this has received surprisingly little attention in the clinical literature. AIMS: The intentions of this review are to provide a qualitative review of the literature as well as a more stringent quantitative review of the existence and presence of cocaine-induced priming effects. METHODS: In order to determine whether priming effects occur following cocaine administration, we conducted qualitative and quantitative reviews of studies in which participants received cocaine under experimentally controlled conditions in the laboratory. RESULTS: The results of the qualitative review were equivocal, while the quantitative review revealed that cocaine administration was associated with a significant increase in craving for cocaine, and the effect size of this relationship was large. CONCLUSION: A review of the individual studies revealed marked variability, suggesting that priming effects did not occur consistently and that there may be factors that mediate or moderate the intensity of the priming effects induced by cocaine. The implications of these findings are discussed.     

Evidence of an association of leptin serum levels and craving in alcohol dependence

Recent studies have described an association of leptin serum levels and craving in alcohol dependent patients. The aim of the present study was to investigate a large patients' sample using a power-based statistical analysis. We included 156 male and 33 female patients suffering from alcohol dependence admitted for detoxification treatment. Leptin serum levels were measured using a commercial ELISA kit. The Obsessive Compulsive Drinking Scale (OCDS) was used to assess alcohol craving at admission. For both genders Spearman's correlation revealed significant results. These findings could be confirmed using multiple linear regression models (males: r=1.881, t=4.338, p<0.001; females: r=6.160, t=5.793, p<0.001) with a power of 1.00. In contrast to previous results describing an association only in female patients, this power-based analysis shows that leptin is associated with alcohol craving in both genders.