Low-dose ondansetron: A candidate prospective precision medicine to treat alcohol use disorder endophenotypes.

BACKGROUND: Alcohol use disorder (AUD) is among the leading causes of morbidity and mortality worldwide, and over 95 million people live with alcohol dependence globally. The estimated heritability of AUD is 50-60 %, and multiple genes are thought to contribute to various endophenotypes of the disease. Previous clinical trials support a precision medicine approach using ondansetron (AD04, a 5-HT3 antagonist) by segregating AUD populations by the bio-genetic endophenotype of specific serotonergic genotypes and the bio-psychosocial endophenotype of the severity of drinking or both. By targeting the modulation of biogenetic signaling within the biopsychosocial context of AUD, low-dose AD04 holds promise in reducing alcohol consumption among affected individuals while minimizing adverse effects. METHODS: This was a phase III, 6-month, 25-site, randomized, placebo-controlled clinical trial using AD04 to treat DSM-V-categorized AUD individuals who were pre-stratified into the endophenotypes of heavy or very heavy drinking individuals and possessed a pre-defined profile of genetic variants related to the serotonin transporter and serotonin-3AB receptor. Participants (N = 303) presented moderate to severe AUD, >80 % were men, mostly in their fifties, and >95 % were of European descent. Low-dose AD04 (approx. 033 mg twice daily) or a matching placebo was administered twice daily for 6 months. Brief Behavioral Compliance Enhancement Treatment (BBCET [53]) was administered every two weeks to enhance medication compliance and clinic attendance. RESULTS: There was a significant reduction in the monthly percentage of heavy drinking days, PHDD (-46·7 % (2·7 %), 95 %CI: -52·1 % to -41·2 % vs. -38·1 % (2·9 %), 95 %CI: -43·8 % to -32·5 %, respectively; LS mean difference=-8·5 %; p = 0.03) among AD04-treated vs. placebo-receiving heavy drinking individuals at month 6. Heavy drinking individuals were also less likely to be diagnosed with AUD [Month 1: -32·0 % (2·8 %), 95 %CI: -37·5 % to -26·5 % vs. -23·2 % (2·9 %), 95 %CI: -28·9 to -17·5 %; LS mean difference= -8·8 %; p = 0·026)], and improved on the WHO quality of life BREF scale with a significant effect for at least a 1-level downward shift (OR = 3.4; 95 % CI: 1·03-11·45, p = 0·044). Importantly, heavy drinking individuals, as distinct from very heavy drinking individuals, were the bio-psychosocial endophenotype more predictive of therapeutic response to AD04. AD04 had an exceptional safety and tolerability profile, like the placebo's. CONCLUSIONS: In this Phase 3 clinical trial, AD04 was shown to be a promising treatment for currently drinking heavy drinking individuals with AUD who also possess a specific genotypic profile in the serotonin transporter and serotonin-3AB receptor complex. Using AD04 to reduce the harm of AUD in heavy drinking individuals who are currently drinking, without the necessity of abstinence or detoxification from alcohol use, is an important advance in the field of precision medicine. AD04's adverse events profile, which was like placebo, should enhance accessibility and acceptance of modern medical treatment for AUD by lowering the incorrect but commonly perceived stigma of personal failure.

Safety and compliance of long-term low-dose ondansetron in alcohol use disorder treatment.

BACKGROUND: The increasing prevalence of alcohol use disorder (AUD) and the parallel surge in alcohol-associated liver disease (ALD) emphasize the urgent need for comprehensive alcohol management strategies. Low-dose ondansetron (AD04, a 5-HT3 antagonist) was shown recently to be a promising treatment for AUD with a specific genotypic profile (5-marker). The liver safety of AD04 has never been evaluated in subjects with AUD. The aim of the present study was to assess the liver safety profile of AD04 compared with placebo in subjects with AUD. METHODS: Liver biochemical parameters were assessed in subjects with AUD with a 5-marker genetic profile who participated in a Phase 3 randomized controlled trial and received either twice-daily, low-dose AD04 (ondansetron 0.33 mg twice daily) or matching placebo, combined with brief psychosocial counseling. ALT, AST, GGT, Serum Bilirubin, MCV, and Prothrombin were evaluated at weeks 0, 12, and 24. Adverse cardiac events, general well-being, and study completion were also assessed. RESULTS: Low-dose AD04 did not significantly change biochemical markers of liver injury, such as ALT, AST, and Serum Bilirubin. While patients with AUD displayed elevated GGT levels, typically associated with increased alcohol consumption, this parameter remained unaffected by low-dose AD04. Notably, no significant adverse effects were observed due to oral low-dose AD04 treatment. CONCLUSIONS: Low-dose AD04 has the potential to be a safe treatment option for subjects with AUD and ALD, indicating the need for an RCT for this specific cohort. Such a trial would pave the way for the design of a precision treatment for combined AUD with ALD.

Sodium Oxybate for Alcohol Dependence: A Network Meta-Regression Analysis Considering Population Severity at Baseline and Treatment Duration.

AIMS: The estimated effect of sodium oxybate (SMO) in the treatment of alcohol dependence is heterogeneous. Population severity and treatment duration have been identified as potential effect modifiers. Population severity distinguishes heavy drinking patients with <14 days of abstinence before treatment initiation (high-severity population) from other patients (mild-severity population). Treatment duration reflects the planned treatment duration. This study aimed to systematically investigate the effect of these potential effect moderators on SMO efficacy in alcohol-dependent patients. METHODS: Network meta-regression allows for testing potential effect modifiers. It was selected to investigate the effect of the above factors on SMO efficacy defined as continuous abstinence (abstinence rate) and the percentage of days abstinent (PDA). Randomized controlled trials for alcohol dependence with at least one SMO group conducted in high-severity and mild-severity populations were assigned to a high-severity and mild-severity group of studies, respectively. RESULTS: Eight studies (1082 patients) were retained: four in the high-severity group and four in the mild-severity group. The high-severity group was associated with larger SMO effect sizes than the mild-severity group: abstinence rate risk ratio (RR) 3.16, P = 0.004; PDA +26.9%, P < 0.001. For PDA, longer treatment duration was associated with larger SMO effect size: +11.3% per extra month, P < 0.001. In the high-severity group, SMO showed benefit: abstinence rate RR 2.91, P = 0.03; PDA +16.9%, P < 0.001. In the mild-severity group, SMO showed benefit only in PDA for longer treatment duration: +23.9%, P < 0.001. CONCLUSIONS: In the retained studies with alcohol-dependent patients, high-severity population and longer treatment duration were associated with larger SMO effect sizes.

Sodium oxybate for the maintenance of abstinence in alcohol-dependent patients: An international, multicenter, randomized, double-blind, placebo-controlled trial.

BACKGROUND: Sodium oxybate (SMO) has been shown to be effective in the maintenance of abstinence (MoA) in alcohol-dependent patients in a series of small randomized controlled trials (RCTs). These results needed to be confirmed by a large trial investigating the treatment effect and its sustainability after medication discontinuation. AIMS: To confirm the SMO effect on (sustained) MoA in detoxified alcohol-dependent patients. METHODS: Large double-blind, randomized, placebo-controlled trial in detoxified adult alcohol-dependent outpatients (80% men) from 11 sites in four European countries. Patients were randomized to 6 months SMO (3.3-3.9 g/day) or placebo followed by a 6-month medication-free period. Primary outcome was the cumulative abstinence duration (CAD) during the 6-month treatment period defined as the number of days with no alcohol use. Secondary outcomes included CAD during the 12-month study period. RESULTS: Of the 314 alcohol-dependent patients randomized, 154 received SMO and 160 received placebo. Based on the pre-specified fixed-effect two-way analysis of variance including the treatment-by-site interaction, SMO showed efficacy in CAD during the 6-month treatment period: mean difference +43.1 days, 95% confidence interval (17.6-68.5; p = 0.001). Since significant heterogeneity of effect across sites and unequal sample sizes among sites (n = 3-66) were identified, a site-level random meta-analysis was performed with results supporting the pre-specified analysis: mean difference +32.4 days, p = 0.014. The SMO effect was sustained during the medication-free follow-up period. SMO was well-tolerated. CONCLUSIONS: Results of this large RCT in alcohol-dependent patients demonstrated a significant and clinically relevant sustained effect of SMO on CAD. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04648423.

Baseline severity and the prediction of placebo response in clinical trials for alcohol dependence: A meta-regression analysis to develop an enrichment strategy.

BACKGROUND: There is considerable unexplained variability in alcohol abstinence rates (AR) in the placebo groups of randomized controlled trials (RCTs) for alcohol dependence (AD). This is of particular interest because placebo responses correlate negatively with treatment effect size. Recent evidence suggests that the placebo response is lower in very heavy drinkers who show no "spontaneous improvement" prior to treatment initiation (high-severity population) than in a mild-severity population and in studies with longer treatment duration. We systematically investigated the relationship between population severity, treatment duration, and the placebo response in AR to inform a strategy aimed at reducing the placebo response and thereby increasing assay sensitivity in RCTs for AD. METHODS: We conducted a systematic literature review on placebo-controlled RCTs for AD.We assigned retained RCTs to high- or mild-severity groups of studies based on baseline drinking risk levels and abstinence duration before treatment initiation. We tested the effects of population severity and treatment duration on the placebo response in AR using meta-regression analysis. RESULTS: Among the 19 retained RCTs (comprising 1996 placebo-treated patients), 11 trials were high-severity and 8 were mild-severity RCTs. The between-study variability in AR was lower in the high-severity than in the mild-severity studies (interquartile range: 7.4% vs. 20.9%). The AR in placebo groups was dependent on population severity (p = 0.004) and treatment duration (p = 0.017) and was lower in the high-severity studies (16.8% at 3 months) than the mild-severity studies (36.7% at 3 months). CONCLUSIONS: Pharmacological RCTs for AD should select high-severity patients to decrease the magnitude and variability in the placebo effect and and improve the efficiency of drug development efforts for AD.

Post-marketing and clinical safety experience with sodium oxybate for the treatment of alcohol withdrawal syndrome and maintenance of abstinence in alcohol-dependent subjects.

Introduction: Sodium oxybate (SMO) has been approved in Italy and in Austria for the treatment of alcohol use disorder (AUD). This study describes the cumulative postmarketing and clinical safety experience with SMO in AUD.Areas covered: Safety data for SMO at approved posology in AUD were identified from: (i) the clinical trial registries of the US National Institutes of Health (NIH) and the European Medicines Agency (EMA), (ii) reports from the biomedical literature and (iii) available pharmacovigilance safety information from the EMA.Expert opinion: Safety data from 3 recent large randomized clinical studies (520 participants) and 43 earlier clinical studies (2547 participants) showed that SMO has a good safety profile in AUD patients. The safety profile was confirmed by pharmacovigilance data resulting from 299 013 patients exposed to SMO in Austria and Italy. Main adverse events were transitory dizziness and vertigo. Serious adverse events were rare. No death attributable to SMO has been reported. Risks of abuse or dependence are low in patients without psychiatric comorbidities or poly-drug use. The adverse events of SMO are transitory and do not require discontinuation of treatment. SMO abuse or dependence are extremely rare in patients without psychiatric comorbidities or poly-drug use.

Efficacy and safety of sodium oxybate in alcohol-dependent patients with a very high drinking risk level.

Medication development for alcohol relapse prevention or reduction of consumption is highly challenging due to methodological issues of pharmacotherapy trials. Existing approved medications are only modestly effective with many patients failing to benefit from these therapies. Therefore, there is a pressing need for other effective treatments with a different mechanism of action, especially for patients with very high (VH) drinking risk levels (DRL) because this is the most severely affected population of alcohol use disorder patients. Life expectancy of alcohol-dependent patients with a VH DRL is reduced by 22 years compared with the general population and approximately 90 000 alcohol-dependent subjects with a VH DRL die prematurely each year in the EU (Rehm et al. ). A promising new medication for this population is sodium oxybate, a compound that acts on GABAB receptors and extrasynaptic GABAA receptors resulting in alcohol-mimetic effects. In this article, a European expert group of alcohol researchers and clinicians summarizes data (a) from published trials, (b) from two new-as yet unpublished-large clinical trials (GATE 2 (n = 314) and SMO032 (n = 496), (c) from post hoc subgroup analyses of patients with different WHO-defined DRLs and (d) from multiple meta-analyses. These data provide convergent evidence that sodium oxybate is effective especially in a subgroup of alcohol-dependent patients with VH DRLs. Depending on the study, abstinence rates are increased up to 34 percent compared with placebo with risk ratios up to 6.8 in favor of sodium oxybate treatment. These convergent data are supported by the clinical use of sodium oxybate in Austria and Italy for more than 25 years. Sodium oxybate is the sodium salt of γ-hydroxybutyric acid that is also used as a recreational (street) drug suggestive of abuse potential. However, a pharmacovigilance database of more than 260 000 alcohol-dependent patients treated with sodium oxybate reported very few adverse side effects and only few cases of abuse. We therefore conclude that sodium oxybate is an effective, well-tolerated and safe treatment for withdrawal and relapse prevention treatment, especially in alcohol-dependent patients with VH DRL.

Multidimensional alcoholism typologies: could they guide clinical practice? Results from a 3-month prospective study.

OBJECTIVE: The current nosological classifications may describe a syndrome of "alcoholism" that is too heterogeneous to produce prognostic models for clinical management. Multidimensional alcoholism typologies (ATs) could represent a valuable paradigm in the search for targeted treatment. The main goal of this study was to evaluate the clinical implications of 3 empirically-validated ATs, focusing on various measures of clinical performance. METHOD: This was a 3-month naturalistic study in which drinking status, and participation in the clinical protocol and group psychotherapy were recorded and used as indicators of treatment performance. The clinical profiles of the subtypes were also compared and graphically presented. Alcohol-dependent outpatients were classified according to the Cloninger, Lesch, and NETER typologies. RESULTS: The results showed that the type II (Cloninger), type IV (Lesch), and sociopathic and addictopathic (NETER) subgroups showed a worse outcome in terms of abstinence rates and clinical healthcare resource use. CONCLUSIONS: Our findings point to the need to differentiate multidimensional alcoholism subtypes before planning the clinical management of alcohol use disorders.

The concept of temperament in psychoactive substance use among college students.

BACKGROUND: Substance abuse is among the leading causes of preventable diseases and premature death but reasons and conditions leading to substance abuse are complex and multifaceted. Different models of abuse and dependence assume an underlying emotional vulnerability. Individual behavioral and emotional reactivity patterns of personality are considered in the concept of temperament but studies linking different types of temperament with substance use are rare. METHODS: In this study we investigated 1380 inhabitants (59.7% females; 40.3% males) of residential student homes in Austria, using Akiskals TEMPS-M auto-questionnaire. Further, we administered the CAGE- and the HSI-questionnaire and assessed other psychoactive substance use to examine associations between traits of temperament and substance abuse using ordered logistic regression. RESULTS: Temperaments follow different distributions in both genders: Women have higher scores on the depressive, cyclothymic, and anxious subscales and lower scores on the hyperthymic scale than men. The cyclothymic and particularly irritable temperament serve as predictors of self-reported nicotine dependence, alcohol abuse and cannabis use. Interestingly, the depressive temperament seems to be protective against self-reported cannabis use. LIMITATIONS: Substance abuse assessment is based on self-reports only and urine drug and blood tests were not performed. Also, the history of substance abuse is not documented thus temperamental factors could have been influenced by substance abuse if the time of onset was in early adolescence. The study design was cross-sectional, thus limiting causal interpretations. CONCLUSIONS: It might be important to consider temperamental traits as protective- and risk factors in the etiology, prevention and therapy of substance abuse in future.

Amino-terminal pro-B-type brain natriuretic peptide: screening for cardiovascular disease in the setting of alcoholism.

AIMS: N-terminal pro-BNP (NtBNP) has attracted attention as a biomarker for heart failure. The aims of our study are (a) to characterize the role of NtBNP as a biological marker in the setting of alcoholism; (b) to describe potential gender differences with respect to NtBNP; (c) to correlate NtBNP with other clinical and haemodynamic variables. METHODS: We examined 83 alcohol-dependent patients according to International Classification of Disease 10th Revision (ICD-10) and Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV; 59 males and 24 females, age: 50 ± 10.5 years) referred to the department of psychiatry for alcohol withdrawal therapy. In these patients, we determined NtBNP, markers of alcohol abuse and transthoracic echocardiography to determine systolic left ventricular ejection fraction (EF). These measurements were repeated after alcohol withdrawal. RESULTS: At Day 1 of alcohol withdrawal, 43 patients (52%; 27 males and 16 females) had elevated NtBNP levels (394.4 ± 438.7 pg/ml) despite normal EF (64.7 ± 6.2%). After withdrawal therapy (16.6 ± 7.8 days), NtBNP decreased significantly (228.6 ± 251.2 pg/ml; P < 0.01), despite unchanged EF (65.0 ± 5.8%; P = ns). This was the case in both males and females (328.9 ± 235.5 to 216.7 ± 194.3 pg/ml; P < 0.05 vs. 492.7 ± 635.7 to 246.6 ± 327.7 pg/ml; P < 0.05). Elevated NtBNP levels were related significantly to the history of arterial hypertension (P < 0.05). CONCLUSION: This study highlights the fact that NtBNP can be elevated in the setting of alcoholism. The elevation in NtBNP is unrelated to EF and is reversible after alcohol withdrawal. We suggest a subclinical detrimental effect of alcohol abuse on cardiac function.

The Lesch alcoholism typology - psychiatric and psychosocial treatment approaches.

In the past three decades, researchers have been attempting to replace the obsolete concept of homogeneity of alcohol dependence, by classifying these patients into specific heterogeneous subtypes. Based on 30 years of experience and research, the Lesch Typology has proved to be very useful in clinical daily routine. The aim of the Lesch Typology is to provide targeted subtype-specific treatments to patients, thereby increasing their probability of long-term abstinence and hence improving their prognosis. The Lesch Typology is based on data from a longitudinal prospective study (with follow ups even 19 years later) on alcohol dependent patients (n=436). By observing the long term development of these patients, four distinct courses could be identified. In the meantime, a computerized version of the Lesch Typology had been created and translated into many languages, and is currently being employed in numerous psychiatric institutions while assisting clinicians in quickly determining a patient's subtype (www.lat-online.at). Based on the patients' drinking patterns and origin of substance craving, hence according to the Lesch Typology, four subtypes of alcohol dependent patients can be distinguished: 1. the "allergy model" (craving caused by alcohol); 2. the "conflict resolution and anxiety model" (craving caused by stress); 3. the "depressive model" (craving caused by mood); and 4. the "conditioning model" (craving caused by compulsion). Pharmacological treatments are not always the most effective way of preventing relapses in alcohol dependent patients. Many times, a combination with psychosocial as well as psychotherapeutic approaches is necessary and essential for helping patients to stay sober. Depending on the patient's Lesch Type, certain therapeutic approaches are more appropriate and subsequently lead to better results and higher chances of lasting abstinence.

The alcoholic phenotypes among different multidimensional typologies: similarities and their classification procedures.

AIM: This detailed cross-sectional analysis, obtained from a sample of alcohol-dependent patients, attempts to compare multiple methods that have been created to classify or subtype alcoholics. METHODS: The sample comprised 318 alcohol-dependent patients recruited from the alcoholism unit (NETER) of the Psychiatric Service of Santa Maria University Hospital in Lisbon (Portugal). All subjects were evaluated during the outpatient therapeutical programme for operationalized criteria, reported by each alcoholism typology. RESULTS: Regarding concordance agreement (kappa values) for the three type I/II classifications, von Knorring versus Sullivan yielded the higher rate of agreement, followed by von Knorring versus Gilligan and Gilligan versus Sullivan criteria. Chi-square comparisons showed a significant overlap between Babor type A and Cloninger type I of von Knorring and Sullivan. Over-two-type classifications showed the following significant positive relations: Lesch type I versus NETER heredopathic subtype; Lesch type II versus NETER anxiopathic subtype and Babor type A; Lesch type III versus NETER tymopathic subtype; Lesch type IV versus Cloninger type II of von Knorring and Sullivan criteria; and NETER adictopathic subtype versus Cloninger type II of von Knorring, Sullivan and Gilligan criteria. CONCLUSIONS: There is a significant overlap across many of the multivariate alcoholic subtypes purposed, in which much of the concordance is a function of common characteristics in subtype operationalization. Commonalities among these different subtyping classification systems offers the possibility of identifying important dimensions that better differentiate individuals among problem drinker's populations.

Cannabinoid receptor 1 blocker rimonabant (SR 141716) for treatment of alcohol dependence: results from a placebo-controlled, double-blind trial.

Multiple lines of evidence suggest that the endocannabinoid system is implicated in the development of alcohol dependence. In addition, in animal models, the cannabinoid receptor 1 blocker rimonabant was found to decrease alcohol consumption, possibly by indirect modulation of dopaminergic neurotransmission. This was a 12-week double-blind, placebo-controlled, proof-of-concept study to assess the possible efficacy of the cannabinoid receptor 1 antagonist rimonabant 20 mg/d (2 x 10 mg) in the prevention of relapse to alcohol in recently detoxified alcohol-dependent patients. A total of 260 patients were included, 258 were exposed to medication, and 208 (80.6%) were men. Patients had an alcohol history of 15 years on average. More patients in the rimonabant group (94/131 [71.8%]) completed treatment compared with the placebo group (79/127 [62.2%]). Although there was a modest effect of rimonabant with respect to relapse rate, there were no statistically significant differences between treatment groups. Approximately 41.5% of the rimonabant group had relapsed to drinking at the end of the study compared with 47.7% of the placebo group (obtained from Kaplan-Meier-curve). Differences were more marked but not statistically significant in patients who relapsed to heavy drinking: 27.7% versus 35.6%, respectively. Safety and tolerance of the drug were good. Similar rates of adverse events were reported between the 2 groups; less patients experienced serious events or discontinued the treatment with rimonabant compared with placebo. Rates of depression-related events were low (3.8% with rimonabant compared with 1.6% with placebo). Patients on rimonabant lost weight (Mean, -1.7 kg) compared with baseline, whereas there was no such change in the placebo group. Weight loss was more pronounced in patients with a higher body mass index. In addition, there was a significant decrease in leptin levels in the rimonabant group compared with baseline. Lack of efficacy in this study may be explained by a very high response rate in the placebo group and a relatively short treatment duration. Taking the substantial numbers of animal studies suggesting a possible role of CB1 antagonists for the treatment of alcohol dependence into account, it seems worthwhile to further test cannabinoid blockers in the treatment of alcoholism.

Efficacy of flupentixol and risperidone in chronic schizophrenia with predominantly negative symptoms.

The study investigated the non-inferiority of flupentixol compared to risperidone in the treatment of negative symptoms. In addition, the effects of flupentixol on mood and cognitive symptoms were explored. In a randomized, double-blind multicenter study, 144 non-acute schizophrenia patients with predominant negative symptoms were treated with a flexible dose of either flupentixol (4-12 mg/d) or risperidone (2-6 mg/d) for up to 25 weeks. In addition to a non-inferiority analysis, a principal component analysis (PCA) of the PANSS was performed post hoc. Regarding negative symptoms, flupentixol proved to be non-inferior to risperidone. Both drugs improved depressed mood with effect sizes favoring flupentixol. PCA suggested a five-factor structure. Effect sizes for the cognitive factor were up to 0.74 for flupentixol and up to 0.80 for risperidone. EPS scores were rather low and Parkinsonism improved in both groups, but anticholinergic drugs were prescribed significantly more frequently in the flupentixol group, which generally showed significantly more adverse events. Results indicate that the 1st generation antipsychotic flupentixol improves negative, affective and cognitive symptoms in chronic schizophrenia comparable to risperidone. Further studies should confirm the latter using neuropsychological performance tests and should investigate whether tolerability improves with a markedly lower dose range.

Gender differences: does alcohol affect females more than males?

Human substance use is complex, being influenced by many psychopathological and sociological factors as well as the substance's pharmacological effects. Dependence development is not attributable directly to the consumed substance, but takes also all the other issues into regard. One of all these issues might be that gender represents an influencing factor and impacts on tolerance of a substance, on abuse patterns and finally on development of dependence as well as on addiction related disorders. Therapeutic programs' needs might be different too. In general, more men than women are alcohol dependent or have alcohol problems, but women are at greater risk for adverse effects and alcohol related diseases. Death rates among female alcoholics are 50 to 100 percent higher than those of men. Major impairments, diagnosis, medical and psychosocial consequences and their implication on treatment will be outlined.

Craving and other characteristics of the comorbidity of alcohol and nicotine dependence.

PURPOSE: In this cross-sectional study we compared alcohol-dependent smokers and non-alcohol-dependent smokers with respect to intensity of nicotine dependence, craving conditions, sleep disturbances, comorbidity with major depression, reasons for smoking, accompanying somatic diseases and patients' prolonged abstinence from smoking during the 3 years preceding the study. SUBJECTS AND METHODS: Fifty-one alcohol-dependent smokers and 327 non-alcohol-dependent smokers diagnosed as ICD-10 and DSM-IV-nicotine dependent, were investigated by means of the Fagerström Test for Nicotine Dependence, the Lübeck Craving-Recurrence Risk Questionnaire and the Lesch Alcohol Dependence Typology (both adapted to smoking). RESULTS: The intensity of nicotine dependence was more enhanced in alcohol-dependent smokers compared to non-alcohol-dependent smokers. Several variables of all factors of craving ("depressive mood", "stimulation", "relaxation", "socially triggered tension") were significantly increased in alcohol-dependent patients (P<0.05). Alcohol-dependent smokers showed depressive symptoms and sleep disturbances, whilst non-alcohol-dependent individuals mainly smoked for stress release and weight control. DISCUSSION: Our study demonstrates that the intensity of nicotine dependence, several conditions of craving for nicotine, sleep disturbances and symptoms of depression appear to be enhanced in alcohol-dependent smokers compared with non-alcohol-dependent smokers. Conclusions. - It is hoped that the factors of craving and reasons for smoking identified in this study will contribute to a better understanding of smoking temptation in alcohol-dependent smokers and non-alcohol-dependent smokers in future.

Reaction to pain stimulus before and during hypnosis measured by pupillary reaction.

The aim of this study was to investigate the analgesic effects of hypnotic pain control on experimental pain by measuring pupil reactions as an objective psycho-physiologic parameter. Twenty-two healthy volunteers (11 female and 11 male) aged between 22 and 35 years participated in the study. Pupil diameter was measured as baseline measurement (i.e., static measurement) in the non-hypnotic and in the hypnotic state. Pupil diameter changes to a standardized pain stimulus were measured in the non-hypnotic and hypnotic state and compared. Additionally, a Fourier analysis of pupil oscillations reflecting central nervous activation during the static measurement (25.6 sec) was calculated. During the hypnotic state the pain related pupil dilation was significantly smaller than during the non-hypnotic state. Pupil oscillations were significantly reduced during hypnosis.

CDT values are not influenced by epithelial cell apoptosis in chronic alcoholic patients-preliminary results.

Carbohydrate-deficient transferrin (CDT) has been well established as a marker for high alcohol consumption. As studies concerning the specificity of CDT in patients with liver disease have shown controversial outcomes, efforts to illuminate mechanisms leading to impaired CDT specificity in this patient group cannot yet be considered successful. Evidence of apoptosis as examined in 72 alcohol-dependent patients using serum contents of caspase-related M30 monoclonal antibody significantly correlated with aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transpeptidase but did not influence CDT levels. These results suggest that impairment of CDT specificity is brought forth by derangement of hepatic metabolism rather than by acute hepatocellular damage.

The Austrian multicentre study on smoking: subgroups of nicotine dependence and their craving.

BACKGROUND: The misconception of tobacco smoking as a 'bad habit' has been replaced by a diagnosis of addiction. Although help to quit is offered by nicotine replacement, antidepressants and psychotherapeutic support, there is no cure yet. One cause of impediment might be psychiatric comorbidity. Therefore, we searched for smoker subgroups, needing different treatments. AIM OF THE STUDY: The study aimed at subtyping smokers in an attempt to better understand the phenomenon of resistant smokers and provide more information that could potentially become useful to treatment centres assuming the subtypes correlate directly with outcomes of different smoking cessation treatments, tailor-made according to subtypes. METHODS: 330 out of 430 recruited smokers were classified as nicotine dependent (ICD-10) and tobacco dependent (DSM-IV) and remained in the study. They were investigated with different diagnostic assessments: Fagerström Test (FT), Lübeck Craving Risk Relapse Questionnaire and Lesch Typology Questionnaire (the last two being modified for smoking). RESULTS: Dependence severity degree is reflected by the FT. FT scores >/=5 indicated higher conspicuousness. Four clusters for nicotine craving were found: (1) 'depressed', (2) 'stimulated', (3) 'relaxed mood state' and (4) 'socially triggered tensed mood'. In contrast to alcoholism, 'stimulation' was one of the major craving conditions in smokers. The decision tree, consisting of the FT and the Lesch Typology Questionnaire, distinguishes four subgroups of nicotine-dependent persons. CONCLUSION: The subgroups reflect different reinforcement and psychosocial disturbances. They match treatment and can be applied as outcome predictors in controlled treatment and relapse prevention studies.