The impact of self-help group attendance on relapse rates after alcohol detoxification in a controlled study.

AIMS: Self-help groups such as Alcoholics Anonymous (AA) are widely recommended for aftercare of alcohol-dependent persons, even though scientific knowledge of its effectiveness is inconsistent. The aim of the present analysis was to elucidate whether persons attending AA groups regularly after detoxification have lower relapse rates within 1 year, compared to persons without self-help group attendance. METHODS: Data for the present analysis were derived from the placebo-group of a multi-centre study in Germany (Wiesbeck et al., 2001). Patients were free to choose either self-help group attendance (N = 50) or no support (N = 28). RESULTS: After 1-month of follow-up, there was a lower relapse rate in patients attending a self-help group as compared to the control group, a difference, however, that leveled off during the following months. Moreover, relapse rates did not differ significantly at any point of time between both groups. Levels of social functioning improved in both groups over 1 year. CONCLUSIONS: The present study was unable to show an advantage of self-help group attendance in reducing relapses compared to the control group.

Gender-related differences in pharmacological relapse prevention with flupenthixol decanoate in detoxified alcoholics.

A study recently finished by our research group elucidated the effectiveness of flupenthixol decanoate (FLX) in maintaining abstinence in detoxified alcoholics. Flupenthixol decanoate is an established antipsychotic drug, which is well known for its mild antidepressant and anxiolytic activity as well as for its minimal sedation at low doses. It blocks dopamine binding at a number of receptor subtypes, primarily at D-1, D-2, D-3 and with less affinity at D4-receptors. It also affects serotonin binding at 5-HT2A and 5-HT2C receptors. In a double-blind placebo-controlled multicenter trial, 77 women and 204 men suffering from moderate or severe DSM-II-R alcohol dependence were randomly assigned to either 10 mg FLX or placebo both injected every second week over a period of 24 weeks (treatment phase) succeeded by a medication-free 24-weeks follow-up period. In the overall analysis the number of patients relapsed after 24 weeks of treatment (=main criterion of efficacy) was significantly higher in the FLX treated group (85.2%) than under placebo (65.5%). However, when differentiating this result according to sex the analysis revealed a gender-related discrepancy: while male patients had an almost 4-fold higher risk to relapse under FLX than under placebo (OR=3.95) this risk was barely elevated for female patients (OR=1.51). A significantly negative outcome due to FLX treatment was restricted to male alcoholics solely. In conclusion, gender-related differences to pharmacological relapse prevention with FLX have probably contributed to a better treatment outcome in women than in men.

Neurobiology of an addiction memory.

The existence of an "addiction memory" (AM) and its importance in relapse occurrence and maintenance of learned addictive behaviour will be explained with neurobiological and clinical arguments. Because the human brain is an open learning system, which reveals its own neuronal connectivity through the experience of the perceived environment with its own state, the personal AM is interpreted as an individual acquired software disturbance in relation to selectively integrating "feedback loops" and "comparator systems" of neuronal information processing. This is in accordance with the experience that the AM and its specific cue reactivity can be activated at any time by relapse-endangering complex internal and/or external situations with cue stimulated craving. The AM becomes part of the personality represented on the molecular level via the neuronal level and the neuropsychological level, especially in the episodic memory. This neurobiological unchangeable imprinted addictive behaviour with "loss of control" and "obsessive-compulsive craving" was also found in a long-term learning model with rats (Wolffgramm). Identical homological phylogenetically old brain structures for learning mechanisms allow the comparison between human and animal behaviour. The AM seems to be a clinical-empirical proved reality. It is compatible with recently discussed results of neurosciences.

Flupenthixol decanoate and relapse prevention in alcoholics: results from a placebo-controlled study.

Flupenthixol, with its broad receptor profile, interacts with a variety of dopamine and serotonin binding sites which are important in the neurobiology of alcohol dependence. Its pharmacology, together with encouraging results from both animal studies and clinical trials with cocaine users, led us to postulate that flupenthixol would significantly prevent relapse in detoxified alcohol-dependent individuals. We conducted a prospective, randomized, double-blind, placebo-controlled, multi-centre trial with two parallel groups and appropriate statistical evaluation. Subjects met criteria for moderate to severe alcohol dependence (DSM-III-R), without any concomitant psychiatric disorder. After complete detoxification, 281 women and men received either 10 mg of flupenthixol decanoate or placebo as i.m. injection every second week for 6 months on an out-patient basis, followed by 6 months of follow-up. Efficacy was based on absolute abstinence, with relapse being defined as consumption of any alcohol after inclusion in the study. In contrast to the hypothesis, flupenthixol did not reduce, but was associated with more, relapses. Though well tolerated, relapse rates after 6 months of treatment were 85.2% (flupenthixol) versus 65.5% (placebo), a highly significant difference from the medication. Flupenthixol was also inferior to placebo with regard to other secondary criteria of efficacy (cumulative abstinence duration, relapse rate after 12 months). These results indicate that a 10 mg dose of flupenthixol decanoate does not have a beneficial effect on abstinence maintenance in alcohol-dependent individuals.

Pharmacological relapse prevention in alcohol dependence: from animal models to clinical trials.

This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The chairs were Jobst August-Ludwig Boening and Otto Michel Lesch. The presentations were (1) Pharmacological validation of a new animal model of alcoholism, by Rainer Spanagel; (2) Persisting loss of control as main criterion for alcohol addiction in rats and mice, by Jochen Wolffgramm; (3) Role of NMDA receptor subunits associated with protein kinase C in the prevention of alcohol dependence, by Minoru Narita; (4) Long-term follow up of continued naltrexone treatment, by David Sinclair; (5) Pharmacological treatment trials with dopaminergic and serotonergic substances: Myths or facts? by Gerhard A. Wiesbeck; and (6) Methodology and behavioral therapy of the U.S. acamprosate study, by Barbara J. Mason.

The effects of ritanserin on mood, sleep, vigilance, clinical impression, and social functioning in alcohol-dependent individuals. Ritanserin in Alcoholism Work Group.

In an international double-blind placebo-controlled trial with 493 detoxified alcohol-dependent individuals, ritanserin, a specific 5-hydroxytryptamine, antagonist, was tested in three different dosages (2.5, 5, and 10 mg/day) against placebo over a period of 6 months. Data on changes in mood state, sleep quality, morning vigilance, clinical impression, and social functioning were analysed. None of the three dosages of ritanserin given revealed any significant effect against placebo on the above-mentioned parameters either at the end of treatment or upon relapse. Therefore, we conclude that patients suffering from alcohol dependence without concomitant psychiatric disorders do not benefit from additional treatment with (2.5, 5, or 10 mg/day) ritanserin.

A comparison of remifentanil and fentanyl in patients undergoing surgery for intracranial mass lesions.

UNLABELLED: We compared the effects of remifentanil versus fentanyl during surgery for intracranial space-occupying lesions. Patients were randomly assigned to receive either remifentanil (0.5 microg. kg(-1). min(-1) IV during the induction of anesthesia reduced to 0.25 microg. kg(-1). min(-1) after endotracheal intubation; n = 49) or fentanyl (dose per usual practice of the anesthesiologist; n = 54). Anesthesia maintenance doses of isoflurane, nitrous oxide, and opioid were at the anesthesiologist's discretion for both groups. There were no differences between opioid groups for the frequency of responses (hemodynamic, movement, and tearing) to intubation, pinhead holder placement, skin incision, or closure of the surgical wound. Adverse event frequencies were similar between groups. Times to follow verbal commands (P < 0.001) and tracheal extubation (P = 0. 04) were more rapid for remifentanil. The percentage of patients with a normal recovery score (were alert or arousable to quiet voice, were oriented, were able to follow commands, had motor function unchanged from their preoperative evaluation, were not agitated, and had modified Aldrete Scores of 9-10) at 10 min after surgery was more for remifentanil (45% vs 18%; P = 0.005). By 20 min, no difference between groups existed (P = 0.27). Anesthesiologists used more isoflurane in the fentanyl group (4.22 vs 1.93 minimum alveolar anesthetic concentration hours). Neurosurgeons, blinded to treatment group, favored the use of remifentanil. Similar frequencies of light anesthesia responses and other adverse events suggest that intraoperative depths of anesthesia were similar in the two groups. Under these conditions, emergence was more rapid with remifentanil. This is consistent with the necessity for less isoflurane use in the remifentanil group and the intrinsic rapid clearance of this opioid. IMPLICATIONS: Patients given remifentanil-based anesthesia for craniotomy had faster recovery times from anesthesia than did those given fentanyl-based anesthesia.

Ritanserin in relapse prevention in abstinent alcoholics: results from a placebo-controlled double-blind international multicenter trial. Ritanserin in Alcoholism Work Group.

Ritanserin, a long-acting specific 5-HT2 receptor antagonist, revealed promising effects on alcohol intake behavior in both animal and preliminary human studies. To test its effectiveness in alcohol dependence this phase III clinical trial was initiated. In a placebo-controlled, randomized, double-blind international multicenter study 493 patients with moderate or severe alcohol dependence (DSM-III-R) were treated with three doses of ritanserin 2.5 mg/day (n = 122), 5 mg/day (n = 123), 10 mg/day (n = 126), or placebo (n = 122) over a period of 6 months. Ritanserin was well tolerated. The most frequent adverse experiences were headache and insomnia. A small increase in weight in the ritanserin-treated patients was observed. There were no significant differences between any dose of ritanserin and placebo in the relapse-rate, the time to relapse, craving for alcohol, or quantity and frequency of drinking after relapse. So far, neither ritanserin nor any other serotonergic medication has shown its specific effectiveness in relapse prevention in alcohol dependence.

Event-related correlates of response suppression as indicators of novelty seeking in alcoholics.

Novelty Seeking including impulsive behaviour is a personality dimension which has been shown to be related to early-onset alcoholism and to high relapse rates. The cued Continuous Performance Test (CPT) is an experimental paradigm for active response control requiring a choice reaction between execution (Go) and inhibition (NoGo) of a prepared motor response. Metabolic functional methods have shown right frontal brain activation throughout the period of a CPT, and the spatial analysis of the associated event-related brain electrical (ERP) field potentials revealed that this right frontal activation was due to the NoGo subset of the task. The ERP fields allow distinction between the Go and NoGo conditions with one spatial parameter (NoGo-anteriorization) in single cases. and the magnitude of this parameter is thought to be related to inhibitory frontal lobe control. Twenty patients with severe alcohol dependence and 20 age- and sex-matched healthy controls were included in the study and investigated with a 21-channel electroencephalogram while performing a cued CPT. Consistent with previous studies, NoGo-anteriorization was present in every case in both groups. The ERP field differed between alcoholics and controls in the Go condition (P < 0.05) and NoGo-anteriorization in alcoholics was correlated inversely with Novelty Seeking in Cloninger's Temperament and Character Inventory (r= 0.67, P < 0.01). This indicates a reduced frontal lobe contribution during response control in alcoholics with impulsive behaviour and identifies a possible biological marker for the clinical evaluation of the risk of relapse in alcoholism.

Growth hormone response to placebo, apomorphine and growth hormone releasing hormone in abstinent alcoholics and control subjects.

Abstinent alcoholics and control subjects were challenged with placebo (saline), growth hormone releasing hormone (GHRH) and apomorphine (APO). While both groups did not differ in their growth hormone response (HGH) to placebo and GHRH, the alcoholics revealed a significant lower HGH response to dopamine receptor stimulation with APO. These findings provide no evidence that in abstinent alcoholics HGH blunting after dopamine receptor stimulation could be related to an alteration at the pituitary level but they give neuroendocrinological support to the hypothesis of a lower dopamine receptor sensitivity in abstinent alcoholics.

Alcohol withdrawal and dopamine receptor sensitivity after prolonged abstinence.

1. Forty-four male inpatients suffering from moderate to severe alcohol dependence (DSM-III-R and ICD-10) as well as 14 healthy controls entered this study. Individuals were classified according to the severity of their withdrawal symptoms during detoxification i.e. group 1) no withdrawal, group 2) autonomic hyperactivity, group 3) withdrawal delirium and group 4) controls. 2. During the 6th week of treatment, that is, when all patients were recovered, controlled abstinent, and several weeks away from the end of their withdrawal syndrome, dopamine receptor sensitivity was neuroendocrinologically assessed by stimulating human growth hormone (HGH) with apomorphine (APO). 3. In a repeated measures model ANOVA, the four groups differed significantly in their HGH release. However, when excluding the controls from the analysis and focusing on alcoholics only (group 1 - 3), the significant difference disappeared. Covariates such as age, weight, quantity of drinking and duration of dependence were not related to the dependent variable. 4. In conclusion, the first significant result (with controls) reflects a blunted HGH response in alcoholics. It confirms earlier reports. The second, non significant result with the alcohol dependents only, suggests that the severity of withdrawal is not reflected by the amount of HGH released. Therefore, in alcoholics, a reduced dopamine receptor function after six weeks of abstinence, as neuro-endocrinologically assessed with apomorphine, seems to be related to alcohol dependence rather than to the severity of alcohol withdrawal.

Sensation seeking, alcoholism and dopamine activity.

Sensation seeking scale (SSS) scores were determined in 15 alcohol dependent men with a positive family history for alcoholism (FHP), in 15 alcohol dependent men with a negative family history for alcoholism (FHN) and in 15 well-matched healthy male controls (CONTR). Both FHPs and FHNs suffered from longlasting alcohol dependence meeting ICD-10 and DSM-III-R diagnostic criteria. Dopamine activity was neuroendocrinologically assessed by measuring the amount of growth hormone released after stimulation with the dopamine receptor agonist apomorphine. Planned comparisons within a one-way ANOVA yielded significantly elevated levels of boredom susceptibility (BOS) in both FHPs and FHNs against CONTRs. SSS total scores, while approaching statistical significance, were elevated in FHPs only. Partial correlations (controlling for age, body weight, alcohol intake and duration of dependence) were calculated to examine the relationship between SSS and dopamine activity. Among the SSS subtraits, BOS revealed the highest correlation in each group. However, only in CONTRs did the relationship between BOS and dopamine activity reach statistical significance.

Alcohol dependence, family history, and D2 dopamine receptor function as neuroendocrinologically assessed with apomorphine.

Fifteen alcohol dependent men with an alcohol dependent first degree relative (i.e. family history positive or FHP), 15 well matched alcohol dependent men without a family history for alcohol dependence (i.e. family history negative or FHN), and 15 healthy controls (CONTR) participated in this study. The three groups were compared according to their postsynaptic D2 dopamine receptor function as assessed by growth hormone release after stimulation with the dopamine receptor agonist apomorphine. Statistical evaluation was done by planned comparisons within a one-way ANOVA. Alcohol dependent subjects significantly differed from CONTRs as long as family history was not taken into account (t(42) = 2.38; P = 0.022*). When differentiating according to family history, both FHPs and FHNs maintained a blunted growth hormone response. However, the difference between FHNs and CONTRs, though present, dropped out of statistical significance (t(42) = 1.65; P = 0.105); at the same time, the difference between FHPs and CONTRs became slightly stronger (t(42) = 2.47; p = 0.017*). In conclusion, our data give neuroendocrinological support to the assumption that a reduced D2 dopamine receptor function in alcohol dependent men is not only a state marker of residual heavy drinking but also a genetically determined trait marker.

Neuroendocrine support for a relationship between "novelty seeking" and dopaminergic function in alcohol-dependent men.

The personality traits "novelty seeking", "harm avoidance", and "reward dependence" were rated using Cloninger's Tridimensional Personality Questionnaire in 20 male inpatients, suffering from moderate to severe alcohol dependence (ICD-10, DSM-III-R). The same individuals' dopamine receptor sensitivity was determined by stimulating a neuroendocrine response with a dopamine receptor agonist (apomorphine). The amount of growth hormone released was measured and taken as a biological parameter for the sensitivity of D2 dopamine receptors located in the hypothalamus. Our data indicate that in abstinent alcohol-dependent men no statistically significant correlation exists between a person's apomorphine-induced growth hormone release and his "harm avoidance" or "reward dependence" score. On the other hand, a significant correlation (r = .47; p = .035) was found between growth hormone release and the person's "novelty seeking" score. This result supports Cloninger's hypothesis by giving neuroendocrine evidence that the personality dimension "novelty seeking" is related to dopaminergic activity in alcohol-dependent men.

Effect of isoflurane (Forane) on intraoperative electrocorticogram.

Isoflurane, an inhalation agent often used for general anesthesia during craniotomy, has been reported to suppress spike activity in the intraoperative electrocorticogram (ECoG) during epilepsy surgery. We studied the effect of isoflurane concentrations of 0.25, 0.5, 0.75, 1, and 1.25% on the number of spike bursts per 5-min epochs in 15 patients undergoing ECoG during epilepsy surgery. N2O in O2 was maintained at 50% in 10 patients, at 60% in 2, and at 70% in 3. End tidal CO2 concentration was maintained in the hypocarbic range, and analgesia was maintained with the narcotic alfentanil in the range of 0.5-2 micrograms/min. The median number of spikes for each isoflurane concentration was 29 (range 3-107) at 0.25%, 27 (range 2-73) at 0.5%; 29 (range 5-90) at 0.75%, 33 (range 2-100) at 1%, and 40 (range 32-140) in 5 patients who tolerated 1.25% without occurrence of burst suppression pattern. No significant difference (Student's paired t test) was noted in the number of spikes for each isoflurane concentration. Therefore, if isoflurane concentrations are maintained between 0.25 and 1.25% or before burst suppression pattern occurs and N2O/O2 is maintained in the 50-70% range, isoflurane has no significant effect on spike activity.

The effect of blocking sodium influx on anoxic damage in the rat hippocampal slice.

The in vitro rat hippocampal slice was used to study the effect of tetrodotoxin, a sodium channel blocker, on anoxic damage. Tetrodotoxin improved recovery of the evoked population spike after anoxia and reduced the fall in adenosine 5'-triphosphate during anoxia. Electrophysiological responses to perforant pathway stimulation were recorded in the dentate granule cell layer before, during and after 10 min of anoxia, with and without tetrodotoxin. Preincubation with tetrodotoxin permitted recovery of the evoked population spike to 43 +/- 10% (mean +/- standard error) in the post-anoxic period; this compared to 3 +/-3% recovery in untreated tissue (P less than 0.005). Similar studies of the CA1 pyramidal cells, which are more sensitive to anoxia, showed that tetrodotoxin improved recovery of the postsynaptic response after 5 min of anoxia. The recovery was 69 +/- 15% of its pre-anoxic level when treated with tetrodotoxin. This compares to no recovery in untreated tissue (P less than 0.005). Biochemical studies demonstrated a significantly reduced fall in adenosine 5'-triphosphate levels during levels in the dentate granule cell layer fell to 1.4 nM/mg dry wt, whereas following treatment with tetrodotoxin they only fell to 2.2 nM/mg. Since it required only 5 min of anoxia to damage the CA1 pyramidal cells, adenosine 5'-triphosphate levels were measured in this region after 5 min of anoxia. Adenosine 5'-triphosphate levels in the CA1 region fell to 2.2 nM/mg in untreated tissue after 5 min of anoxia, compared to 2.9 nM/mg in the tetrodotoxin-treated tissue.(ABSTRACT TRUNCATED AT 250 WORDS)

Report on a double-blind comparison of two different regimens of dothiepin (prothiaden).

Thirty patients diagnosed as suffering from endogenous depression were entered into a 3-week double-blind trial comparing three times a day dosage of dothiepin with a single night-time dosage in a dosage range of 75 mg to 225 mg per day. The trial was conducted on in-patients and assessments were made pretrial and after 1 and 3 weeks. The patients were assessed by clinician-rated scales for psychomotor and psychic symptoms and by Zung's self-rating scale. Fifteen patients received dothiepin three times a day (day-time group) and fifteen received it as a single night-time dose (nocte group). There were two withdrawals in the day-time group and three in the nocte group. All withdrawals were due to lack of therapeutic effect. Over the 3-week trial 67% of the day-time group and 47% of the nocte group showed a clinical improvement. It was found that there was no statistically significant difference between the two methods of treatment. In the day-time group seven patients and in the night-time group nine patients suffered from side-effects. No particular pattern of side-effects emerged. There were no drug-related changes in the laboratory results. It was concluded that the therapeutic effect of both dosage regimes should be regarded as equivalent. Advantages, due to the specific action of dothiepin, compared with classical antidepressants for reference, could, however, not be presumed by the clinical impression.