Sodium oxybate in maintaining alcohol abstinence in alcoholic patients with and without psychiatric comorbidity

Sodium oxybate (SMO) is a GABA-ergic drug currently used for the treatment of alcohol-dependence in some European countries. In particular, clinical studies have shown a role of SMO in promoting alcohol abstinence, as well as in relieving withdrawal symptoms. The aim of this study was to describe alcohol abstinence and the onset of craving for and abuse of SMO in alcohol-dependent subjects with and without psychiatric co-morbidity. Forty-eight patients were enrolled and classified into two groups: group A (20 alcoholics without any psychiatric co-morbidity) and group B (28 alcoholics with a psychiatric co-morbidity). All patients were treated with oral SMO (50 mg/kg of body weight t.i.d.) for 12 weeks. Alcohol abstinence as well as alcohol drinking during the 12 weeks of treatment did not differ between the two groups at the end of treatment (p = 0.9). In addition, a reduction of alcohol intake in both groups has been observed (p < 0.0001). On the other hand, craving for SMO was significantly more frequent in group B than group A (p = 0.001). Cases of SMO abuse were observed in almost 10% of group B patients. In conclusion, alcohol abstinence achieved through SMO administration does not differ in patients with and without psychiatric co-morbidity. However, alcoholics with co-morbid borderline disorders appear to be at high risk of developing craving for and abuse of the drug; therefore, SMO may not be indicated in these patients.     

Dexamethasone suppression test in recently detoxified alcoholics: clinical implications

An overnight dexamethasone suppression test (DST) was performed on 66 nondepressed primary alcoholics, a mean of 20.79 +/- 11.5 days after last alcohol intake. The Beck Depression Inventory (BDI) was given concurrently. Only 6% of the subjects were nonsuppressors. There was no correlation between cortisol levels at 17 and 24 hours postdexamethasone and the age of the subjects or duration of abstinence. There was a low level correlation between cortisol values at 24 hours and the BDI scores. Review of published data indicates that the DST may be abnormal in alcoholics in the first 2 weeks of abstinence, probably a result of abnormal liver function and withdrawal phenomena. DST response of alcoholics resembles that of normal controls after more than 2 weeks of abstinence. Alcoholics with clinical features of depression and an abnormal DST after 2 weeks of abstinence may be candidates for antidepressant therapy or electroconvulsive therapy.     

The effect of abstinence in alcoholics of erythrocyte gangliosides

The pattern of gangliosides in membranes of erythrocytes was examined in healthy and in alcoholic subjects on the second and on the 28th day of detoxification therapy. The GM3 and GD3 fraction were decreased significantly in alcoholics on the 2nd day. After 4 weeks of abstinence all changes had returned to the level of healthy subjects.     

Difficulties in emotion regulation and impulse control in recently abstinent alcoholics compared with social drinkers

BACKGROUND: Early abstinence from chronic alcohol dependence is associated with increased emotional sensitivity to stress-related craving as well as changes in brain systems associated with stress and emotional processing. The aim of the current study was to examine potential difficulties in emotion regulation during early alcohol abstinence using the recently validated Difficulties of Emotion Regulation Scale (DERS). METHOD: Recently abstinent treatment-seeking alcohol abusers (n=50) completed the DERS during their first week of inpatient treatment and at discharge (5 weeks later). These responses were compared to a group of social drinkers (n=62). RESULTS: Compared with social drinkers, alcohol-dependent patients reported significant differences in emotional awareness and impulse control during week 1 of treatment. Significant improvements in awareness and clarity of emotion were observed following 5 weeks of protracted abstinence. However, significant difficulties with impulse control persisted until discharge. CONCLUSION: Findings from the DERS indicate protracted stress-related impulse control problems in abstinent alcoholics, which may contribute to increased relapse vulnerability.     

Variations in drug free fraction during alcohol withdrawal.

1 Free fractions of diazepam, propranolol and warfarin were determined in 15 male chronic alcoholics in alcohol withdrawal. 2 On admission the mean free fraction of diazepam was 25% above and propranolol 44% below the limits of normal range, while the mean warfarin free fraction was in high normal range. One week later mean free fraction of diazepam declined by 20% while propranolol and warfarin increased by 24% and 19% respectively (P less than 0.05). 3 Propranolol free fraction and alpha 1-AGP concentrations were highly correlated (linear r = -0.83, P less than 0.001). In contrast the sources of variation in diazepam and warfarin free fraction were more complex and less certain. 4 Statistically significant changes of drug free fractions in serum of chronic alcoholics were observed during alcohol withdrawal. The extent and direction of these changes differed for various classes of drugs and their potential causes appear to be quite different. 5 Clinically important changes in drug effect may be present acutely, within the dosing interval, as a result of altered drug binding. These are more likely when the clinical response is closely related to drug concentration and will occur within the dosing interval due to larger fluctuations in free drug concentration, even though the average free drug concentration will remain unchanged. 6 Total drug level changes will be observed during alcohol withdrawal even in absence of detectable changes of drug metabolism.     

Emergence of depression during early abstinence in depressed and non-depressed women smokers

The emergence of depression early in a quit attempt and its relationship to ability to maintain abstinence were studied in 99 depressed and non-depressed women smokers. Participants rated withdrawal symptomatology during a baseline week and the first two weeks of a quit attempt, during which they used a 21-mg nicotine patch and received behavioral counseling. Depressed women experienced greater difficulty maintaining early abstinence than non-depressed women. They were significantly more likely to smoke on the first day of abstinence and smoked marginally more days during the first week. Among participants who relapsed during the first two weeks, latency to relapse was significantly shorter for depressed women. Although craving and all withdrawal symptoms except insomnia showed significant increases over baseline, only depression showed significant group differences, with trend analyses suggesting that depression asymptotes in non-depressed women after the first week but continues increasing in depressed women. Larger increases in depression on the first day of abstinence were associated with earlier lapse. Because depression is relatively infrequent as a withdrawal symptom, it may not be a "true" withdrawal symptom except in depressed people. Identification of depressed smokers and anticipation of their increased need for support during this period may help to counteract the "first-day effect" and difficulties during early abstinence.     

Effects of selegiline (l-deprenyl) during smoking and short-term abstinence

RATIONALE: Changes in dopamine level are thought to play an important role in both smoking reward and withdrawal symptoms during abstinence. Medications that modulate dopamine levels may have beneficial effects on both withdrawal symptom levels and on response to smoking lapses during abstinence. OBJECTIVES: To examine the effects of the selective MAO-B inhibitor selegiline on withdrawal symptoms, smoking behavior and smoking satisfaction ratings. METHODS: Fifteen smokers received selegiline (10 mg/day) and placebo (in counterbalanced order) on Monday through Thursday of 2 study weeks, separated by a 2-week washout. During each study week, ad lib smoking sessions were scheduled to assess smoking behavior both before and after a brief period of abstinence. Subjective withdrawal symptoms and mood were measured daily, and a modified Stroop test sensitive to withdrawal was scheduled during the period of abstinence. RESULTS: Selegiline decreased craving, especially during abstinence, and impaired performance on the modified Stroop test during subjects' attempts to abstain. Medication also reduced number of cigarettes smoked and smoking satisfaction ratings during the smoking sessions both before and after the brief abstinence attempt. CONCLUSION: These results are consistent with an important role of dopamine in smoking behavior and abstinence. They suggest that pharmacological reduction of MAO-B levels during the early part of a quit attempt may aid in smoking cessation.     

Cortisol and beta-endorphin response in alcoholics and alcohol abusers following a high naloxone dosage

The course of plasma cortisol and beta-endorphin-like immunoreactivity (beta-EP-IR) was determined following a single i.v. administration of 20 mg naloxone. The test subjects included 20 male alcoholics (medication-free), investigated one to three days and four weeks after the onset of abstinence, as well as 10 short-time abstinent alcohol abusers and 10 healthy control subjects. The mean baseline values of cortisol and beta-EP-IR remained within normal limits in all groups. The significant decrease in the plasma cortisol baseline values in the alcoholics after 4 weeks abstinence may indicate a lower level of the regulation of the hypothalamic-pituitary-adrenal axis (HPA) under conditions of abstinence. After naloxone administration an increase in plasma cortisol and beta-EP-IR was observed in all groups. The multivariate trend analysis showed significant differences in the time course of plasma cortisol between the three groups, however not in the course of beta-EP-IR. The changes in the dynamic regulation of the HPA axis, resulting from chronic alcohol consumption, appears to be irrespective of whether the drinking pattern is dependent or abusive. In alcoholics these changes could still be identified following a 4-week abstinence period.     

Effects of morphine and naloxone on separation distress and approach attachment: Evidence for opiate mediation of social affect

In order to determine the relationship between endorphins and social attachment, the effects of morphine (an opiate agonist) and naloxone (an opiate antagonist) on various indices of attachment in guinea pigs were studied. In infants, crying or separation-induced distress vocalizations were significantly decreased by single injections of low morphine doses (0.25, .050 and 0.75 mg/kg) in a dose-dependent manner. Naloxone (1 mg/kg) reliably increased separation distress vocalizations in both juvenile and adult guinea pigs. Therefore, similar to opiate withdrawal symptoms, separation distress appeared to be alleviated by morphine and potentiated by naloxone. As for approach attachment, offspring/maternal proximity-maintenance time was significantly decreased by morphine (1.0, 2.5 and 5.0 mg/kg), suggesting that opiates may be capable of replacing a function normally subserved by endorphins in reinforcing attachments. These data support the hypothesis that an endorphin-based addiction-like process may underlie the maintenance of social attachments, and that separation distress may reflect a state of endogenous “endorphin withdrawal”.     

Attenuated beta endorphin response to acute stress is associated with smoking relapse

Stress has been cited as an important precipitator of smoking relapse. Dysregulation of neurobiological pathways related to stress might mediate effects of stress on smoking relapse. This study assessed the extent to which beta endorphin response to stress is associated with early smoking relapse. Forty-five smokers interested in smoking cessation were recruited and attended a laboratory session 24 h following the beginning of their abstinence period. During this session beta endorphin samples were collected before and after performing two acute stressors (public speaking and cognitive tasks). Participants also attended four weekly follow-up sessions to assess their smoking status. Results were compared between smokers who relapsed within the 4-week follow-up period and those who maintained abstinence over the same period. The acute stressors were associated with significant increases in measures of craving and withdrawal symptoms (ps<0.01). While baseline measures of beta endorphin did not differ between relapsers and successful abstainers (F<1), results demonstrated that smokers who relapsed exhibited attenuated beta endorphin response to the two stressors relative to those who maintained abstinence over the same period (ps<05). These results support recent evidence indicating that a dysregulated stress response is a key component in predicting smoking relapse.     

Changes in dopamine receptor sensitivity in humans after heavy alcohol intake

Dopamine (DA) sensitivity, assessed through maximal growth hormone (GH) response to stimulation by apomorphine (APO) (0.18–0.24 mg iv) was studied in 16 chronic alcoholics newly admitted after a period of heavy alcohol intake. Repeated hormonal tests were thereafter performed during a 2-month period under strictly controlled conditions to avoid relapse into alcohol consumption. Eight healthy volunteers with alcohol consumption slightly less than that of the general population were used as controls. It was found that DA sensitivity in the early abstinence phase was higher than later in the 2-month recovery period but not significantly different from control values. The relatively higher DA sensitivity in the early abstinence phase might be responsible for a lower threshold for psychotic symptoms and neuroleptic-induced extrapyramidal side effects. The results of this study give further evidence of a prolonged recovery phase after heavy alcohol intake.     

Is withdrawal-induced anxiety in alcoholism based on β-endorphin deficiency?

RATIONALE: Associations between several psychopathological alterations and lowered beta-endorphin(beta E) plasma levels have already been stated in former studies. However, whereas single measures during static conditions generally failed in linking beta E levels with psychopathology, dynamic changes of beta E in particular have been shown to be associated with spells of anxiety and depression. During alcohol withdrawal, a decreased secretion of beta E with a delayed normalization has been reported, but up to now only few data became available regarding the interaction of plasma beta E and psychopathological parameters. OBJECTIVES: The aim of our study was to test the hypothesis whether beta E during acute alcohol withdrawal is associated with anxiety, depression, and craving. METHODS: We observed self-rated anxiety, depression, and craving during alcohol withdrawal and assessed beta E levels (RIA) in a consecutive sample of 60 alcoholics on day 1 and day 14 after onset of withdrawal, and in 30 healthy volunteers. To control for mutual interactions of beta E and the pituitary-adrenocortical hormone secretion, plasma corticotropin (ACTH) and cortisol were also determined. RESULTS: In accordance with prior studies, beta E was significantly lowered on day 1 and day 14 of alcohol withdrawal relative to controls. Plasma levels of ACTH correlated significantly with beta E in alcoholics at both time points and in controls, without differing significantly between the groups. Self-rated anxiety, depression, and alcohol craving decreased significantly between day 1 and day 14. Levels of beta E were inversely correlated with anxiety day 1 (r=-0.58) and day 14 (r=-0.71). Partial correlation coefficients controlling for ACTH plasma levels revealed that this correlation was largely independent from ACTH. In addition, a significant inverse relationship was found between beta E and craving on day 14 (r=-0.28). No association appeared between beta E and depression. CONCLUSIONS: Our results give first evidence that lowered beta E during alcohol withdrawal may contribute to anxiety as a common disturbance during this state.     

Excessive ethanol drinking following a history of dependence: animal model of allostasis.

Alcohol withdrawal symptoms, particularly negative emotional states, can persist for months following the removal of alcohol. These protracted withdrawal symptoms have been implicated as an important trigger of relapse to excessive drinking in alcoholics and may represent a long lasting shift in affective tone as a result of chronic alcohol exposure. It was shown previously that ethanol-dependent rats increased their operant responding for ethanol when tested during the first 12 hr after withdrawal. The purpose of the present experiments was to determine the persistence of this finding by examining operant oral ethanol self-administration in rats with a history of physical dependence upon ethanol, detoxified and then allowed a two week period of protracted abstinence. The results of these experiments indicate that operant responding for ethanol was enhanced during protracted abstinence by 30-100% and remained elevated for 4-8 weeks post acute withdrawal. These results have important implications for understanding the characteristics and mechanisms underlying vulnerability to relapse.     

Plasma homovanillic acid: a significant association with alcoholism is independent of a functional polymorphism of the human catechol-O-methyltransferase gene.

The central dopamine system seems to influence addictive disorders. Plasma homovanillic acid (HVA) is an indicator of central dopaminergic activity. In this study the hypothesis that plasma HVA is associated with alcoholism or with delirium tremens (DT) during alcohol withdrawal was tested. A functional genetic polymorphism of the enzyme catechol-O-methyltransferase (COMT) that participates in converting dopamine into its final metabolite HVA was investigated for an association with alcoholism or DT during alcohol withdrawal. In addition, a relation between the functional polymorphism of COMT and plasma HVA concentrations was studied. Plasma HVA concentrations and COMT genotypes were determined in 142 German alcoholics and 101 German healthy controls. Alcoholic patients were examined after a minimum of 3 weeks after cessation of drinking. Mean plasma HVA concentrations were significantly lower in alcoholic patients compared to healthy controls. A group of alcoholics with a history of DT during alcohol withdrawal (n=62) did not differ significantly in plasma HVA concentrations from alcoholics with a history of only mild withdrawal symptoms (n=67). The functional polymorphism of the human COMT gene was neither significantly associated with the diagnosis of alcoholism or DT during alcohol withdrawal nor with plasma HVA concentrations.     

Basal serum cortisol and dexamethasone-induced growth hormone release in the alcohol dependence syndrome

We assessed the basal serum cortisol and the growth hormone (GH) response to dexamethasone in a group of completely detoxified male alcoholics and a group of healthy controls. There was a significant baseline elevation of serum cortisol in the alcoholics relative to the controls, and in the type 2 alcoholics relative to the type 1 alcoholics. There was no difference found in GH response to dexamethasone between the alcoholics and controls or between the types of alcoholics. There was no relationship found between the age of subject, length of abstinence from alcohol or severity of alcohol dependence and GH response. There was a significant relationship between severity of alcohol dependence and type of alcohol abuser. This may indicate a subtle impairment of the HPA in post withdrawal alcoholics, and between types of alcoholics, which does not appear to be at the pituatary or hypothalamic level.     

Measuring the learning potential of abstinent alcoholics.

The performance of 89 Finnish alcoholics was measured on a Vygotskian test of learning potential. There were four questions to analyse: (1) can the performance of alcoholics be improved by means of instruction in non-verbal problem solving tasks; (2) how extensive is the transfer effect; (3) how does the duration of abstinence affect test performance; and (4) how does the actual performance level affect post-test results? Results indicated that instruction had a clear positive effect on the performance of alcoholics in simple tasks, but no transfer effect was evident in the more complex tasks. The duration of abstinence had no general effect. Although analysis of the mean scores of time-level groups showed some improvement in performance with increasing duration of abstinence, intra-group deviation was so high that the trends were not statistically significant. The subjects' actual performance level, on the other hand, was a very relevant factor. This was particularly evident in complex transfer tasks.     

Pseudo-Cushing's Syndrome: An example of alcohol-induced central disorder in corticotropin-releasing factor-ACTH release?

Six chronic alcoholics with stigmata of Cushing's syndrome were studied before and after a period of alcohol abstinence. In all of them, after a minimum period of 3-4 weeks, a marked clinical and laboratory improvement was noted. The authors suggest that damage at brain level, with neurotransmitters' disturbance, caused by chronic alcoholism underlies the Pseudo-Cushing's Syndrome. The primum movens could be a disorder of the pituitary-adrenal axis secondary to a dysfunction of neurotransmitters with stimulation of ACTH-secreting cells of the adenohypophysis by the certicotropin-releasing factor (CRF).     

Alcohol protracted withdrawal syndrome: the role of anhedonia

AIMS: The aim of the present study is to characterize the relevance of withdrawal symptoms during the first 12 months of abstinence and their relation to anhedonia and craving. METHODS: 102 detoxified subjects meeting clinical criteria for Alcohol Dependence in Remission were recruited at various time since the detoxification and subdivided into four groups according to the length of abstinence (group 1: 15-30 days; group 2: 30-90 days; group 3: 90-180 days; group 4: 180-360). Withdrawal symptomatology was assessed through the Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar). The Visual Analogue Scale (VAS) for craving, the Snaith-Hamilton Pleasure Scale (SHAPS) and the Subscale for Anhedonia in the Scale for the Assessment of Negative Symptoms (SANSanh) where the other instruments employed. RESULTS: Both anhedonia and withdrawal symptoms were identified in all the groups considered. SHAPS score and VAS for craving showed a significant difference between group 1 and groups 2, 3, and 4. As to CIWA-Ar items, apart from "orientation/clouding of sensorium" that was higher in groups 3 and 4 with respect to both groups 1 and 2, withdrawal symptoms were not significantly different between the periods considered. SHAPS and SANSanh were positively correlated to CIWA-Ar total score, "nausea and vomiting," and "headache/fullness in head." DISCUSSION: The results of this study suggest the relevance of protracted withdrawal well beyond the limited period following the abrupt cessation of alcohol intake. The clinical dimension of anhedonia cannot be separated from the other behavioral symptoms of withdrawal and should be considered as part of the same process.     

Chronic alcohol abuse and the acute sedative and neurophysiologic effects of midazolam

The aim of the present investigation was to examine benzodiazepine sensitivity in abstinent alcoholics. For this purpose, two escalating doses of the benzodiazepine midazolam were IV administered to nine alcohol-dependent patients after 2–3 weeks of abstinence and 12 healthy, non-alcoholic volunteers. A variety of dependent measures were examined, including the power spectrum of the resting electroencephalogram (EEG) and evoked EEG responses, saccadic eye movements, self-reported sedation, and vigilance task performance. Analyses revealed a significant association between plasma midazolam levels and changes in EEG beta power, pattern shift visual evoked potential amplitude, heart rate, and saccade amplitude and velocity. The patient and control groups differed significantly in the onset latencies of their saccadic eye movements, and marginally in EEG beta power, both before and after midazolam. However, no differences were detected between the groups in the dose of midazolam required to produce sedation or in midazolam’s neurophysiological effects. Received: 29 February 1997/Final version: 30 April 1997     

Intensive intervention for alcohol-dependent smokers in early recovery: a randomized trial

Introduction

The purpose of this study was to investigate the efficacy of an intensive tobacco cessation intervention for alcohol-dependent smokers in early recovery.

Methods

A total of 162 alcohol-dependent smokers were randomized to either intensive intervention for smoking cessation or usual care. The intensive intervention consisted of 16 sessions of individual cognitive behavior therapy (CBT) and combination nicotine replacement therapy that lasted 26 weeks. Usual care involved referral to a free-standing smoking cessation program that provided smoking cessation counseling of varying duration and guideline-concordant medications. The primary cessation outcome was verified 7-day point prevalence abstinence (PPA) at 12, 26, 38, and 52 weeks.

Results

At 12 and 26 weeks, the verified 7-day point-prevalence quit rate was significantly higher for the intensive intervention group than for the usual care group (both p = 0.03). However, the quit rates for the two treatment groups were not significantly different at 38 or 52 weeks. Verified 30-day alcohol abstinence rates were not significantly different for the two treatment groups at any of the follow-up assessments.

Conclusions

The intensive smoking cessation intervention yielded a higher short-term smoking quit rate without jeopardizing sobriety. A chronic care model might facilitate maintenance of smoking cessation during the first year of alcohol treatment and perhaps for longer periods of time. It is hoped that studies such as this will inform the development of more effective interventions for concurrent alcohol and tobacco use disorders.