Intravenous Flunitrazepam in the Treatment of Alcohol Withdrawal Delirium

Alcohol withdrawal delirium (AWD) requires treatment with an adequate sedative, anticonvulsant, and antipsychotic agent next to general intensive care measures, Optimal medication should have a rapid onset of action and the possibility of parenteral application. A specific antagonist should be available. Flunitrazepam is a benzodiazepine that fulfills all these criteria.
Twenty five patients suffering from AWD (mean age 45 years) took part in an open trial and underwent treatment with infusions of flunitrazepam (concentration: 8 mg/250 ml NaCl; speed, 250 ml/hr). Psychopathological, vegetative, and vital parameters were assessed every hour.
All patients survived. They were treated with a mean total dose (SD) of 83.9 (45.4) mg of flunitrazepam (1.3 mg/kg body weight), which induced sedation 13.2 (5.3) min after the initiation of intravenous treatment. The mean duration of AWD (85.1 ± 39.4 hr) corresponded to other studies, whereas the frequency of preexisting and concomitant diseases was higher (92%) in our patients. A patient who suffered from bronchitis and had a nasopharyngeal tamponade showed severe respiratory depression after having received 4 mg of flunitrazepam. This complication remitted immediately when 0.5 mg of flumazenil was given intravenously. No epileptic manifestation was observed during the treatment or after discontinuation of flunitrarepam. Vegetative and psychopathological symptoms (tremor, sweating, hallucinations, confusion, and restlessness) remitted rapidly.
Our data suggest that intravenous flunitrazepam can be an efficacious and safe alternative to traditional treatment strategies of AWD.     

Late-Onset Seizures in Alcohol Withdrawal

Purpose: To describe the clinical characteristics of alcohol withdrawal seizures in patients treated with a standardized protocol of short-acting benzodiazepines. Methods: Grand ma1 seizures were prospectively identified in a cohort of 1044 patients consecutively admitted to an inpatient alcohol detoxification unit at a Veterans Affairs Medical Center. All patients received a 72-hr structured taper of oxazepam with additional oxazepam given without limit in amount and duration in response to alcohol withdrawal symptoms. Results: Eleven seizures occurred for an overall rate of 1.1%. All were single grand ma1 seizures. Seizures occurred from 52 to 306 hr after admission, with a mean of 122 hr (5 days). A consistent relationship between the seizures and the cessation of oxazepam was noted, with peak incidence occurring 12–48 hr after the last oxazepam dose. In no case did recurrent withdrawal symptoms or delirium tremens develop after the seizure. Patients with seizures were slightly older, more likely to have had withdrawal seizures before (50% vs. 13%, p = 0.03), and had a more severe withdrawal course than controls. Conclusions: Seizures continued to occur at a low but measurable rate in alcohol withdrawal treated with a short-acting benzodiazepine. Clinical characteristics of the seizures are different from that classically described in untreated patients, with the seizures being closely related to the cessation of oxazepam rather than the cessation of alcohol.     

Reduced Expression of Circadian Clock Genes in Male Alcoholic Patients

Background: There are clear interactions between chronic alcohol consumption and circadian rhythmicity that is regulated by several circadian clock genes. The altered expressions of these genes have been mainly described in animals. The mammalian master clock in the suprachiasmatic nuclei orchestrates the biological rhythms in peripheral tissues. As peripheral blood mononuclear cells (PBMCs) are the most accessible tissue clinically, we assessed the mRNA levels of these genes in patients with alcohol dependence (AD) undergoing alcohol‐withdrawal (AW) treatment. Methods: Twenty‐two male patients fulfilled the DSM‐IV diagnostic criteria of AD, and 12 comparison healthy control subjects were recruited. The patients with AD were further divided by the presence of delirium tremens (DTs), the most severe form of AW syndrome, into DT group and non‐DT group. All the participants received blood withdrawal at 9 am, while the patients with AD had blood collection twice: on the next morning of admission (baseline) and on the seventh day. PBMCs were isolated from whole blood, and the mRNA expression profiles of hClock1, hBmal1, hPer1, hPer2, hCry1, and hCry2 were determined by quantitative real‐time PCR. Results: The baseline mRNA levels of the target circadian clock genes were markedly lower in patients with AD than in control subjects. After 1 week of alcohol detoxification, there were very limited restorations of discrete circadian gene expressions. DT group did not differ in the expression patterns of circadian clock genes from non‐DT group. Conclusions: This is the first study demonstrating the overall lowering of circadian clock genes among patients with AD. The expression pattern is comparable between patients with and without DTs. Although preliminary with data at only one single time point, the observation of strikingly reduced mRNA levels supports the association between circadian clock gene dysregulation and chronic alcohol intake.     

Gamma-Hydroxybutyric Acid (GHB) in the Treatment of Alcohol Withdrawal Syndrome: A Randomized Comparative Study Versus Benzodiazepine

BACKGROUND: Benzodiazepine has been shown to be one of the most effective class of drugs in the management of alcohol withdrawal syndrome (AWS). Gamma-hydroxybutyric acid (GHB) has recently been introduced in the treatment of alcohol problems, including AWS. At present there are no comparative studies between benzodiazepines and GHB in AWS treatment. The aim of the present randomized, controlled, single-blind study was to evaluate the efficacy and safety of GHB compared with diazepam in the treatment of AWS. METHODS: Sixty alcoholics affected by AWS were enrolled in the study. Diazepam (0.5-0.75 mg/kg body weight for 6 days, tapering the dose 25% daily until day 10) was administered orally to 30 patients (25 males, 5 females; mean age 44.3 +/- 10.9 years); GHB (50 mg/kg body weight for 10 days) was administered orally to 30 patients (26 males,4 females; mean age 41.7 +/- 10.4 years).The Clinical Institute Withdrawal Assessment for Alcohol-revised scale (CIWA-Ar) was used to evaluate the AWS physical symptoms. The State Anxiety Inventory test for current anxiety assessment and the Zung self-rating Depression Scale for current depression assessment were performed. RESULTS: Eight patients (26.6%) in the diazepam group and 4 patients (13.3%) in the GHB group dropped out. Both treatments were effective in reducing AWS. No significant difference was found between the groups in CIWA-Ar total score at baseline and at the different times of observation. Considering the CIWA-Ar subscore and Zung scale, a significant reduction of anxiety on day 4 (p < 0.02), agitation on day 5 (p < 0.02) and time of recovery of depression on day 5 (p < 0.02) was observed in the GHB group with respect to the diazepam group. Drowsiness and vertigo developed after initial drug administration in the GHB (19.2%) and diazepam (36.4%) groups and quickly resolved in both groups. CONCLUSIONS: GHB is as effective in the management of AWS as benzodiazepine and it seems to be quicker in reducing anxiety, agitation, and depression. Both drugs are safe and well-tolerated in AWS management.     

Differences in the Course of Alcohol Withdrawal in Women and Men: A Polish Sample

A retrospective study compared the course of alcohol withdrawal, including delirium tremens, in women and men hospitalized in the Nowowiejski Hospital in Warsaw from 1973 to 1987. Medical records pertaining to 1179 patients were analyzed; 13.8% of these patients were women and 86.2% were men. The study showed that women began intensive alcohol drinking later than men ( p < 0.0001), but the period between the onset of alcohol abuse and the first occurrence of alcohol withdrawal was shorter in women than in men ( p < 0.0001). In the period of heavy drinking before hospitalization, women consumed significantly less alcohol then men ( p < 0.0001); moreover, women drank nonbeverage alcohol less frequently than men ( p < 0.05). Women were hospitalized substantially longer than men ( p < 0.0001), whereas the duration of alcohol withdrawal symptoms at the time of hospitalization was comparable in both groups. Withdrawal seizures were significantly more frequent among men than among women ( p < 0.001). Significant differences in the patients'somatic conditions were not noted between the groups, with the exception of anemia and decreased potassium concentration, which were more frequently observed in women (both p < 0.0001), and of increased concentration of ALT and hypoproteinemia, which were more frequent in men (respectively, p < 0.05 and p < 0.01). Co-existing personality disorders, depressive disorders, and anxiety disorders—as well as abuse of benzodiazepines and barbiturates—were more frequently observed in women ( p < 0.0001). The period between the first hospitalization due to alcohol withdrawal and the time of death was significantly shorter in men than in women ( p < 0.05). The results point to differences in the conditions and the course of alcohol dependence and alcohol withdrawal between women and men.     

Severity and Treatment of Alcohol Withdrawal in Elderly Versus Younger Patients

We conducted a retrospective chart review of older ( n = 48; mean age = 69) and younger ( n = 36; mean age = 30) patients who were admitted to residential/inpatient treatment for alcohol withdrawal and dependence. Although the two age groups did not differ in terms of recent drinking history, the elderly group had significantly more withdrawal symptoms for a longer duration than the younger group. The elderly group also had more symptoms of cognitive impairment, daytime sleepiness, weakness, and high blood pressure. Finally, no significant differences were found between age groups in either the dosage or number of days of detoxification medication, although a trend was found for more days of medication in the elderly. We conclude that alcohol withdrawal may be more severe in elderly than in younger persons. Accordingly, treatment may take longer and should target the specific profile of symptoms that characterize alcohol withdrawal in the elderly.     

Irreversible Exocrine Pancreatic Insufficiency in Alcoholic Rats Without Chronic Pancreatitis After Alcohol Withdrawal

Background: Long‐term alcohol consumption alone did not cause chronic pancreatitis (CP) but impaired exocrine pancreatic function. This study is to explore the reversibility of exocrine pancreatic insufficiency in the abstinent rats and its mechanism. Methods: Forty‐eight healthy male Wistar rats were divided randomly into 4 groups: 6‐month control, 6‐month ethanol, 9‐month control, and 9‐month ethanol + withdrawal. Morphological changes of pancreatic acinar cells were observed. Pancreatic amylase and lipase were measured using an automatic biochemical analyzer. Free fatty acid (FFA) in rat intestinal chyme was measured. Cholecystokinin (CCK) levels were determined by radioimmunoassay. The expression of CCK‐A receptors was quantitatively analyzed by Western blot. Results: Alcohol‐induced ultramicrostructure changes of pancreatic acinar cells, including lipid droplets, myelinoid inclusion bodies, dilated rough endoplasmic reticulums, and diminished zymogen granules, were not attenuated after alcohol abstinence. The outputs of amylase and lipase, FFA content in intestinal chyme, and the intestinal and the pancreatic CCK levels in rats were reduced after chronic alcohol intake and were still lower than the control after cessation of alcohol use. Chronic ethanol intake or abstinence did not induce any change in the expression of CCK‐A receptors. Conclusions: Exocrine pancreatic insufficiency was irreversible in alcoholic rats without CP after alcohol withdrawal. It may be attributed to reduced pancreatic CCK, long‐standing fatty infiltration, ultramicrostructure injuries in pancreatic acinar cells, and aging.     

Changes in Human Plasma Nerve Growth Factor Level after Chronic Alcohol Consumption and Withdrawal

Numerous studies reported in recent years have shown that withdrawal from chronic consumption of drugs induces high levels of anxiety, both in humans and in animal models. In the present study, we demonstrated that withdrawal from chronic consumption of either ethanol or heroin causes a significant increase in plasma nerve growth factor, suggesting that the resulting anxiety condition triggers the release of this molecule. Although the functional significance of this phenomenon needs to be better defined, it is hypothesized that the increased levels of circulating nerve growth factor might be involved in homeostatic adaptive and/or reparative mechanisms.     

Differential patterns of serum brain-derived neurotrophic factor levels in alcoholic patients with and without delirium tremens during acute withdrawal

Background: Brain‐derived neurotrophic factor (BDNF) is associated with alcohol addiction and withdrawal‐related neurotoxicity. Delirium tremens (DT) is the most serious complication of alcohol withdrawal syndrome (AWS). In this study, we explored the differences in serum BDNF levels, measured at baseline and 1 week after alcohol withdrawal among alcoholic patients with and without DT. Methods: Sixty‐five inpatients, fulfilling the DSM‐IV criteria of alcohol dependence and admitted for alcohol detoxification, as well as 39 healthy control subjects were enrolled. The alcoholic patients were divided by the appearance of DTs into the DT group (n = 25) and non‐DT group (n = 40). We collected blood samples of the patient groups on the first and seventh days of alcohol withdrawal and measured serum BDNF levels by sandwich enzyme‐linked immunosorbent assay. Results: Serum BDNF levels differed significantly among the three groups: (i) control group 14.8 ± 4.7 ng/ml; (ii) non‐DT group 12.3 ± 3.3 ng/ml; (iii) DT group 6.2 ± 2.6 ng/ml (p < 0.001). One week after alcohol withdrawal, the BDNF levels increased significantly for both alcoholic groups. While non‐DT group had comparable BDNF levels (13.4 ± 3.5 ng/ml) with controls, the DT group still exhibited lower levels (8.9 ± 4.4 ng/ml). Conclusions: This study suggests chronic drinking leads to a reduction in BDNF levels, and patients with more deficient BDNF expression are vulnerable to the development of DTs. Additionally, BDNF levels elevated after prompt alcohol detoxification treatment. These findings indicate that BDNF could involve modifying the phenotypes of AWS as well as the pertinent neuroadaptive processes of alcohol dependence.     

Hypothalamic-Pituitary-Thyroid (HPT) Axis in Chronic Alcoholism. I. HPT Axis in Chronic Alcoholics During Withdrawal and After 3 Weeks of Abstinence

Thyroxine (T₄), free T₄ (fT₄), triiodothyronine (T₃ free T₃ (fT₃), reverse T₃ (rT₃), thyrotropine (TSH), thyroxine binding globulin (TBG), and T₃ uptake were measured in 14 chronic alcoholics during withdrawal and after 21 days of abstinence. Results were compared with those of 16 healthy volunteers. During withdrawal, the fT₄ and fT₃ concentrations were subnormal, whereas the respective protein-bound fractions were normal. T₄, T₃, and TBG increased during the abstinence period, T₃ and TBG being significantly higher than in normals at the second measuring time. T₃ uptake values fell, but remained well within the normal range at both measuring times. During abstinence, the fT₃ levels remained significantly lower than in healthy subjects. rT₃ concentrations decreased, but not significantly. The TSH values were normal throughout. These results showed numerous abnormalities in the hypothal-amic-pituitary-thyroid axis in alcoholics, the reasons for which are as yet unclear. The following possible interpretations are suggested: 1. The abnormally low serum fT₃ and ff₄ levels during withdrawal might reflect an increase in tissue uptake. 2. The increases in T₄-and partty those in T₃-during abstinence seem to reflect increased binding by TBG, the level of which rose markedly for reasons as yet unknown. 3. If increases in TBG during abstinence are taken into account, the decreases in rT₃ concentrations may reach the level of statistical significance. These falls in rT₃ concentrations may reflect an increase in rT₃ metabolization (deiodination) in various tissues, including the CNS, leading to a reduction in serum rT₃ bioavail-ability. 4. Factors such as liver disease, protein caloric malnutrition, and “psychological stress” do not fully explain all these abnormalities. A direct effect of ethanol on intracellular thyroid hormone metabolism and/or function seems conceivable.     

Neuropsychological Deficits in Adolescents with Fetal Alcohol Syndrome: Clinical Findings

Understanding the nature of cognitive deficits among adolescent patients with fetal alcohol syndrome (FAS) can direct future research on assessment and intervention. In an exploratory study, nine non-retarded teenagers with FAS were administered tests of IQ and adaptive behavior, and neuropsychological tests presumed sensitive to alcohol effects. Their performance was compared with psychometric norms and to data from a sample of 174 adolescents with minimal or no prenatal alcohol exposure. These nonretarded FAS patients commonly showed behavior problems, decreased social competence, and poor school performance. Neuropsychological testing revealed significant deficits, although no one neuropsychological profile characterized all patients and not all tests revealed problems. Relatively intact performance was observed in procedural memory, some measures of reaction time, and some reading measures. Deficits were seen on attentional and memory tasks tapping visual-spatial skills, short-term auditory attention and memory, declarative learning, and cognitive flexibility and planning. Difficulties in processing speed and accuracy were also seen. Comparison with a subgroup of 52 nonalcohol-exposed or minimally alcohol-exposed adolescents with a similar range of IQ scores demonstrated that deficits among these FAS patients were not fully explained by a general lowering of IQ.     

The Interaction of Ethanol and Vitamin A as a Potential Mechanism for the Pathogenesis of Fetal Alcohol Syndrome

The mechanism of the fetal embryopathology resulting from ethanol ingestion during pregnancy is not established. This review summarizes recent research on the interaction of ethanol and vitamin A in models that explore if an interaction between these two compounds might potentially be the mechanism for fetal alcohol syndrome. The rationale for this hypothesis includes the known facts that: (1) in adults, ethanol ingestion alters vitamin A metabolism and tissue distribution; (2) there are many phenotypic similarities between fetal alcohol syndrome and malformations of both vitamin A toxicity and deficiency; and (3) the vitamin A metabolite, retinoic acid (RA), is a potent mediator in embryogenesis and differentiation. One interaction that could possibly alter fetal development is that the synthesis of RA from retinol, catalyzed by alcohol dehydrogenase, might be competitively inhibited by ethanol leading to RA deficiency. Controversy over this hypothesis continues. Another model demonstrates in vivo effects of pregnant rat mother's ethanol consumption on retinol, retinyl ester, RA content, RA receptor (RAR) binding, and the levels of RAR expression in developing fetal organs. The variable responses in this model still need clarification, and specific defects resulting from specific RAR changes have not yet been identified. In a quail embryo model, ethanol treatment mimics vitamin A deficiency, and RA appears to prevent the adverse effects of ethanol. Finally, RA and ethanol reverse or block each other's effects in studies on isolated neuroblastoma cells. Taken together, these experiments show definite interactions between ethanol and vitamin A. Further studies are needed to determine if any of these mechanisms significantly contribute to prenatal ethanol consumption embryopathy; but, clearly this hypothesis is gaining experimental support.     

Carbohydrate-Deficient Transferrin and Alcohol Dependency: Variation in Response to Alcohol Intake among Different Groups of Patients

Carbohydrate-deficient transferrin (CDT) and γ-glutamyltransferase (GT) were evaluated as markers of alcohol dependency in two different groups of patients. Sensitivity of CDT was nearly 75% for patients hospitalized for detoxification, but lower than 50% for alcohol-dependent patients admitted to acute surgery. CDT correlated with self-reported alcohol consumption in both groups, and sensitivity increased with higher alcohol intake. Sensitivity of CDT for females in both groups was considerably lower than for males, although their alcohol consumption was not significantly different. Serum activity of GT showed almost identical performance as CDT when evaluated by receiver-operating characteristics curve analysis (ROC-analysis), but sensitivity and specificity of the two markers varied differently with both alcohol consumption and age. Among the surgical patients, the highest sensitivity of CDT was found for the middle-aged patients (36 to 50 years), whereas the highest sensitivity of GT was found for the eldest. A tendency for similar age-related differences were also observed among the patients warded for detoxification, but these differences were not statistically significant. A particular difference between the two groups was noted among the youngest patients (21 to 35 years), with a very low sensitivity of CDT (<20%) for the surgical patients and a high sensitivity (77%) for the detoxification group. This difference was not only caused by differences in the present alcohol consumption, but would also be related to differences in drinking pattern or duration. Two commercial kits analyzing CDT were compared and ROC-analysis indicated identical performance of the two. However, a kit determining CDT as percentage of total transferrin showed a somewhat higher sensitivity among patients with low serum transferrin. We conclude that CDT and GT show variant responses to alcohol consumption in different groups of patients. The level of the two markers are related to sex, age, and alcohol consumption. Furthermore, the performance of both markers depend on the patients' history of alcohol abuse. CDT and GT are statistically independent markers and may therefore supplement each other.     

A Comparison of Children Affected by Prenatal Alcohol Exposure and Attention Deficit, Hyperactivity Disorder

Behavioral deficits are often noted in children with fetal alcohol syndrome (FAS) and other individuals with prenatal alcohol exposure, including mental retardation, learning problems, social problems, and deficits in attention. Because attention deficit, hyperactivity disorder (ADHD) has been diagnosed so frequently in children with FAS and other alcohol related birth defects, there has been speculation that alcohol is an etiological factor in ADHD. To examine the relationship between behavior characteristics of children with fetal alcohol exposure and those seen in children with a diagnosis of ADHD, 149 low socioeconomic status (SES), African-American children (mean age = 7.63 years) were given a battery of neuropsychological and behavioral tests. One hundred and twenty-two were a sub-sample from a longitudinal study of prenatal alcohol exposure, whereas twenty-seven were identified in an ADHD Clinic. Children were given two sets of tests: (1) “traditional model” of conventional behavioral and psychiatric measures of ADHD and externalizing behavior; and (2) measures of neurocognitive functioning reflecting a four-factor model of the neurological basis of the components of attention (Mirsky AF, in Integrated Theory and Practice in Clinical Neuropsychology, Hillsdale, NJ, Lawrence Erlbaum Associates, 1989). Results indicated that children with the physical characteristics associated with prenatal alcohol exposure and those with a diagnosis of ADHD had equivalent intellectual abilities with both clinical groups performing more poorly than contrast children from the same SES and ethnic groups. However, there were clear distinctions on behavioral and neurocognitive measures between the two clinical groups with those with ADHD performing more poorly on conventional tests sensitive to attentional problems and conduct disorder. When these two groups were compared on measures designed to measure the model of the four factors of attention by Mirsky, they were noted to have distinct patterns of deficits. These results suggested that the alcohol-affected children did not have the same neurocognitive and behavioral characteristics as children with a primary diagnosis of ADHD.