Linear correlation between phenobarbital dose and concentration in alcohol withdrawal patients.

INTRODUCTION: Barbiturates are potent drugs for treatment of alcohol withdrawal symptoms, but they entail a risk of over-dosage and respiratory depression. The purpose of the present study was to investigate the correlation between phenobarbital dose and phenobarbital blood concentration in patients withdrawing from long-term alcohol intoxication. MATERIAL AND METHODS: A total of 497 patients who were hospitalized for treatment of alcohol withdrawal symptoms during an 18-month period were enrolled in the study. Phenobarbital 200 mg was administered orally every 30 or 60 minutes in response to the observed symptoms. Within the first 24 hours after admission, i.e. at 8 AM, blood was collected for determination of phenobarbital concentration, and the cumulated dose of phenobarbital at the time of the blood sampling was registered. RESULTS: The mean cumulated phenobarbital dose at the time of the blood sampling was 877 mg +/- 557 mg, while the mean plasma phenobarbital concentration was 104 micromol/l +/- 62 micromol/l. A statistically significant linear correlation between phenobarbital dose and concentration was found for both males and females as 83% and 84% of the variation in drug concentration, respectively, could be explained by the phenobarbital dose. We observed no serious complications of the phenobarbital treatment--including respiratory problems or severe sedation. DISCUSSION: The strong linear correlation between phenobarbital dose and concentration suggests that absorption of plasma phenobarbital from the gastrointestinal system is highly predictable.

Phenobarbital versus diazepam for delirium tremens--a retrospective study.

INTRODUCTION: Delirium tremens (DT) is a severe and potentially fatal condition that may occur during withdrawal from chronic alcohol intoxication. The purpose of the present study was to compare the effects and the rates of complications of phenobarbital and diazepam treatment in DT. MATERIAL AND METHODS: Data were collected retrospectively from the medical files of patients who had received DT treatment (n = 194) at two psychiatric departments located in the general Copenhagen area in the 1998-2006 period. At one department, all patients were treated with phenobarbital (n = 53), while the treatment regimen at the other department was changed from phenobarbital (n = 53) to diazepam (n = 88) in 2002. RESULTS: Length of DT and hospitalization, mortality and rate of pneumonia (26%) were not affected by treatment. A subpopulation (9%) in the diazepam group was resistant to treatment. Respiratory depression occurred in 4% of the phenobarbital and in 1% of the diazepam-treated patients. Wernicke's encephalopathy was established in 47% of the patients. CONCLUSION: Phenobarbital is a safe alternative to diazepam in the treatment of DT.

[Wernicke's encephalopathy in patients with alcohol withdrawal symptoms]. / Wernickes encefalopati hos patienter med alkoholabstinenssymptomer.

INTRODUCTION: Wernicke's encephalopathy (WE) is caused by lack of thiamin. In Denmark, WE most often occurs in alcoholics. In the present study, we wanted to investigate the frequency of WE in patients hospitalized for treatment of alcohol withdrawal symptoms in a psychiatric emergency ward. MATERIAL AND METHODS: Prospective registration of symptoms and treatment regimen in all patients admitted for alcohol withdrawal treatment in the period 22.02.2007-31.08.2008. RESULTS: Symptoms of WE occurred in 52 of a total of 497 patients (11%). Ataxia of gait was the predominant symptom, succeeded by cognitive impairment, whereas ocular palsy was unusual. Patients with WE were on average administered approximately 50% more phenobarbital than patients without symptoms of WE (p < 0.01), probably reflecting a more severe withdrawal reaction. In 21 of the 52 patients with WE (41%) the preceding period of alcohol intake was shorter than 14 days. DISCUSSION: WE is a frequently occurring condition among patients treated for alcohol withdrawal symptoms in psychiatric wards. A possible pathogenetic factor is the alcohol withdrawal reaction, as cerebral hyperactivity may lead to increased thiamin consumption and thus depletion of the depots. To avoid insufficient treatment, routine administration of large doses of intravenous thiamine to all patients admitted with alcohol withdrawal symptoms should be considered.

Disulfiram in severe alcoholism--an open controlled study.

BACKGROUND: Disulfiram is used to a great extent in Denmark to treat alcoholism but the evidence is limited. AIM: To study the effect of supervised disulfiram treatment in alcohol dependence. Subjects were recruited from a psychiatric emergency ward following alcohol withdrawal treatment. METHODS: A total of n=39 patients were openly randomized to either disulfiram 800 mg twice a week for 26 weeks (n=19) or no disulfiram (n=20). All patients were also treated with cognitive behavioural therapy (CBT) in groups. RESULTS: The rate of abstinence was 20% and 26% in the control and disulfiram group, respectively. This difference was not statistically significant (NS). A trend towards increased mean time to first drink was found in the disulfiram group (96 vs. 76 days in the control group, NS), while fewer patients in this group completed CBT group therapy (41% vs. 67% in the control group, NS). Alcohol-free days were 100 days in both groups (NS). CONCLUSION: Supervised disulfiram administration did not have any major impact on the treatment outcome.

Gene expression in the neuropeptide Y system during ethanol withdrawal kindling in rats.

BACKGROUND: Multiple episodes of ethanol intoxication and withdrawal result in progressive, irreversible intensification of the withdrawal reaction, a process termed "ethanol withdrawal kindling." Previous studies show that a single episode of chronic ethanol intoxication and withdrawal causes prominent changes in neuropeptide Y (NPY) and its receptors that have been implicated in regulating withdrawal hyperexcitability. This study for the first time examined the NPY system during ethanol withdrawal kindling. METHODS: Ethanol withdrawal kindling was studied in rats receiving 16 episodes of 2 days of chronic ethanol intoxication by intragastric intubations followed by 5 days withdrawal. The study included 6 groups: 4 multiple withdrawal episode (MW) groups [peak withdrawal plus (MW+)/minus (MW-) seizures, 3-day (MW3d), and 1-month (MW1mth) withdrawal], a single withdrawal episode group (SW), and an isocalorically fed control group. Gene expression of NPY and its receptors Y1, Y2, and Y5 was studied in the hippocampal dentate gyrus (DG) and CA3/CA1, as well as piriform cortex (PirCx), and neocortex (NeoCx). RESULTS: MW+/- as well as SW groups showed decreased NPY gene expression in all hippocampal areas compared with controls, but, in the DG and CA3, decreases were significantly smaller in the MW- group compared with the SW group. In the MW+/- and SW groups, Y1, Y2, and Y5 mRNA levels were decreased in most brain areas compared with controls; however, decreases in Y1 and Y5 mRNA were augmented in the MW+/- groups compared with the SW group. The MW+ group differed from the MW- group in the PirCx, where Y2 gene expression was significantly higher. CONCLUSION: Multiple withdrawal episodes reversibly decreased NPY and NPY receptor mRNA levels at peak withdrawal, with smaller decreases in NPY mRNA levels and augmented decreases in Y1/Y5 mRNA levels compared with a SW episode. Multiple withdrawal-induced seizures increased the Y2 mRNA levels in PirCx. These complex changes in NPY system gene expression could play a role in the ethanol withdrawal kindling process.

[Respiratory depression in delirium tremens patients treated with phenobarbital. A retrospective study]. / Respirationsproblemer ved phenobarbitalbehandling af delirium tremens. Et retrospektivt studie.

INTRODUCTION: Delirium tremens (DT) is the most severe manifestation of alcohol withdrawal which--if untreated--has a high rate of mortality. Barbiturates are the most effective drug but respiratory depression may occur. In the present study we investigated the frequency of respiratory problems in DT patients treated with phenobarbital. MATERIALS AND METHODS: We examined the medical records of patients who were treated as inpatients in 1998-2006 and discharged with the ICD-10 diagnoses F10.4 (alcohol withdrawal delirium) or F10.5 (alcohol induced psychotic disorder). Patients with pre-DT and full blown DT were included in the study. RESULTS: While we did not detect any respiratory problems among patients with pre-DT, we found 9 cases among 73 patients with full blown DT, 5 of which were considered serious. In two of these the frequency of respiration (FR) was decreased (5-6 per min). Both cases occurred in the same patient at two different admissions. It was not considered necessary to move the patient to the Intensive Care Unit (ICU). Three patients developed pneumonia and were moved to the ICU, one of whom developed a life-threatening sepsis. One patient with chronic emphysema died due to ketoacidosis. The death could not be attributed to the phenobarbital treatment. CONCLUSION: In conclusion, we found that the frequency of phenobarbital-induced respiratory depression was low. However, if the DT was complicated with pneumonia, life-threatening respiratory insufficiency could be the outcome. An intensive focus on the patient's somatic condition in DT is therefore recommended, and it should always be possible to move the patient to the ICU.

Decreased gene expression of neuropeptide Y and its receptors in hippocampal regions during ethanol withdrawal in rats.

Ethanol withdrawal is associated with neuronal hyperexcitability and increased hippocampal glutamate release. Neuropeptide Y (NPY) appears to play an important role in regulation of hippocampal neuronal excitability by inhibiting glutamate release. Expression of NPY and its receptors Y1, Y2, and Y5 was studied in hippocampal areas of rats during ethanol withdrawal after repeated intragastric ethanol administration for 2 or 4 days using in situ hybridization. Withdrawal was associated with decreased hippocampal expression of NPY and each of its receptors, particularly Y2, after 2 and/or 4 days of ethanol compared to control rats. These data suggest that the hippocampal NPY system is downregulated during ethanol withdrawal and these neuroadaptational changes could play a role in mediating withdrawal hyperexcitability.

Upregulation of glutamate receptor subtypes during alcohol withdrawal in rats.

AIMS: To investigate glutamate receptor subtypes during alcohol withdrawal. METHODS: Rats were exposed to severe alcohol intoxication for 84 h and then decapitated at 0, 12 and 36 h after the last alcohol dose (n = 7 per group). Alcohol was administered five times a day by intragastric intubation. The densities of N-methyl-D-aspartate (NMDA) and 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors were studied in membranes from the forebrain by using the specific ligands [3H]MK-801 and [3H]AMPA, respectively. RESULTS: Although no change in the maximal density (B(max)) of [3H]MK-801 binding sites was observed at the time of withdrawal, [3H]MK-801 binding was increased by 49% 12 h into the withdrawal reaction compared with the control group. At 36 h post alcohol the B(max) of the [3H]MK-801 binding was still increased by 24% compared with the control group; however, this difference was not statistically significant. When investigated at the time of withdrawal from chronic alcohol intoxication, no significant alterations in the B(max) of the [3H]AMPA binding was detected, but 12 h into the withdrawal reaction the [3H]AMPA binding was markedly increased by 94%. At 36 h post alcohol the [3H]AMPA binding had returned to control levels. No significant alterations in the dissociation constant (K(D)) of either [3H]MK-801 or [3H]AMPA binding was observed at any time point. CONCLUSIONS: NMDA and AMPA receptors are involved in the cerebral hyperactivity of alcohol withdrawal.

Ethanol withdrawal in rats is attenuated by intracerebroventricular administration of neuropeptide Y.

AIMS: The effects of intracerebroventricular administration of neuropeptide Y (NPY) on ethanol withdrawal were studied in rats. METHODS: Ethanol was administered intragastrically five times daily for 4 days. At 16-17 h after the last infusion of ethanol, rats were rated for withdrawal using a score based on three signs: irritability, tremor and rigidity. Subsequently, the rats received an injection of NPY (12 or 24 nmol) or vehicle and were rated for signs of withdrawal. RESULTS: At both doses, NPY significantly reduced ethanol withdrawal, the effect of the larger dose being more pronounced. CONCLUSIONS: Our results are consistent with the concept that NPY receptors are centrally involved in the regulation of neuronal excitability and might form a novel therapeutic target for treatment of ethanol withdrawal and other states of neuronal hyperexcitability.