Treatment Of Alcohol Withdrawal Research Articles

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Introduction: Benzodiazepines (BZD) are initially used for treatment of alcohol withdrawal. Phenobarbital (PB) is a barbiturate agent that has also been used in managing alcohol withdrawal symptoms, especially refractory to BZD. However, limited data is available in critically ill patients. The purpose of our study is to describe our institution’s experience with adjunctive PB use in managing severe alcohol withdrawal in the intensive care unit (ICU). Hypothesis: PB can be safely used adjunctively with BZD in managing severe alcohol withdrawal symptoms in the ICU. Methods: A retrospective review was performed for patients who received PB for severe alcohol withdrawal admitted to the medical ICU from July 2011 to February 2012. Patients were managed with the medical ICU severe alcohol withdrawal protocol which utilizes a step-wise approach with BZD and PB. IRB approval was granted. Data were collected on demographics, time to symptom control, medication doses, ventilator days, ICU length of stay and adverse effects of PB. Results: Of the 28 patients analyzed, the mean values for medication requirements were as follows: average amount of PB administered = 1086 mg + 390 mg, cumulative dose of lorazepam administered in the first 24 hours of protocol initiation = 209 mg + 145 mg and duration of continuous sedative infusions = 97 + 59.8 hours. The average time to symptom control was 1.4 + 0.7 hours. The majority of patients (18/28) requiring mechanical ventilation were for reasons unrelated to PB. Average duration of mechanical ventilation was 5.7 + 2.1 days and average ICU length of stay was 7.9 + 2.4 days. Complications of PB included respiratory failure requiring intubation in 2/28 (7.1%) and hypotension in 3/28 (10.7%) of the study population. Conclusions: PB when used adjunctively with BZD was able to control severe alcohol withdrawal symptoms in the ICU with minimal complications. PB may have a potential role for managing severe alcohol withdrawal symptoms in critically ill patients that are not adequately controlled with BZD. Continued work is directed at comparing outcomes before and after PB use in the medical ICU.

Long-Term Benzodiazepine Use and Mortality: Are we Doing the Right Studies?

Benzodiazepines are World Health Organisation essential medicines used in the treatment of alcohol withdrawal, anaesthesia, sedation, anxiolysis, behavioural disturbance, epilepsy, insomnia, palliative care, and muscle spasm. Despite their widespread use concerns remain over their long-term safety through both neuronal and non-neuronal effects. We conducted a systematic review to identify vulnerable populations of patients who may be at increased risk of harm from benzodiazepines. We identified three potentially "at risk" groups of patients, those with renal disease, lung disease and those recently hospitalised. However methodological limitations including selection bias, vague descriptors of benzodiazepine use and inappropriate grouping together of benzodiazepines with other medications, precluded definitive conclusions. Future studies should concentrate on these groups to identify the long-term safety of benzodiazepines in these patient groups.

351 The Effect of an Alcohol Withdrawal Treatment Protocol on Alcohol Withdrawal Syndrome Patient Outcomes

351 The Effect of an Alcohol Withdrawal Treatment Protocol on Alcohol Withdrawal Syndrome Patient Outcomes

Benzodiazepine loading versus symptom-triggered treatment of alcohol withdrawal: a prospective, randomized clinical trial

ObjectivesThe objectives were to compare the efficacy of a benzodiazepine loading versus a symptom-triggered protocol in the management of alcohol withdrawal. MethodsWe conducted a prospective, randomized, controlled trial including 47 consecutive patients admitted to one of two tertiary care medical centers who developed alcohol withdrawal syndrome. Patients were randomly assigned to either a benzodiazepine loading protocol or a symptom-triggered treatment protocol. The Clinical Institute Withdrawal Assessment for Alcohol-Revised scale (CIWA-Ar) was recorded throughout the length of stay, along with measures of autonomic system functioning. ResultsThe average rate of change of CIWA-Ar scores was −1.5±1.3 for the symptom-triggered group and −2.3±2.5 for the loading group. Average rate of change for systolic blood pressure was −2.7±5.3 for the symptom-triggered group and −2.3±6.4 for the loading group. There was no significant difference between the rates of change for either group on either measure. Similarly, there was no significant difference in total benzodiazepine use between groups. Within 72 h of treatment, 69.6% of patients in the loading group were free of withdrawal symptoms versus 41.7% in the symptom-triggered group, a difference not reaching statistical significance. ConclusionsThis study did not reveal clear evidence of a clinical advantage for choosing either treatment method.

Levetiracetam in the Treatment of Alcohol Dependence: Toward the End of the Story?

Levetiracetam exhibited 2 promising results in preclinical studies as well as in treating alcohol withdrawal in humans. Two open-label trials suggested that levetiracetam may be efficient in alcohol-related disorder. The study by Fertig and colleagues (2012) examines the effects of levetiracetam using a double-blind, placebo-controlled design including 130 participants. Fertig and colleagues' study included alcohol-dependent participants drinking heavily. Double-blind medication was dispensed for 16 weeks, with a target dose of 2,000 mg per day from week 5 to week 14, and then tapered. The results are negative both on the primary and on the secondary outcomes, except from lower alcohol-related consequences in the levetiracetam extended-release (XR) group, and a trend for a lower quality of life in the levetiracetam XR group. These last 2 results would have been nonsignificant after controlling for multiple testing. By conducting a state-of-the-art randomized-controlled clinical trial with negative results, Fertig and colleagues have filled an important gap in the existing literature.

The Use of Dexmedetomidine in Alcohol Withdrawal

The Use of Dexmedetomidine in Alcohol Withdrawal

Gamma-hydroxybutyrate (GHB) for mid/long term treatment of alcohol dependence: a systematic review

Gamma-hydroxybutyric acid (GHB) is used to treat alcohol withdrawal syndrome (AWS) at short term, and to reduce alcohol relapses among alcohol dependent subjects at mid-term. The objective of this paper is to synthesize results of a Cochrane review on efficacy of GHB for treating alcohol dependence at mid-term. The search strategy was conducted on MEDLINE, EMBASE, PsycINFO, CINAHL and on the Cochrane Library. Pharmaceutical companies were contacted and references of papers were checked in order to identify unpublished studies. Randomized controlled trials (RCT), clinical controlled trials (CCT), and controlled prospective studies (CPS) were considered. Three authors blindly evaluated the quality of the studies and extracted the data. Seven RCT studies evaluating efficacy of GHB for treating alcohol dependence at mid-term were included in the review; all were conducted in Italy. GHB appears to be more effective than placebo on alcohol abstinence (RR 2.63; 1.22-5.71), controlled drinking (RR 2.43; 1.07-5.54), relapses to heavy drinking (RR 0.37; 0.21-0.63), and number of daily drinks (MD -4.60; -6.18,-3.02). GHB appears to be more effective than naltrexone on alcohol abstinence (RR 1.78; 1.21-2.62) but not on other outcomes. The effect on Alcohol Craving Scale favours GHB vs placebo (MD -4.50; -5.81,-3.19), vs naltrexone (MD -1.90; -2.45,-1.35) and vs disulfiram (MD -1.40; -1.86,-0.94). Side effects are similar to naltrexone and disulfiram. The low number of available studies, the low sample size and the low quality of the included studies limit the validity of the results and suggest the need of conducting new high-quality randomized trials with appropriate sample size.

Catatonia and Alcohol Withdrawal: A Complex and Underestimated Syndrome

Catatonia is a neuropsychiatric syndrome characterized by alterations in motor behavior, vigilance, thought and mood. Catatonia syndrome occurs in many neuropsychiatric and medical conditions, but it is very rarely mentioned as occurring during alcohol withdrawal. We think that this co-occurrence could be underestimated in clinics because alcohol withdrawal symptoms may distract from its identification. We report the case of a patient presenting with catatonia during the benzodiazepine reduction period of alcohol detoxification. A 65-year-old woman presented with a 15-year history of alcohol dependence and developed catatonic episodes several times during alcohol withdrawal treatment. Misdiagnosis delayed specific treatment. Symptoms of episodes dramatically improved 48 h after treatment with diazepam and revealed an anxiety disorder. This report confirms that catatonia is a non-specific response to psychological, physical and psychosocial stress factors. Recent alcohol withdrawal may sensitize the patient to benzodiazepine withdrawal catatonia, and this phenomenon is probably underestimated. Catatonia Rating Scales can be useful when diagnosis is complicated as in alcohol and benzodiazepine withdrawal. In that situation, misdiagnosis is common and may delay specific treatment.

Dexmedetomidine as adjunct treatment for severe alcohol withdrawal in the ICU.

BackgroundPatients undergoing alcohol withdrawal in the intensive care unit (ICU) often require escalating doses of benzodiazepines and not uncommonly require intubation and mechanical ventilation for airway protection. This may lead to complications and prolonged ICU stays. Experimental studies and single case reports suggest the α2-agonist dexmedetomidine is effective in managing the autonomic symptoms seen with alcohol withdrawal. We report a retrospective analysis of 20 ICU patients treated with dexmedetomidine for benzodiazepine-refractory alcohol withdrawal.MethodsRecords from a 23-bed mixed medical-surgical ICU were abstracted from November 2008 to November 2010 for patients who received dexmedetomidine for alcohol withdrawal. The main analysis compared alcohol withdrawal severity scores and medication doses for 24 h before dexmedetomidine therapy with values during the first 24 h of dexmedetomidine therapy.ResultsThere was a 61.5% reduction in benzodiazepine dosing after initiation of dexmedetomidine (n = 17; p < 0.001) and a 21.1% reduction in alcohol withdrawal severity score (n = 11; p = .015). Patients experienced less tachycardia and systolic hypertension following dexmedetomidine initiation. One patient out of 20 required intubation. A serious adverse effect occurred in one patient, in whom dexmedetomidine was discontinued for two 9-second asystolic pauses noted on telemetry.ConclusionsThis observational study suggests that dexmedetomidine therapy for severe alcohol withdrawal is associated with substantially reduced benzodiazepine dosing, a decrease in alcohol withdrawal scoring and blunted hyperadrenergic cardiovascular response to ethanol abstinence. In this series, there was a low rate of mechanical ventilation associated with the above strategy. One of 20 patients suffered two 9-second asystolic pauses, which did not recur after dexmedetomidine discontinuation. Prospective trials are warranted to compare adjunct treatment with dexmedetomidine versus standard benzodiazepine therapy.

Evaluation of an Alcohol Withdrawal Protocol and a Preprinted Order Set at a Tertiary Care Hospital

Alcohol withdrawal protocols involving symptom-triggered administration of benzodiazepine have been established to reduce the duration of treatment and the cumulative benzodiazepine dose (relative to usual care). However, the effects of a protocol combining fixed-schedule and symptom-triggered benzodiazepine dosing are less clear. To assess the efficacy and safety of a combination fixed-scheduled and symptom-triggered benzodiazepine dosing protocol for alcohol withdrawal, relative to usual care, for medical inpatients at a tertiary care hospital. A chart review of admissions to the internal medicine service for alcohol withdrawal was conducted to compare treatment outcomes before (October 2005 to April 2007) and after (October 2007 to April 2009) implementation of the combination protocol. The primary outcome was duration of benzodiazepine treatment for alcohol withdrawal. The secondary outcomes were cumulative benzodiazepine dose administered, safety implications, and use of adjunctive medications. A total of 159 patients met the inclusion criteria. Assessable data were available for 71 charts from the pre-implementation period and 72 charts from the post-implementation period. The median duration of benzodiazepine treatment was 91 h before implementation and 57 h after implementation (p < 0.001). Use of the protocol was also associated with a significant reduction in severe complications of alcohol withdrawal (50% versus 33%, p = 0.019), median cumulative benzodiazepine dose (in lorazepam equivalents) (20.0 mg versus 15.5 mg, p = 0.026), and use of adjunctive medications (65% versus 38%, p = 0.001). The incidence of serious adverse outcomes of treatment with benzodiazepines was not significantly different between the 2 groups. Implementation of an alcohol withdrawal protocol with a combination of fixed-schedule and symptom-triggered benzodiazepine dosing in a medical ward was associated with a shorter duration of benzodiazepine use and a lower incidence of severe complications of alcohol withdrawal.

Determination of endogenous/exogenous γ-hydroxybutyric acid (GHB) in urine

γ-Hydroxybutyric acid (GHB) is an endogenous metabolite and a precursor of the neurotransmitter γ-aminobutyric acid. In some European countries GHB is also used as an anaesthetic agent and in the treatment of alcohol withdrawal. The purpose of the present study was to determine GHB concentrations in urine to enable discrimination between endogenous GHB and exogenous GHB derived from therapeutic administration (Alcover®, Laboratorio farmaceutico C.T.Srl, Sanremo). 34 urine samples from 17 alcoholics under treatment for alcohol withdrawal with GHB (group 1) and 12 urine samples from healthy volunteers without GHB intake (group 2) were collected anonymously and analysed by HPLC/MS/MS. The urine concentrations of GHB were determined from two standard curves with the following concentrations: 0.25, 0.50, 1.00, 2.50,5.00 and 10.00 μg/ml, and 5.00, 10.00, 25.00, 50.00 and 100.00 μg/ml. Acceptable linear regression was obtained for both calibration curves: R2 = 0.9950 and R2 = 0.9994, respectively. Intraday precision and accuracy were calculated as coefficient of variation (%) and bias (n = 10) on three positive control specimens at three different concentrations (0.50, 2.50 and 7.50 μg/ml). The limit of quantification was determined to be 0.50 μg/ml. The median and average concentrations of GHB in group 2 (no GHB intake) were 3.55 and 3.49 μg/ml, respectively, while 52.90% of group 1 (subjects treated with GHB) had urinary GHB concentrations less than the currently used cutoff of 10.00 μg/ml. In the absence of a rapid immunoassay for the detection of GHB in urine, LC/MS/MS analysis was found to be specific and reasonably fast for clinical and forensic toxicology applications. Of the subjects being treated with GHB, 52.90% were found to have a urinary GHB concentration less than 10.00 μg/ml, with GHB concentrations ranging from 2.95 to 8.50 μg/ml. Thus the widely accepted 10.00 μg/ml cut-off could be too high so that there is the risk of false-negative samples.

Treating alcohol withdrawal with oral baclofen: A randomized, double‐blind, placebo‐controlled trial

Abrupt cessation of alcohol intake causes habituated drinkers to experience symptoms of alcohol withdrawal syndrome (AWS). To determine the effect of the gamma-aminobutyric acid (GABA)-B agonist baclofen on the course of acute symptomatic AWS. Prospective, randomized, double-blind, placebo-controlled clinical study. Two tertiary-care hospitals in Duluth, Minnesota. Inpatient adults admitted for any reason (including AWS) judged to be at high risk for AWS. Inpatients who developed symptoms of AWS received symptom-triggered benzodiazepine treatment using lorazepam by standard protocol, and were randomized to receive baclofen 10 mg or placebo, 3 times per day, orally. AWS severity was assessed using the Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA-Ar); lorazepam dose was monitored. Seventy-nine subjects were enrolled. The 44 subjects who developed symptoms of AWS were randomized to baclofen or placebo. Thirty-one subjects (18 baclofen, 13 placebo) completed 72 hours of assessments, either entirely as inpatients or with outpatient follow-up. The need for high doses of benzodiazepines (20 mg or more of lorazepam over 72 hours) to control AWS was less likely in the baclofen treatment group (1 of 18) than in the placebo-treated group (7 of 13) (P = 0.004). We found that the use of baclofen was associated with a significant reduction in the use of high doses of benzodiazepine (lorazepam) in the management of symptomatic AWS. The use of low-dose baclofen in the management of AWS deserves further study, as reduced dependence on high-dose benzodiazepines in AWS management could improve patient safety.

SAT2 * TREATMENT OF ALCOHOL ADDICTION: HOW TO USE SODIUM OXIBATE? (D&amp;A) * SAT2.2 * NEUROBIOLOGY OF GHB IN RELATION TO ALCOHOL DEPENDENCE

SAT2 * TREATMENT OF ALCOHOL ADDICTION: HOW TO USE SODIUM OXIBATE? (D&amp;A) * SAT2.2 * NEUROBIOLOGY OF GHB IN RELATION TO ALCOHOL DEPENDENCE

S13 * NONINVASIVE SCREENING FOR LIVER CIRRHOSIS IN ADDICTIVE PATIENTS * S13.1 * IS LIVER STIFFNESS THE NOVEL GOLD STANDARD TO ASSESS LIVER CIRRHOSIS?

S13 * NONINVASIVE SCREENING FOR LIVER CIRRHOSIS IN ADDICTIVE PATIENTS * S13.1 * IS LIVER STIFFNESS THE NOVEL GOLD STANDARD TO ASSESS LIVER CIRRHOSIS?

Tizanidine for alcohol withdrawal treatment

The noradrenergic system is an important neurotransmission system implicated in the occurrence of alcohol withdrawal symptoms and anxiety leading to relapse during abstinence from alcohol usage. Tizanidine can play a role in alcohol withdrawal since it interferes with the noradrenergic system neurotransmission. Many noradrenergic system inhibitors in the central nervous system have proven their efficacy in the treatment of alcohol withdrawal syndrome. Imidazoline receptors have been also implicated in the pathophysiology of addiction. Tizanidine is an α2-adrenoreceptor agonist that inhibits noradrenaline release and binds to imidazoline receptors. It is used as an antispastic agent due to its central action on noradrenergic system. Although Tizanidine has been tested as a treatment for opioid withdrawal it has not been tried in alcohol withdrawal yet. A theoretical rationale supports the fact that it can be an efficient treatment for the alcohol withdrawal syndrome as well as for the prevention of relapses.

Efficacy and safety of pharmacological interventions for the treatment of the Alcohol Withdrawal Syndrome.

Alcohol abuse and dependence represents a very serious health problem worldwide with major social, interpersonal and legal interpolations. Pharmacological treatments presently used are of uncertain effectiveness and there is even more doubt on the comparative effects and value for money. To summarize Cochrane reviews that assess the effectiveness and safety of pharmacological interventions in the treatment of alcohol withdrawal. We searched the Cochrane Database of Systematic Reviews (30 November 2010). Two authors independently screened, extracted data, summarised key characteristics of the included reviews and assessed their quality using AMSTAR; the quality of the evidence was summarised according to the GRADE methodology. Five reviews, 114 studies, 7333 participants, satisfied criteria for inclusions. The outcomes considered were alcohol withdrawal seizures, adverse events and dropouts. Comparing the five treatments with placebo, benzodiazepines performed better for seizures, three studies, 324 participants, RR 0.16 (95% CI 0.04 to 0.69), moderate quality of evidence. Comparing each of the five treatments versus specific class of drugs, benzodiazepines performed better than antipsychotics for seizures, 4 studies, 633 participants, RR 0.24 (95% CI 0.07 to 0.88) high quality of the evidence. Comparing different benzodiazepines and anticonvulsants among themselves, 28 comparisons, results never reached statistical significance but chlordiazepoxide performed better. The quality of evidence was high for 3% of the results, moderate for 28%, low for 48% and very low for 20%. Among the treatments considered, benzodiazepines showed a protective benefit against seizures, when compared to placebo and a potentially protective benefit for many outcomes when compared with antipsychotics. Nevertheless, no definite conclusions about the effectiveness and safety of benzodiazepines were possible, because of the heterogeneity of the trials both in interventions and in the assessment of outcomes. Data on potential harms are sparse and fragmented. Results do not provide sufficient evidence in favour of anticonvulsants for the treatment of AWS, but anticonvulsants seem to have limited side effects. There is also not enough evidence of effectiveness and safety of baclofen, because only one study consider this treatment and of GHB for which no strong differences were observed in the comparisons with placebo, benzodiazepines and anticonvulsants.

Effects of Alcoholism and Continued Abstinence on Brain Volumes in Both Genders

Alcohol abuse has detrimental effects on cerebral function, metabolism, and volume. Some of these effects were found to be at least partially reversible with continued abstinence. Furthermore, it has been reported that there are different effects of alcohol on brain volumes for women compared with men, but the results concerning the interaction between alcohol dependence and gender are inconsistent. With this study, we aimed to further investigate this question by examining the global gray matter (GM) and white matter (WM) changes as well as regional and local GM changes detected by voxel-based morphometry (VBM) in male and female alcoholic patients a few weeks after detoxification and the corresponding changes in a subgroup of these patients 3 months later. A total of 50 patients, consecutively admitted for alcohol withdrawal treatment, participated in this study and were followed up for at least 3 months into abstinence. High-resolution structural images were processed with SPM8 using an optimized VBM protocol. Global cerebrospinal fluid (CSF) volume was increased and WM and GM volume decreased equally in male and female patients. A gender by diagnosis interaction was found neither for global nor for regional volumes or VBM data. VBM whole brain analysis yielded a significant GM volume loss in the patient group in the cingulate gyrus and the insula in both hemispheres. Region of interest analysis for the initial and 3 months follow-up scans yielded significant gains in regional volumes, particularly the cingulate gyrus and the insula in the group of abstinent patients, whereas no volume change at all is found in the patients who had relapsed. Our study confirms widespread cerebral volume loss in recently detoxified alcoholics. The effects of alcohol dependence seem to have equally adverse effects on brain morphometry in males and females.

Role of α2-Agonists in the Treatment of Acute Alcohol Withdrawal

To evaluate literature reporting on the role of norepinephrine in alcohol withdrawal and to determine the safety and efficacy of α(2)-agonists in reducing symptoms of this severe condition. Articles evaluating the efficacy and safety of the α(2)-agonists clonidine and dexmedetomidine were identified from an English-language MEDLINE search (1966-December 2010). Key words included alcohol withdrawal, delirium tremens, clonidine, dexmedetomidine, α(2)-agonist, norepinephrine, and sympathetic overdrive. Studies that focused on the safety and efficacy of clonidine and dexmedetomidine in both animals and humans were selected. The noradrenergic system, specifically sympathetic overdrive during alcohol withdrawal, may play an important role in withdrawal symptom development. Symptoms of sympathetic overdrive include anxiety, agitation, elevated blood pressure, tachycardia, and tremor. Therefore, α(2)-agonists, which decrease norepinephine release, may have a role in reducing alcohol withdrawal symptoms. The majority of controlled animal and human studies evaluated clonidine, but the most recent literature is from case reports on dexmedetomidine. The literature reviewed here demonstrate that these 2 α(2)-agonists safely and effectively reduce symptoms of sympathetic overdrive and concomitant medication use. Dexmedetomidine may offer an advantage over current sedative medications used in the intensive care unit, such as not requiring intubation with its use, and therefore further study is needed to fully elicit its benefit in alcohol withdrawal. Clonidine and dexmedetomidine may provide additional benefit in managing alcohol withdrawal by offering a different mechanism of action for targeting withdrawal symptoms. Based on literature reviewed here, the primary role for clonidine and dexmedetomidine is as adjunctive treatment to benzodiazepines, the standard of care in alcohol withdrawal.

Carbamazepine and Valproate as Adjuncts in the Treatment of Alcohol Withdrawal Syndrome: A Retrospective Cohort Study

To compare the clinical course, incidence of withdrawal seizures (WS) or delirium tremens (DT) and side effects during treatment of alcohol withdrawal in patients treated with either carbamazepine (CBZ) or valproate (VPA) as an adjunct to clomethiazole and clonidine therapy. Retrospective analysis of charts of two cohorts of inpatients treated during 2000-2009: CBZ 374 patients, VPA 453 patients. At baseline, those treated with VPA and those treated with CBZ were similar except for a trend to younger age and a higher incidence of previous WS in the CBZ group. The median duration of pharmacological treatment (91 vs. 76h; P<0.001) and the length of stay (8 vs. 6 days; P<0.001) as well as the need for intensive care treatment (7 vs. 2%; P=0.001) were significantly higher in the CBZ than the VPA group. Additionally, withdrawal-related complications such as WS occurred more often in the CBZ group (9.6 vs. 5.5%; not significant after adjusting for potential confounders); the incidence of DT in the CBZ group was insignificantly higher (6.6 vs. 4.4%; P=0.52). Admittance with seizures and older age were predictors of WS and DT, respectively. Adverse drug reactions, mainly affecting the central nervous system, were significantly more frequent with CBZ than VPA (7.6 vs. 2%; P<0.001). During alcohol withdrawal, VPA may offer some benefits compared with CBZ due to favorable tolerability, possibly less incidence of WS and a shorter duration of pharmacological treatment.

Efficacy and Safety of Gamma-Hydroxybutyrate in Treating Alcohol Withdrawal Syndrome in an Alcohol-Dependent Inpatient With Decompensated Liver Cirrhosis

1Department of Internal Medicine SS Annunziata Hospital Cento (Ferrara), Italy 2"G. Fontana" Centre for the Study and Multidisciplinary Treatment of Alcohol Addiction Department of Clinical Medicine University of Bologna Bologna, Italy [email protected]