Andrew J. Muzyk

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

Objective: To evaluate literature reporting on the role of norepinephrine in alcohol withdrawal and to determine the safety and efficacy of α2-agonists in reducing symptoms of this severe condition. Data Sources: Articles evaluating the efficacy and safety of the α2-agonists clonidine and dexmedetomidine were identified from an English-language MEDLINE search (1966-December 2010). Key words included alcohol withdrawal, delirium tremens, clonidine, dexmedetomidine, α2-agonist, norepinephrine, and sympathetic overdrive. Study Selection and Data Extraction: Studies that focused on the safety and efficacy of clonidine and dexmedetomidine in both animals and humans were selected. Data Synthesis: 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, α2-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 α2-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. Conclusion: 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.

Defining the Role of Baclofen for the Treatment of Alcohol Dependence

The pharmacological properties of baclofen, a GABAB receptor agonist, have led to investigation of its use for the off-label treatment of alcohol dependence. Literature examining the role of baclofen in alcohol dependence suggests that it may be a useful medication in the treatment armamentarium with an additional benefit of promoting abstinence and reducing alcohol-associated cravings and anxiety. We conducted a systematic review of prospective, randomized controlled trials comparing baclofen with placebo for the treatment of alcohol dependence. Four randomized controlled trials were identified but only three met criteria for inclusion. The excluded trial was a post hoc analysis of data collected from an original trial whose primary outcome did not fit our inclusion criteria and was terminated prior to completion. Compared with placebo, subjects randomized to baclofen experienced higher rates of abstinence and lower anxiety scores; the effect of baclofen was statistically significant in two trials assessing patients with more severe alcohol dependence and non-significant in a trial of outpatients receiving concomitant manualized psychotherapy. Baclofen appeared to be safe, well tolerated and to have low addiction liability even in the setting of moderate-to-severe liver cirrhosis, a known complication of alcohol dependence. Though baclofen may hold promise, the different outcomes and sample populations of the three studies highlight the need for more research to better understand the appropriate target patient population to benefit from this medication. Questions still remain about optimal dosing and duration. There is not enough evidence to support the use of baclofen as a first-line treatment option, except for those alcohol-dependent patients with moderate-to-severe liver cirrhosis in whom other pharmacological treatments are not safe or practical.

Clinical effectiveness of baclofen for the treatment of alcohol dependence: a review

Baclofen, an agonist at the B subunit of gaba-aminobutyric acid receptor, possesses pharmacologic properties that may confer utility for the treatment of alcohol dependence. Research suggests that not only can it be useful in promoting maintenance of alcohol abstinence but also it may play a key role in decreasing alcohol cravings and anxiety often associated with alcohol dependence. To assess the benefit of baclofen for alcohol dependence, a review of the literature was conducted to identify published data investigating this off-label treatment. Four randomized controlled trials to date have been published and were included in this review. Although primary outcomes differ between studies, patients randomized to baclofen experience higher rates of abstinence from alcohol than those taking placebo in two of the trials. Secondary analyses indicate that baclofen is safe in patients with alcohol dependence, including those with moderate to severe liver cirrhosis, and may provide beneficial anxiolytic effects. Despite some positive data, the largest available randomized controlled trial failed to find any differences between baclofen and placebo. In all studies, individuals with severe medical comorbidities, seizure disorders, and psychiatric disorders were excluded from trials, which may limit external validity. In summary, there may be beneficial effects from using baclofen for the treatment of alcohol dependence; however, limited conclusions can be drawn from the small number of studies currently available for review. Larger well-designed trials are needed to further define baclofen’s role for the treatment of alcohol dependence.

The Role of Diazepam Loading for the Treatment of Alcohol Withdrawal Syndrome in Hospitalized Patients

BACKGROUND Alcohol withdrawal accounts for a significant amount of hospital admissions and can quickly progress to the development of delirium tremens (DTs), seizures, and death. Rapid identification and management of alcohol withdrawal syndrome (AWS) is vital and can be managed with a number of different treatment strategies. Diazepam loading is a treatment strategy that utilizes the pharmacokinetics of this agent to achieve a rapid reduction in symptoms followed by sustained benefit over a period of days. OBJECTIVE The purpose of this review is to evaluate the role of diazepam loading for AWS. METHODS A literature search of four databases-Pubmed, PsychInfo, Biosis, and Embase-was conducted to identify publications between 1960 and August 2011 that described the use of diazepam loading for the treatment of AWS. Eight trials, both open-label and controlled trials were identified. Only four randomized controlled-trials (RCTs) have been published and they are reviewed in this paper. RESULTS Included trials of hospitalized inpatients found that diazepam loading provided rapid symptom relief as well as reduced the incidence of seizures and duration of DTs. In patients diagnosed with severe DTs, rapidly administered doses of diazepam produced a quick calming effect. While no adverse events resulting from diazepam loading were noted, no formal assessment tool was used to evaluate its safety. Larger randomized controlled-trials are needed to better evaluate safety outcomes. CONCLUSIONS Diazepam loading is an effective treatment option for hospitalized patients experiencing AWS. Diazepam loading uses the concept of symptom-triggered therapy, a mainstay of current AWS treatment, while exploiting its prolonged elimination half-life and eliminating the need for additional pharmacologic therapy. Studies reviewed found diazepam loading significantly improved a number of important outcomes in AWS, including time in DTs, compared to traditional treatment strategies.

Dexmedetomidine for the Treatment of Alcohol Withdrawal Syndrome: Rationale and Current Status of Research

Dexmedetomidine is currently used in the US in the treatment of alcohol withdrawal syndrome (AWS) in the intensive care unit (ICU) setting, although data to support this practice are limited. Dexmedetomidine targets the noradrenergic system, an important but frequently overlooked secondary mechanism in the development of AWS, and, in doing so, may reduce the need for excessive benzodiazepine use which can increase the risk of γ-aminobutyric acid (GABA)-mediated deliriogenesis and respiratory depression. The purpose of this narrative review is to evaluate available literature reporting on the safety and efficacy of dexmedetomidine for AWS in the ICU setting. An English-language MEDLINE search (1966 to July 2013) was performed to identify articles evaluating the efficacy and safety of dexmedetomidine for AWS. Case series, case reports and controlled trials were evaluated for topic relevance and clinical applicability. Reference lists of articles retrieved through this search were reviewed to identify any relevant publications. Studies focusing on the safety and efficacy of dexmedetomidine for AWS in humans were selected. Studies were included if they were published as full articles; abstracts alone were not included in this review. Eight published case studies and case series were identified. Based on a limited body of evidence, dexmedetomidine shows promise as a potentially safe and possibly effective adjuvant treatment for AWS in the ICU. Prospective, well-controlled studies are needed to confirm the safety and efficacy of the use of dexmedetomidine in AWS.

Quetiapine for the treatment of delirium.

BACKGROUND Delirium is associated with high rates of morbidity and mortality in hospitalized medically ill patients. Haloperidol has historically been the agent of choice for the treatment of delirium, but recent studies have explored the efficacy of second-generation antipsychotics such as quetiapine. The unique pharmacology of quetiapine may allow it to treat delirium and provide sedation without causing significant extrapyramidal side effects. PURPOSE To evaluate the efficacy of quetiapine for the treatment of delirium. DATA SOURCES A search was conducted in MEDLINE and Embase (January 1960–December 2012) using keywords “quetiapine,” “second-generation antipsychotic,” “atypical antipsychotic,” “delirium,” and “agitation.” STUDY SELECTION AND DATA EXTRACTION The search was limited to English-language articles and trials with treatment of delirium as the primary end point. Eight trials met this inclusion criterion. DATA SYNTHESIS Two randomized controlled trials, 5 open-label studies, and 1 retrospective cohort study evaluating quetiapine for the treatment of delirium were reviewed. One randomized controlled trial showed no differences in total mean delirium scores, but found the rate of delirium improvement was significantly shorter with quetiapine. The second randomized controlled trial showed the time to first resolution of delirium was shorter with quetiapine compared to placebo. Results of the open-label and retrospective cohort trials have also shown significant resolution of delirium from baseline and equal efficacy with quetiapine compared to amisulpride and haloperidol. CONCLUSIONS Quetiapine appears to be an effective and safe agent for the treatment of delirium in both general medicine and intensive care unit patients. The trials summarized suggest that quetiapine resolves symptoms of delirium more quickly than placebo and has equal efficacy compared to haloperidol and the atypical antipsychotic amisulpride. Further study is needed. Journal of Hospital Medicine 2013;8:215–220.

Examination of baseline risk factors for QTc interval prolongation in patients prescribed intravenous haloperidol.

AbstractBackground: Intravenous haloperidol can increase the risk for corrected QT interval (QTc) prolongation, torsades de pointes (TdP) and sudden death. There are a number of risk factors reported in the literature for QTc prolongation and TdP with intravenous haloperidol. Objective: The purpose of this study was to determine the prevalence of baseline risk factors for QTc prolongation and TdP in hospitalized medical inpatients prescribed intravenous haloperidol. Methods: This is a retrospective cohort study of medically ill hospitalized inpatients prescribed intravenous haloperidol between 30 June 2007 and 1 January 2010. Records were ascertained for the presence of baseline risk factors for QTc prolongation and TdP. Results: A total of 175 subjects were identified as receiving intravenous haloperidol during the study period. Mean age was 62.9±19.1 years, and 48.6% of subjects were female. At baseline, 85.7% of subjects had ≥1 risk factor for QTc prolongation and TdP, with the majority of these subjects (58.0%) having between two and five risk factors. Of the total study sample, 74.9% had a baseline ECG; mean QTc value was 457 msec (± 40.8 msec). Greater than 50% of subjects had a sex-specific QTc value higher than the increased risk threshold of 450 msec in males or 460 msec in females at baseline. Following intravenous haloperidol administration, 46.9% of subjects had a follow-up ECG obtained within 24 hours. At the time of intravenous haloperidol administration, 93.1% of subjects had a potassium value available and 62.9% had a magnesium value. Approximately 30% of subjects had either a potassium or magnesium value below the normal laboratory range. Of the 175 subjects, 43.4% were taking ≥1 concomitant QTc prolongation medication at the time of intravenous haloperidol administration. Conclusions: Consistent with previously published reports, patients in this study prescribed intravenous haloperidol had multiple risk factors, both modifiable and non-modifiable, at baseline for QTc prolongation and TdP. The modifiable risk factors may be important targets of interventions aimed at optimizing the safety of the use of intravenous haloperidol, while the non-modifiable risk factors may warrant closer scrutiny with consideration of alternative therapies and continuous monitoring.

Testosterone Supplementation for Hypoactive Sexual Desire Disorder in Women

Over 50% of women are believed to be affected by female sexual dysfunction (FSD). When particularly distressful, FSD is known as hypoactive sexual desire disorder (HSDD). In contrast to male sexual dysfunction that has been extensively researched, there is less evidence addressing the treatment of HSDD in women, particularly with regard to the use of androgen therapy. A variety of testosterone products, including oral, injectable, and transdermal preparations, has been prescribed for the treatment of HSDD in premenopausal women, as well as in those with naturally occurring or surgically induced menopause. Although studies have shown some benefit with testosterone supplementation in women with HSDD, conflicting evidence and debate regarding the clinical efficacy of testosterone remain. Because of concern over potential adverse events, additional studies with longer follow‐up periods are necessary before use of testosterone in women with HSDD becomes widespread. Initiation of testosterone therapy must be considered on an individual basis after a thorough discussion with the patient about risks and benefits.

A case of delirium, motor disturbances, and autonomic dysfunction due to baclofen and tizanidine withdrawal: a review of the literature ☆

We report a case of delirium accompanied by extrapyramidal symptoms and autonomic dysfunction in a 59-year-old man following abrupt cessation of baclofen and tizanidine. An extensive search for the etiology was undertaken, but it was only after a careful history was taken that suspicion for baclofen and tizanidine withdrawal was raised. The delirium and motor disturbances resolved within 24 h of reintroduction of baclofen. Withdrawal from muscle relaxants requires a high index of suspicion but should be considered in patients who manifest signs and symptoms of withdrawal from the medications, particularly visual hallucinations, rigidity and autonomic dysfunction.

Defining the Role of Dexmedetomidine in the Prevention of Delirium in the Intensive Care Unit

Dexmedetomidine is a highly selective α 2 agonist used as a sedative agent. It also provides anxiolysis and sympatholysis without significant respiratory compromise or delirium. We conducted a systematic review to examine whether sedation of patients in the intensive care unit (ICU) with dexmedetomidine was associated with a lower incidence of delirium as compared to other nondexmedetomidine sedation strategies. A search of PUBMED, EMBASE, and the Cochrane Database of Systematic Reviews yielded only three trials from 1966 through April 2015 that met our predefined inclusion criteria and assessed dexmedetomidine and outcomes of delirium as their primary endpoint. The studies varied in regard to population, comparator sedation regimen, delirium outcome measure, and dexmedetomidine dosing. All trials are limited by design issues that limit our ability definitively to conclude that dexmedetomidine prevents delirium. Evidence does suggest that dexmedetomidine may allow for avoidance of deep sedation and use of benzodiazepines, factors both observed to increase the risk for developing delirium. Our assessment of currently published literature highlights the need for ongoing research to better delineate the role of dexmedetomidine for delirium prevention.