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

Transcription

1 The American Journal on Addictions, 22: , 2013 Copyright American Academy of Addiction Psychiatry ISSN: print / online DOI: /j x The Role of Diazepam Loading for the Treatment of Alcohol Withdrawal Syndrome in Hospitalized Patients Andrew J. Muzyk, PharmD, 1,2 Jonathan G. Leung, PharmD, BCPS, 3 Sarah Nelson, PharmD, 3 Eric R. Embury, PharmD, 4 Sharon R. Jones, PharmD 5 1 Department of Pharmacy Practice, Campbell University College of Pharmacy and Health Sciences, Buies Creek, North Carolina 2 Department of Psychiatry and Behavioral Sciences, Duke University, Durham, North Carolina 3 Mayo Clinic, Rochester, Minnesota 4 Department of Veterans Affairs, Fayetteville, North Carolina 5 CS Mott Children s Hospital, Ann Arbor, Michigan 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. (Am J Addict 2013;22: ) Received August 29, 2011; revised September 26, 2011; accepted November 10, Address correspondence to Dr. Muzyk, P.O. Box 3089 Pharmacy, Durham, NC E mail: andrew.muzyk@duke.edu. INTRODUCTION Alcohol dependence accounts for approximately 20% of hospital admissions and approximately 39% of intensive care unit (ICU) admissions. 1,2 In those experiencing alcohol withdrawal the initial clinical signs and symptoms may include irritability, agitation, tremor, hypertension, and tachycardia. 3 However, 5 10% may develop more severe symptoms of withdrawal consistent with delirium tremens (DTs) or seizure. 4 Symptoms of alcohol withdrawal syndrome (AWS) can present within 24 hours of drinking cessation, therefore prompt medical care is required to prevent negative sequelae. Benzodiazepines, through their enhancement of GABA s inhibitory signaling, 5,6 are the drugs of choice for the treatment of AWS. 2,7,8 Currently no literature exists suggesting one benzodiazepine has greater efficacy over another although differences in their pharmacokinetic properties can guide selection. 9,10 Diazepam has a rapid onset of action and rapidly reaches its maximum concentration in the central nervous system (CNS) due to its highly lipophilic nature. Diazepam is metabolized by the liver to form the active metabolite, desmethyldiazepam (DMDZ) and both are slowly eliminated from the body This slow elimination allows for prolonged therapeutic concentrations to exist even after short treatment durations. Like all benzodiazepines common adverse events that may occur with diazepam include sedation, respiratory depression, hypotension, anterograde amnesia, and possible paradoxical reactions. 4 Clinically, diazepam s rapid onset of action followed by its long elimination half life confers immediate and sustained symptom control. The notion that these properties result in a smoother withdrawal with less breakthrough symptoms is supported by three fixed equivalent dose trials comparing oral diazepam to oral lorazepam These trials showed that although both benzodiazepines adequately reduced the core 113

2 symptoms of AWS, patients randomized to diazepam reported a more comfortable withdrawal with fewer complaints. A fourth trial evaluating IV formulations of diazepam and chlordiazepoxide reported similar findings to the three fixed equivalent dose trials. 17 Diazepam s pharmacokinetic profile allows clinicians to initially load a patient to provide an immediate and sustained treatment effect. To the authors knowledge no data exists to support the use of other benzodiazepines as a loading strategy in alcohol withdrawal. However, diazepam loading is supported by a few randomized controlled trials The purpose of this review is to evaluate the role of diazepam loading for AWS. METHODS We performed an English language literature search of four databases Pubmed, PsychInfo, Biosis, and Embase to identify journal articles published between 1960 and August We also conducted a secondary bibliography search of all references cited in found articles. Keyword search terms included diazepam, diazepam loading, alcohol withdrawal, AWS, and DTs. Published articles were included in our review if they described the use of diazepam loading or highdose diazepam for the treatment of AWS. Case reports, foreign language articles, and poster presentations on this topic were not included. After search completion, eight trials were identified Four randomized controlled trials are described in the text below The four non controlled trials are described in Table 1. RESULTS The first controlled trial utilizing diazepam loading was published in 1975 by Thompson et al. 18 Thirty four patients admitted for hospitalization with advanced DTs were randomized to diazepam (n ¼ 17) or paraldehyde (n ¼ 17), a sedative hypnotic with anticonvulsant properties. Only patients who had severe agitation requiring chemical and mechanical restraint, as opposed to supportive care, were included in this study. Seventeen patients had a co morbid medical illness including pneumonia (n ¼ 8), pancreatitis (n ¼ 6), alcoholic hepatitis (n ¼ 1), pneumonia and pancreatitis (n ¼ 1), and pneumonia and alcoholic hepatitis (n ¼ 1). Additionally, the majority of patients had signs and symptoms consistent with ethanol hepatotoxicity, such as biomarker elevations and enlarged livers on examination. There were no significant differences in baseline demographics or laboratory values between treatment groups. No patients were able to take oral medications due to agitation. Treatment occurred in two phases described as the induction and maintenance phases. During the induction phase patients received either diazepam 10 mg IVonce, followed by 5 mg IV every 5 minutes, or paraldehyde 10 ml every 30 minutes rectally until a calm state was achieved. In the maintenance phase, IV diazepam 5 10 mg was given every 1 4 hours and paraldehyde was given 5 10 ml rectally every 2 4 hours as needed to sustain a calm state until the resolution of DTs. Resolution was determined when patients were oriented, able to have oral intake, and were without agitation, hallucinations, incontinence, or the need for restraints. Patients treated with paraldehyde required greater than twice the time to achieve a calm state as compared to diazepam loading (p ¼.018). The length of the induction phase with diazepam ranged from less than 1 4 hours compared to less than 1 12 hours with paraldehyde. The mean dose of diazepam required during the induction phase was mg for patients with solely DTs, while a slightly higher mean dose, mg was needed in patients with DTs plus a co morbid medical illness. A mean dose of 155 mg of diazepam was required in the maintenance phase which lasted up to several days. The mean duration of DTs was 56 hours with no significant difference between groups. No untoward adverse reactions were reported by patients receiving diazepam, whereas nine patients treated with paraldehyde experienced adverse events, including injuries from severe agitation (n ¼ 5), apnea (n ¼ 2), and death (n ¼ 2). This study demonstrated that frequent administration of diazepam in short intervals can quickly produce a calm state in patients with AWS without producing any untoward adverse effects. This trial provides evidence that diazepam loading may be a safe and effective treatment option, even in patients with co morbid medical illnesses. Several limitations are present. The method in which diazepam was administered, primarily the use of a maintenance phase, distracts from the results achieved after induction (loading phase) of a calm state occurred. As mentioned previously, diazepam and DMDZ exhibit a long elimination half life, suggesting scheduled maintenance dosing is not necessary to maintain suppression of symptoms consistent with AWS. Additionally, the small sample size, lack of blinding, and comparison to an agent no longer in use limit the findings of this study. Eight years following this initial study, Sellers et al. 19 compared diazepam loading to placebo in a randomized double blind clinical trial. Medically stable patients admitted to a medical unit for moderate to severe alcohol withdrawal were included. Excluded were those expected to be administered general anesthesia within 48 hours, with head injury, admitted for drug overdose, or had a history of a benzodiazepine allergy. Fifty patients meeting inclusion criteria were randomized to one of two treatment arms, supportive care and diazepam loading (n ¼ 25) or supportive care and placebo (n ¼ 25). Any patient with a history of withdrawal seizures also received oral phenytoin 300 mg daily for 5 days for seizure prophylaxis. There were no differences between groups in regard to age, years of alcohol consumption, daily alcohol consumption, blood alcohol content on admission, or time since last drink. Baseline Clinical Institute Withdrawal Assessment for Alcohol (CIWA A) scores also did not differ 114 Diazepam Loading for Alcohol Withdrawal March April 2013

3 TABLE 1. Non controlled trials Study Study design Patients included in analyses (n) Treatment Baseline CIWA A scores Diazepam dose (mg) (mean SD or range if reported) Mean time to load (hour) Efficacy measures Results Devenyi and Harrison 22 OL 20 Oral diazepam 20 mg Q1 hour 3 doses (initially). Further diazepam doses were given to control symptoms based on CIWA A scores Gold et al. 23 RC 54 Comparison between two treatments protocols. Protocol # 1 diazepam administered based on a Riker Sedation Analgesia Score and a Sedation Analgesia Scale score. Protocol # 2 IV diazepam 10 mg 1, followed by escalating diazepam doses up to 150 mg/dose. Phenobarbital may be added if the maximal diazepam dose did not control agitation Hyatt et al. 24 OL 50 Oral diazepam 20 mg Q1H 12 hours, then diazepam 10 mg Q1H if the patients experienced withdrawal symptoms as assessed by intoxication withdrawal scale Salloum et al. 25 OL 152 Patients with a modified CIWA A scale >15 received oral diazepam 20 mg, re dosed every 2 hours if the CIWA A score remained > NR Alcohol withdrawal seizures NR Mean total (248 vs. 562; p ¼.001) mean maximal individual dose (32 vs. 86; p ¼.001) 24 Ability to achieve adequate sedation NR Assessment of alcohol withdrawal symptoms NR (range) (range) Assessment of alcohol withdrawal symptoms No patients experienced an alcohol withdrawal seizure Escalating the diazepam dose significantly reduced the need for mechanical ventilation (p ¼.008). In this treatment arm, there was a trend towards significance in reduction in ICU length of stay and incidence of nosocomial pneumonia No alcohol withdrawal seizures, DTs, hallucinations, or agitation were reported Thirty seven patients received diazepam loading based on the modified CIWA A scale. Of diazepam patients 75% were detoxified within hours. All patients were detoxified without any reported complications CIWA A, Clinical Institute Withdrawal Assessment for Alcohol scale; DTs, delirium tremens; ICU, intensive care unit; IV, intravenous; NR, not reported; OL, open label; Q, every; RC, retrospective cohort; SD, standard deviation. Muzyk et al. March April

4 between the treatment and placebo group and were and , respectively. Treatment groups received either oral diazepam 20 mg or placebo every 1 to 2 hours. Patients in both groups were treated until achieving clinical improvement, defined as a CIWA A score of 10 or less. Patient assessments with the CIWA A scale were conducted 1 hour before receiving the initial treatment and every hour thereafter. If any patient did not achieve clinical improvement after six blinded doses they were entered into an open label arm to receive oral diazepam 20 mg every 1 2 hours until CIWA A scores were less than 10. Of those randomized to the diazepam group, 72% of patients achieved a CIWA A score of 10. This occurred within hours after doses of diazepam. The diazepam group also had a faster and greater improvement in CIWA A scores compared to those receiving placebo. Using a multivariate analysis of covariance to assess variation between groups the authors found a significant difference in drug effect (p <.0001) and time to effect (p <.0001). Including 11 patients in the placebo group who required open label diazepam, those who received diazepam (n ¼ 36) achieved goal CIWA A scores in a mean of hours and required doses of diazepam. Complications of AWS, including occurrence of seizures, arrhythmias, delirium, and hallucinations were assessed for 5 days. No complications were reported in the diazepam loading group, however seven (28%) of these patients did require open label treatment after failing to achieve goal CIWA A scores during the experimental phase. Authors also noted that while more patients in the placebo group received phenytoin for seizure prophylaxis (52% vs. 24%, p <.025), these patients also had greater incidence of alcohol withdrawal seizures (p <.05). Several limitations are present within this study. The main limitation identified is the classification of severity of alcohol withdrawal in patients included in the study. At baseline, patients randomized to diazepam had a CIWA A score of and those randomized to placebo had a score of This correlates to a patient population with mild (CIWA A score <20) to moderate (CIWA A score 20 24) alcohol withdrawal. This limitation is strengthened by the fact that 56% of patients randomized to placebo did not require any drug therapy for the treatment of AWS, suggesting their withdrawal symptoms were mild at best. Additionally, adverse events associated with drug therapy, including over sedation or apnea, were never addressed. Although a small study, it did demonstrate that diazepam loading can successfully reduce mild to moderate AWS in 90% of patients within 24 hours, without the need for additional scheduled drug therapy. The third trial assessing the efficacy of diazepam loading was reported by Manikant et al. 20 Patients included in the trial were admitted to an inpatient care unit and diagnosed with alcohol withdrawal as defined by the DSM III criteria of alcohol dependence in the withdrawal state. Patients were excluded if they had a history of multiple drug abuse, head trauma, a preexisting psychiatric disorder, or if they were, or had experienced DTs or alcoholic hallucinations. Forty four male patients, aged years, were enrolled and randomized to one of two groups. Group A (n ¼ 21) received conventional therapy consisting of a 7 day diazepam taper. These patients received diazepam 60 mg orally on Day 1, 40 mg orally on Days 2 and 3, 20 mg orally on Days 4 and 5, and 10 mg orally on Days 6 and 7. Group B (n ¼ 20) received diazepam dosed in a loading fashion, given 20 mg orally every 2 hours until the patient was sedated or had achieved a CIWA A score <10. CIWA scores were assessed in each group at a fixed time every morning during the study period. No differences were noted between the two groups in regard to baseline characteristics. By nature of the study design, the conventional treatment (Group A) group received more diazepam during the study period as compared to those randomized to the intervention group (Group B), receiving 200 and 67 mg, respectively. While patients in both groups demonstrated a significant clinical improvement in CIWA A scores from Day 1 to 7, Group B experienced a more robust improvement by Day 2 (p <.05), suggesting a more rapid resolution of alcohol withdrawal symptoms. Additionally, as the average CIWA A score on Day 2 in Group B was <10, most patients in this group did not require additional drug therapy after the first day. This finding suggests resolution of AWS occurred within 24 hours of initial diazepam administration. No subjects in either group experienced adverse effects of diazepam which were assessed in a systematic manner. This study validates the effectiveness and safety of a diazepam loading regimen in a patient population with mild alcohol withdrawal. While no patients experienced adverse effects associated with therapy, three patients were eliminated from the study for reasons including pancreatitis, need for additional diazepam, and leaving against medical advice. Many limitations are present in this study including a lack of blinding and including only a very select patient population. Nevertheless, the study demonstrated that early aggressive diazepam administration allows for prompt resolution of AWS with the need for minimal additional drug therapy. The most recent diazepam loading study was conducted by Wasilewski et al. 21 in hospitalized patients admitted for the treatment of AWS with the presence of delirium. The purpose of this study was to evaluate the efficacy of diazepam loading compared to traditional therapy, a non loading alcohol withdrawal protocol. Patients were between the ages of 20 and 60 years and excluded if they had received psychotropic medications prior to admission, were without delirium, or had polysubstance dependence or psychosis (alcohol and nonalcohol related). Additional exclusion criteria were recent head trauma, hepatic dysfunction, respiratory disease, or the detection of serum alcohol upon admission. The mean age for the treatment group was approximately years and patients had an approximate mean alcohol abuse history of years. There were no significant differences in baseline demographics between groups; except for patients in the diazepam loading arm who had a greater mean daily ethanol 116 Diazepam Loading for Alcohol Withdrawal March April 2013

5 consumption ( ml vs ml; p ¼.02). Additionally, there were no significant differences in any somatic disorders, electrolytes, or laboratory markers of hepatic dysfunction. Fifty one patients were randomized to receive diazepam loading and 45 patients were randomized to the traditional dosing regimen group, which consisted of divided doses of diazepam plus concomitant medications such as antipsychotics. If a measured CIWA A score was greater than 10, patients in the treatment arm received mg of oral diazepam. Assessments and diazepam administration was continued every 1 2 hours until CIWA A scores were less than 10. The total amount of diazepam used ranged from 40 to 210 mg (mean: mg) in the treatment group compared to 60 to 9,840 mg (mean: 1,748 1,800 mg) in the control group. Two patients in the treatment group were changed to oxazepam due to suspected toxic hepatitis. The mean duration of delirium in the treatment group was hours compared to a mean of hours in the control group (p <.001). Thirty one patients in the control group required co administration of an antipsychotic, while no antipsychotic was administered to any patients loaded with diazepam. Patients receiving diazepam loading compared to traditional therapy required significantly less diazepam and were delirious for a significantly shorter time period. This trial confirms the findings of Sellers et al. that diazepam loading has utility in treating patients with mild to severe AWS, but also demonstrates its benefit in patients experiencing alcohol withdrawal associated delirium. No significant adverse events, including respiratory depression, were noted with diazepam loading. Other adverse events were not identified, assessed, or reported. DISCUSSION Diazepam loading may be an effective treatment strategy for the management of AWS. The four randomized controlledtrials included in this review found that diazepam loading quickly and significantly reduced withdrawal symptoms in patients presenting with AWS, including patients in DTs. In those patients diagnosed with DTs, rapidly administered doses of diazepam produced a quick calming effect without any untoward adverse effects, even in patients who were medically ill. Additional literature, non controlled trials, found in conducting this review support these findings (see Table 1). In three of the included trials, diazepam loading was dosed based on a patient s CIWA score rather than given as a single mg/kg dose. In this sense, loading was done in a symptom triggered approach and it is the rapid accumulation of diazepam and its long elimination half life that creates this loading scenario. Symptom triggered treatment, in which a patient receives a benzodiazepine in response to their CIWA score, has become a more desirable approach to AWS following the publication of two trials comparing this treatment strategy to a fixed dosed method. 26,27 The main findings from these two trials were that patients treated by the symptomtriggered method required significantly less benzodiazepines and a shorter duration of AWS treatment. Of note, similar findings were also seen in the diazepam loading trials included in this review. Also guidelines published by the Substance Abuse and Mental Health Services Administration (SAMHSA) comment that many different methods for treating alcohol withdrawal are acceptable and method selection should be based on clinical scenario. Yet these guidelines emphasize that when utilizing loading strategies experienced staff with adequate time to frequently monitor the patient and provide medication is necessary. The SAMHSA guidelines also note that a loading method may cause over sedation and respiratory depression. This may especially be true in the elderly and in patients with hepatic dysfunction. Although no elderly patients were involved in the included diazepam loading articles, a pharmacokinetic study of diazepam loading found that only increased age, not liver function, correlated with a prolonged elimination half life. 13 Thompson et al. 18 included patients with alcoholic hepatitis and evidence of ethanol hepatoxicity and had no reports of adverse events associated with oversedation in those receiving diazepam. Also, another study that examined escalating doses of diazepam for the treatment of AWS found an inverse association between diazepam dose and need for intubation. 23 This finding suggests that aggressive treatment of AWS with diazepam may decrease the need for intubation during the alcohol withdrawal period due to prompt treatment and control of AWS symptoms. Despite these findings, many other guidelines do recommend treating these patient populations with a non loading treatment strategy using a benzodiazepine that undergoes phase II metabolism and has no active metabolites, such as lorazepam or oxazepam. 2,7,8 CONCLUSION Diazepam loading may be an effective treatment for patients experiencing AWS. Diazepam s quick onset of effect produces rapid symptom reduction, while its long elimination half life ensures therapeutic drug concentrations for several days without requiring more medication. Additionally, aggressive early treatment with diazepam loading provides targeted symptom treatment and may potentially minimize the risk of under medication, which may lead to a worsening of this acute condition. Larger RCTs, including those in medically ill patients with AWS, comparing loading versus symptom triggered management are needed to support the use of one strategy over another. Declaration of Interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this paper. Muzyk et al. March April

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