Efficacy and Safety of Levetiracetam for Outpatient Alcohol Detoxification

• Abstract
• Introduction
• Subjects and Methods
• Inclusion criteria of the outpatient detoxification
• Exclusion criteria of the outpatient detoxification
• Selection of patients for the outpatient detoxification
• Clinical procedure
• Assessement and analysis of data
• Results
• Clinical characteristics
• Retention rate and side effects
• Medication
• Withdrawal symptoms
• Further treatment and 6-month follow-up
• Discussion
• Acknowledgements
• References

Abstract

Introduction: Anticonvulsant drugs are increasingly being used for alcohol detoxification in in- and outpatient settings. The aim of this study was to examine the efficacy, medical safety and mid-term outcome of levetiracetam, a drug with no marked liver toxicity, for outpatient alcohol detoxification.

Methods: This was an open-label observational study. After screening eligibility for outpatient alcohol detoxification, patients were seen daily for 5 days and received levetiracetam in a flexible dosage regime between 500 and 4 000 mg/d for a maximum of 7 days. Diazepam was used as a rescue medication. The severity of alcohol withdrawal was evaluated daily using the Alcohol Withdrawal Syndrome Scale (AWSS). Mid-term treatment outcome was assessed at a 6-month follow-up.

Results: A total number of 131 consecutively admitted alcohol-dependent patients received an outpatient detoxification treatment, 122 (93.1%) completed the programme successfully. The mean initial dose of levetiracetam was 1 850 mg/d. Alcohol withdrawal syndrome as indicated by the AWSS score decreased clearly over 5 days. Overall, the medication was well tolerated. There was no treatment discontinuations due to side effects of levetiracetam. No serious medical complications, especially seizures or deliria, were observed during the detoxification. At the 6-month follow-up, 57 patients (43.5%) were still abstinent. Patients with previous detoxifications had a significant higher risk for relapse (HR=1.88; p=0.016; CI 95%: 1.12–3.14) than patients without previous treatments.

Discussion: The findings of this study provide some evidence that levetiracetam is an efficacious and safe treatment option for outpatient alcohol detoxification. Further randomised, controlled trials including mid- and long-term follow-ups are needed to confirm these findings.

Introduction

Alcohol dependence constitutes one of the most common psychiatric disorders [42]. As a serious complication of this disease, the alcohol withdrawal syndrome (AWS) often requires intensive medical treatment. While inpatient alcohol detoxification is widely implemented in various medical care settings, only little attention has been paid to outpatient alcohol detoxification, especially to pharmacotherapy [7] [35] [41]. At present, there is no approved pharmacological treatment for outpatient alcohol detoxification in Germany.

Current treatment recommendations in the US favour benzodiazepines for the pharmacotherapy of AWS [24] [25]. Also, anticonvulsant drugs (e. g., valproate and carbamazepine) have been shown to be efficacious in the treatment of AWS in several controlled trials [16]. However, one of the major concerns about using these drugs in AWS is the fact that most of the antiepileptic drugs and also benzodiazepines showed liver toxicity as an important side effect [22] [33]. Furthermore, the use of benzodiazepines in outpatient settings is limited by the risks of intoxication, interaction with alcohol and abuse.

As an alternative treatment of AWS, levetiracetam, a pyrrolidine derivative structurally related to the nootropic drug piracetam, shows a minimal metabolism, has a low risk of drug interactions and is almost completely excreted through the urinary system [30] [31]. Levetiracetam seems to have a high tolerability, especially in patients with hepatic diseases [6] [32].

The mechanism of action of levetiracetam in AWS is still unclear; it seems to be devoid of direct effects on GABAergic neurotransmission. Levetiracetam has no significant affinity to GABAergic or glutamatergic receptors and does not directly interact with the benzodiazepine binding site [13] [23] [29]. Levetiracetam was reported to bind to the synaptic vesicle protein 2A (SV2A), which is involved in synaptic vesicle function and calcium-dependent regulation of neurotransmitter release during repetitive stimulation [11] [12] [21] [29] [37].

In alcohol-dependent mice, levetiracetam has been shown to reduce AWS [2]. Recently, an open-label pilot trial provided some evidence that levetiracetam is safe and efficacious in the inpatient treatment of AWS [17]. The major aim of this study was to examine the efficacy, medical safety and mid-term outcome of levetiracetam for outpatient alcohol detoxification.

Subjects and Methods

Inclusion criteria of the outpatient detoxification

Patients between 18 and 70 years of age had to meet ICD-10 [40] and DSM-IV [1] criteria for alcohol dependence. Alcohol consumption within the last 24 hours was an inclusion criterion for the outpatient detoxification. Informed consent to the off-label use of levetiracetam and participation in the evaluation was obtained from all patients.

Exclusion criteria of the outpatient detoxification

Recent history of alcohol withdrawal-related complications (e. g., delirium tremens, seizures), other major psychiatric disorders like schizophrenia or severe depressive syndromes, brain injuries or other major neurological diseases were exclusion criteria of the outpatient detoxification. Patients with current use of anticonvulsive medication or benzodiazepines, polysubstance use, pregnancy, and severe medical conditions (e. g., severe cirrhosis of the liver, erosive gastritis, pancreatitis and cardiovascular disorders) were also excluded from the outpatient detoxification. For these cases, an inpatient alcohol detoxification was recommended.

Selection of patients for the outpatient detoxification

Patients admitted for an outpatient alcohol detoxification to the psychiatric outpatient department of the Charité – Universitätsmedizin Berlin from January 2006 to October 2007 were included in the analysis.

Clinical procedure

All patients underwent a thorough examination with focus on major psychiatric and somatic/neurological disorders including several diagnostic instruments (breathalyser, drug screening, detailed laboratory examination, ECG). During detoxification, patients were seen on a daily basis for a minimum of 5 days by an experienced psychiatrist and a medical assistant. The severity of AWS was assessed once daily using the AWS scale [39], a validated and reliable measure of mental and somatic symptoms of the current severity of alcohol withdrawal, which consists of 10 items (blood pressure, pulse rate, breathing rate, sweating, tremor, agitation, contact, orientation, hallucinations, and anxiety) scored from 0 (no withdrawal) to 32 (maximum withdrawal severity). Symptoms were assessed in the morning before medication was given.

Patients received levetiracetam in a flexible dosage regime between 500 and 4 000 mg/d, depending on the severity of AWS. Medication was given twice daily in a morning and an evening dose for a maximum of 7 days. Starting on day 2, the dosage of levetiracetam could gradually be tapered in 500–1 000 mg steps to a final dose of 500 or 1 000 mg/d on day 7.

Diazepam was handed out in 5 mg-tablets on a daily basis up to 30 mg/d as a rescue medication in case of persistent severe withdrawal symptoms. Diazepam use and possible adverse events were assessed daily during the visits.

All patients received vitamin B1 200 mg/d orally for 7 days. The first follow-up visit was performed on day 8. After detoxification, all patients received one session of a cognitive-behavioural oriented psychotherapeutic intervention as well as a counselling regarding further treatment of alcohol dependence (e. g., self-help group, dehabituation treatment). The duration of abstinence was assessed at a 6-month follow-up. Abstinence was defined as no subjective report or objective indication (i. e., breath alcohol concentration) of alcohol consumption since treatment beginning.

Assessement and analysis of data

All data were assessed by a systematic retrospective chart review. Group differences were examined using the Mann-Whitney U test for variables which were not normally distributed. Cumulative survival over 6 months was calculated using Kaplan-Meier analysis. All patients lost to follow-up were considered as relapsers and included in the analysis with data available at the time of the last visit. To identify possible predictors of relapse, Cox regression analyses were performed. P-values ≤0.05 were considered significant. Statistical analyses were performed using the Statistical Package for Social Sciences (Version 12.0 for Windows, SPSS Inc., Chicago, IL, USA).

This evaluation was approved by the local ethics committee.

Results

Clinical characteristics

A total number of 131 patients were included in the analysis. 79 patients (60.3%) were male, 52 (39.7%) were female. Mean age was 47.2 years (SD 11.2; range: 21–70) and the mean duration of alcohol dependence was 14.7 years (SD 9.9). Mean last daily alcohol consumption was 272.4 g/d (SD 131.4). Mean gamma-GT at baseline was 271.8 U/L (SD 1142.5), mean GPT 56.6 U/L (SD 57.6) and mean GOT was 79.1 U/L (SD 149.9). Patient characteristics are given in [Table 1].

Retention rate and side effects

122 of 131 patients (93.1%) successfully completed the alcohol withdrawal treatment. Reasons for dropout (n=9) were relapse during the detoxification (n=4), i. e., the first 7 days of treatment, lack of motivation (n=1) and medical complications (n=4). These were 3 cases of worsening of pre-existing liver parameter elevations and one case of ECG abnormalities.

Overall, the medication was well tolerated; there was no treatment discontinuation due to side effects of levetiracetam. The most frequently mentioned side effects were mild sedation (63.4%), vertigo (12.2%) and pruritus (2.3%). No serious medical complications, especially seizures, deliria, overdoses or intoxications, were observed during the treatment.

Medication

Mean dosages of levetiracetam over 7 days are given in [Fig. 1]. The use of the rescue medication diazepam is listed in [Table 2].

Withdrawal symptoms

The courses of mean AWSS scores during the first 5 treatment days for both the levetiracetam monotherapy group and the group that received a combination of levetiracetam and diazepam are given in [Fig. 2]. In the levetiracetam monotherapy group, mean AWSS score on day 1 was 2.7 (SD 2.2) and decreased to 0.6 (SD 1.0) on day 5. In the group of patients who received levetiracetam and diazepam, mean AWSS score was 4.3 (SD 2.4) on day 1 and decreased to 2.1 (SD 1.9) on day 5. The decline of mean AWSS scores over 5 days did not differ significantly between the groups (Z=−1.11, p=0.266).

Further treatment and 6-month follow-up

After completed detoxification, 26 patients (19.8%) received medical care by a registered psychiatrist, 8 patients (6.1%) received further treatment at a drug counselling office, and 61 patients (46.6%) at the psychiatric outpatient department of the Charité – Universitätsmedizin Berlin. 36 patients (27.5%) received no addiction-specific treatment after detoxification.

At the 6-month follow-up visit, 57 patients (43.5%) were still abstainers, 59 (45.0%) reported relapse and 15 patients (11.5%) were lost to follow-up. [Fig. 3] shows the cumulative survival of the sample, assuming that all patients lost to follow-up had relapsed.

Analysis of possible predictors of relapse revealed that patients with previous detoxifications had a significant higher risk for relapse than patients without previous detoxifications (HR=1.88; p=0.016; CI 95%: 1.12–3.14, see [Fig. 4]). Neither gender (HR=1.3; p=0.339; CI 95%: 0.76–2.21) nor a positive psychiatric history including depressive episodes and attempted suicides significantly predicted relapse (HR=1.01; p=0.974; CI 95%: 0.55–1.84). Furthermore, smoking status (HR=1.2; p=0.681; CI 95%: 0.66–1.91) and unemployment (HR=1.13; p=0.649; CI 95%: 0.67–1.91) did not significantly influence the risk of relapse in the described sample.

Discussion

Optimal pharmacotherapy of AWS in an outpatient detoxification setting is still a matter of debate [35] [41]. Potential treatment concepts have to reliably avoid complications of AWS such as seizures and deliria, and furthermore have to minimise the risks of abuse, overdose and interaction with alcohol in case of relapse. Findings of previous studies suggested that a combination of carbamazepine and tiapride might be an effective and safe treatment option for mild to moderate AWS, especially for outpatient detoxification [10] [20] [34] [35]. However, these studies did not have a randomised, controlled design and the use of carbamazepine is limited by side effects, especially liver toxicity [22]. Therefore, new outpatient treatment concepts of AWS are necessary.

In line with previous findings of an open-label pilot trial [17], our results provide some evidence that levetiracetam is an efficacious and safe treatment option also in an outpatient alcohol detoxification setting. A large sample of 131 patients with a long-term history of alcohol dependence was analysed. The retention rate was similar to those of previous studies [35] [38] [41], a total of 122 patients (93.1%) successfully completed the outpatient alcohol withdrawal treatment. Overall, levetiracetam was well tolerated; there was no treatment discontinuation due to side effects of the medication, also no serious medical complications were observed during the detoxification. The advantageous safety profile of levetiracetam has already been demonstrated in placebo-controlled trials in epilepsy [18]. Levetiracetam also seems to have a low risk of interaction with alcohol in case of relapse due to its lack of effects on GABAergic transmission [18] [23]. In addition, levetiracetam has been shown to have antikindling effects [19], a feature that might be relevant for the treatment of AWS [9].

However, some studies described depressiogenic effects including suicidal ideations during the treatment with levetiracetam in patients with epilepsy [8] [27]. On the other hand, one study reported beneficial effects of levetiracetam on depressive syndromes in epileptic patients [26]. In our evaluation, neither severe depressive syndromes nor suicidal ideation or even suicide attempts were observed. Nevertheless, a close monitoring for depressive symptoms during therapy with levetiracetam, especially in case of relapse, should be performed.

In terms of efficacy of levetiracetam, alcohol withdrawal syndrome as indicated by the AWSS score decreased clearly over 5 days in the group of patients that received levetiracetam monotherapy and the group that received levetiracetam and diazepam; the decline of mean AWSS scores over 5 days did not differ significantly between the groups. The use of diazepam was relatively low in our study compared to the dosages reported from previous alcohol detoxification trials [20]. These observations support the efficacy of levetiracetam and indicate the possibility to further reduce or displace diazepam as a standard medication due to its risks of intoxication and interaction with alcohol. To also minimise the risk of abuse, especially in an outpatient setting, a combination of levetiracetam and tiapride could be reasonable, based on the reported experiences with the combination of carbamazepine and tiapride [10] [20] [34] [35], but prospective controlled trials are needed.

With regard to the mid-term outcome of the outpatient alcohol detoxification with levetiracetam, a minimum of 43.5% of the patients were still abstainers at the 6-month follow-up, assuming that all patients lost to follow-up were relapsers. Direct comparisons with other studies on measures of abstinence are difficult due to wide variations in duration and setting of treatment, pharmacological treatment, further psychotherapeutic or pharmacological support after detoxification and time to follow-up. Klijnsman et al. found an abstinence rate of 29% at a 2-month follow-up after a completed outpatient detoxification [15]. Further studies focusing on outpatient treatment reported abstinence rates of 34–64% for the 6-month outcome, but all patients studied in these trials participated in different intensive rehabilitation programmes immediately after detoxification [3] [5] [28].

The identification of predictors of relapse constitutes one of the most important clinical issues to improve treatment outcome [14]. In this study, a previous detoxification treatment was found to be a significant predictor of a relapse. This is in line with previous studies that found not only the number of previous treatments, but also female gender, prior treatments for mental problems and attempted suicides as risk factors for a negative treatment outcome [4] [36].

Several limitations of this study have to be discussed. First, this was an open-label observational study without a control group. The effects of levetiracetam therefore have not been compared to the potential effects of an alternative treatment. Furthermore, the dosage of levetiracetam was not standardised, but given based on the physician's discretion depending on severity of AWS. Finally, the described outpatient sample had specific characteristics, mainly a relatively high proportion of patients who received their first treatment (64.9%) and a high number of patients who were employed (61.8%). Consequently, the results of this study have to be considered as preliminary until randomised, controlled trials including mid- and long-term follow-ups confirm these findings.

Altogether, new pharmacological concepts are urgently needed for alcohol-dependent patients seeking for outpatient treatment. In this regard, our results suggest that levetiracetam might be an efficacious and safe option for outpatient alcohol detoxification.

Acknowledgements

We thank our study nurses Petra Albrecht and Olga Vitlif for their dedicated work and all patients who contributed to this study.

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Correspondence

C. A. MüllerMD 

Department of Psychiatry

Charité Campus Mitte

Charité – Universitätsmedizin

Berlin

Charitéplatz 1

10117 Berlin

Germany

Email: ch.mueller@charite.de

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Correspondence

C. A. MüllerMD 

Department of Psychiatry

Charité Campus Mitte

Charité – Universitätsmedizin

Berlin

Charitéplatz 1

10117 Berlin

Germany

Email: ch.mueller@charite.de