Sodium oxybate: a review of its use in alcohol withdrawal syndrome and in the maintenance of abstinence in alcohol dependence.

Clin Drug Investig (2014) 34:63–80 DOI 10.1007/s40261-013-0158-x

ADIS DRUG EVALUATION

Sodium Oxybate: A Review of Its Use in Alcohol Withdrawal Syndrome and in the Maintenance of Abstinence in Alcohol Dependence Gillian M. Keating

Published online: 4 December 2013 Ó Springer International Publishing Switzerland 2013

Abstract A liquid formulation of sodium oxybate (AlcoverÒ), the sodium salt of c-hydroxybutyric acid (GHB), is approved in Italy and Austria for use in alcohol withdrawal syndrome and for the maintenance of abstinence in alcohol dependence. This article reviews the efficacy and tolerability of sodium oxybate in alcohol withdrawal syndrome and in the maintenance of abstinence in alcohol dependence, as well as summarizing its pharmacological properties. Results of randomized controlled trials indicate that sodium oxybate was at least as effective as diazepam and clomethiazole in patients with alcohol withdrawal syndrome, rapidly alleviating symptoms, and was at least as effective as naltrexone or disulfiram in the maintenance of abstinence in alcohol-dependent patients. Sodium oxybate was generally well tolerated. The risk of sodium oxybate abuse is generally low when it is administered to alcohol-dependent patients at its approved dosage, under the supervision of a designated family member and with continuous strict medical surveillance. However, certain patient groups, such as patients with alcohol dependence and borderline personality disorder or who are in remission from heroin or cocaine addiction, may not be suitable candidates for sodium oxybate therapy because of an

The manuscript was reviewed by: G. Addolorato, Department of Internal Medicine, Catholic University of Rome, Rome, Italy; F. Caputo, Department of Internal Medicine, SS Annunziata Hospital, Cento, Ferrara, Italy; O. M. Lesch, Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria; F. Vigna-Taglianti, Department of Clinical and Biological Sciences, University of Torino, Torino, Italy. G. M. Keating (&) Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, North Shore 0754, Auckland, New Zealand e-mail: [email protected]

increased risk of abuse. In conclusion, sodium oxybate is a useful option for the treatment of alcohol withdrawal syndrome and for the maintenance of abstinence in alcohol dependence. Sodium oxybate (AlcoverÒ) in alcohol withdrawal syndrome and for the maintenance of abstinence in alcohol dependence: a summary Liquid formulation of the sodium salt of c-hydroxybutyric acid (GHB) At least as effective as diazepam and clomethiazole in alcohol withdrawal syndrome, providing rapid alleviation of symptoms At least as effective as naltrexone or disulfiram in the maintenance of abstinence in alcohol-dependent patients Generally well tolerated Low risk of abuse when administered at the recommended dosage under the supervision of a designated family member and with continuous strict medical surveillance

1 Introduction Alcohol dependence is a major public health problem that is both underdiagnosed and undertreated [1, 2]. For example, there are almost 15 million alcohol-dependent patients in Europe [3], with\10 % of those diagnosed with alcohol abuse or dependence thought to receive any treatment [4].

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Fig. 1 Sodium oxybate chemical structure

Alcohol dependence is associated with considerable social harm, and is characterized by craving, tolerance, a preoccupation with alcohol and continued drinking despite harmful consequences [1, 5]. Alcohol-dependent patients are also at increased risk of experiencing physical and mental disorders [1, 5, 6]. Some alcohol-dependent patients who abruptly discontinue or decrease their alcohol consumption may develop alcohol withdrawal syndrome [7]. Withdrawal symptoms typically develop 6–24 h after the last drink, and include increased heart rate and blood pressure, tremors, hyperreflexia, irritability, anxiety and depression [7]. Patients with more severe alcohol withdrawal syndrome may develop delirium tremens, seizures and coma. Although symptoms of alcohol withdrawal usually disappear within 2–7 days of the last drink, treatment may be needed in more severe and/or complicated cases [7]. Although alcohol affects many neurotransmitter systems, its main effect is on c-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the CNS [8]. Thus, drugs that act on the GABA system have been a focus of investigation in alcohol dependence. In Italy and Austria, a liquid formulation of sodium oxybate (the sodium salt of c-hydroxybutyric acid [GHB]; Fig. 1) [AlcoverÒ] is approved for use in alcohol withdrawal syndrome and for the maintenance of abstinence in alcohol dependence [9, 10]. This article reviews the efficacy and tolerability of sodium oxybate in alcohol withdrawal syndrome and in the maintenance of abstinence in alcohol-dependent patients, as well as summarizing its pharmacological properties.

2 Pharmacodynamic Properties This section summarizes the pharmacodynamic effects of GHB and sodium oxybate. Two studies discussed in this section are only available as abstracts [11, 12]. 2.1 Mechanism of Action GHB is a short-chain fatty acid that is structurally similar to GABA [7, 13]. GHB occurs naturally in the brain and is both a precursor and a degradation product of GABA [13, 14]. GHB appears to function as a neurotransmitter or neuromodulator [13–15]. For example, GHB modulates the

G. M. Keating

neurotransmitters dopamine, serotonin, acetylcholine and endorphin [7, 13, 16]. GHB binds with low affinity to GABA subtype B (GABAB) receptors and with high affinity to GHB-specific receptors; both receptor types are coupled to the G protein Gi/o [11, 13, 17]. In particular, GABAB receptors appear to play a major role in mediating the pharmacological effects of exogenous GHB, as GABAB receptor antagonists have been shown to block the effects of GHB and its analogues [17–19]. a4bd GABAA receptors were recently identified as a possible high-affinity target for GHB [20]. Indirect activation of GABAA receptors is also postulated to contribute to the suppression of symptoms of alcohol withdrawal by sodium oxybate [17]. The mechanism of action of sodium oxybate in alcohol dependence has not been fully explained [10]. However, given that the pharmacological profile of GHB has similarities to that of alcohol, one proposed mechanism is that sodium oxybate has an alcohol-mimicking effect (i.e. substitutes for alcohol) in the CNS [21–23]. GHB administration decreases the release of GABA from pre-synaptic GABAergic neurons through direct activation of GHB receptors [13, 17]. This may lead to the disinhibition of dopaminergic neurons in the ventral tegmental area and an increase in dopamine release, resulting in the alcoholmimicking effect of GHB [17, 21, 22]. 2.2 Effects on Alcohol Withdrawal and Intake in Animal Models GHB ameliorated symptoms of alcohol withdrawal in alcohol-dependent rats [24]. For example, dose-dependent suppression of tremors and seizures was seen in rats receiving intraperitoneal GHB 0.25, 0.5 or 1 g/kg [24]. Only modest sedation was seen with the GHB 1 g/kg, a dose sufficient to produce anaesthesia in control rats [24]. The lack of major sedation seen in alcohol-dependent rats was attributed to cross tolerance between GHB and alcohol [24, 25]. GHB also reduced voluntary alcohol intake in alcoholpreferring rats [12, 26]. For example, intraperitoneal GHB 300 and 400 mg/kg significantly (p \ 0.05 vs. salinetreated rats) reduced voluntary alcohol intake in a dosedependent manner at the 15 and 30 min observation times in alcohol-preferring rats, with no significant differences seen between rats receiving GHB and those receiving saline at later time points [26]. The short duration of effect seen with GHB in alcohol-preferring rats reflects its short elimination half-life (Sect. 3.2) [26]. Intraperitoneal sodium oxybate 25, 50 or 100 mg/kg also significantly (p \ 0.001 vs. saline-treated rats) suppressed the motivational properties of alcohol in alcoholpreferring rats [27].

Sodium Oxybate: A Review

2.3 Abuse Potential Sodium oxybate generally has a low risk of abuse when it is administered to alcohol-dependent patients at its approved dosage, under the supervision of a designated family member and continuous strict medical surveillance [28, 29] (see also Sect. 6.2). A liquid formulation of sodium oxybate (XyremÒ) is also available in various countries (including the USA [30] and the EU [31]) to treat narcolepsy. A safety overview indicated that among 26,000 patients prescribed sodium oxybate for the treatment of narcolepsy, there were ten cases (0.039 %) of abuse, four cases (0.016 %) of dependence and eight cases (0.031 %) of withdrawal after the discontinuation of sodium oxybate [32]. However, adverse effects may occur when illicit GHB is abused as a recreational drug for its euphorigenic and relaxant properties or as a growth promoter [15, 33]. The steep dose-response curve associated with GHB, inexact dosing of illicit GHB and increased consumption to enhance effects contribute to the risk of overdose [15, 33]. Adverse effects associated with GHB abuse include drowsiness, dizziness, nausea and amnesia, while high doses (i.e.[10–20 g [34]) may be associated with seizures, severe respiratory depression and coma [13, 33–35]. Although deaths associated with GHB abuse have been reported, most deaths appeared to involve the mixing of GHB with other drugs [13, 15]. There are a lack of data supporting a link between use of GHB alone and death [15]. There is no specific antidote to GHB and treatment of GHB intoxication in patients who are breathing spontaneously is primarily supportive [13]. Supportive measures include airway stabilization, oxygen supplementation, use of atropine for persistent bradycardia and establishment of intravenous access; intubation is rarely necessary [13]. Long-term use of high doses of illicit GHB (i.e. 18–250 g/day [32]) may induce physical dependence and severe withdrawal symptoms (including anxiety, insomnia, agitation, tachycardia, tremors, delirium, hallucinations and seizures) [13, 36, 37]. 2.4 Other Effects A single dose of sodium oxybate 50 mg/kg did not significantly affect heart rate or blood pressure in healthy volunteers [38]. Sodium oxybate stimulated slow wave sleep and growth hormone secretion in healthy volunteers [39]. However, there is no evidence that the short-term increases in growth hormone levels induced by sodium oxybate increase muscle mass [15]. Indeed, 6 months’ administration of sodium oxybate 50 mg/kg/day did not affect basal growth hormone

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secretion or fat-free mass in alcohol-dependent patients who had achieved abstinence [40]. In healthy volunteers, single doses of sodium oxybate 12.5 or 25 mg/kg did not affect attention, vigilance, alertness, short-term memory or psychomotor co-ordination [41]. Significant (p \ 0.05) increases from baseline in calmness occurred with sodium oxybate 12.5 mg/kg and contentedness significantly (p \ 0.05) decreased from baseline with sodium oxybate 12.5 or 25 mg/kg [41]. Administration of single doses of sodium oxybate 1.125, 2.25 or 4.5 g/70 kg to healthy volunteers significantly (p \ 0.05) impaired working memory and the encoding of episodic memory during the period of drug effect [42]. However, at doses producing equivalent subjective ratings of ‘drug effect’, the effect of sodium oxybate on memory was significantly (p \ 0.05) less than that of triazolam [42]. In patients with severe alcohol withdrawal syndrome and hypercortisolism, plasma cortisol levels at weeks 1, 2 and 3 were significantly (p \ 0.01) lower in recipients of sodium oxybate 50 mg/kg/day than in recipients of diazepam 0.5 mg/kg/day [43]. Sodium oxybate may ameliorate the immune system dysfunction seen in alcohol-dependent patients [44]. For example, production of tumour necrosis factor was significantly (p \ 0.01) higher in peripheral blood mononuclear cells (PBMCs) from abstinent patients receiving sodium oxybate 50 mg/kg/day, naltrexone 50 mg/day or disulfiram 400 mg/day than from patients who continued to drink alcohol. In addition, interleukin-4 production was significantly lower in PBMCs from abstinent patients receiving sodium oxybate or naltrexone than from patients who continued to drink alcohol [44].

3 Pharmacokinetic Properties This section provides an overview of the pharmacokinetic properties of sodium oxybate as an oral solution. Data were obtained from a study in alcohol-dependent patients receiving sodium oxybate 25 mg/kg every 12 h for 7 days [45], supplemented by information from the Austrian summary of product characteristics (SPC) [10] and other articles [14, 17, 38]. The recommended dosage of sodium oxybate is usually 50 mg/kg/day administered in three divided doses, with a maximum recommended dosage of 100 mg/kg/day [10] (Sect. 7). 3.1 Absorption and Distribution Oral sodium oxybate is rapidly absorbed and has a bioavailability of &30 % [10, 45]. Following administration of sodium oxybate 25 mg/kg every 12 h for 7 days, a mean

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maximum plasma concentration of 55 lg/mL was reached in a median 30 min [45]. The mean area under the plasma concentration-time curve (AUC) was 3,125 lgmin/mL [45]. No accumulation of sodium oxybate was seen in plasma [45]. Sodium oxybate readily crosses the blood-brain barrier [14]. 3.2 Metabolism and Elimination Sodium oxybate is metabolized in part to succinic acid in the CNS, which then enters the Krebs cycle, and is also eliminated via b-oxidation [10, 17, 38]. Sodium oxybate undergoes extensive first-pass metabolism and is primarily eliminated by the liver, with &1 % of the dose eliminated in the urine as unchanged drug [10, 17, 45]. In alcohol-dependent patients receiving sodium oxybate 25 mg/kg every 12 h, the mean oral clearance of sodium oxybate was 9.2 mL/min/kg, with a mean renal clearance of 0.06 mL/min/kg [45]. Sodium oxybate was rapidly eliminated, with a mean terminal elimination half-life (t) of 26 min [45]. 3.3 Special Patient Populations Compared with healthy adults, AUC values were doubled, clearance was reduced and t was prolonged in patients with liver cirrhosis receiving a single dose of oral sodium oxybate 25 mg/kg [10]. For example, the apparent oral clearance of sodium oxybate was 9.1 mL/min/kg in healthy adults, 4.5 mL/min/kg in patients with Class A liver cirrhosis (without ascites) and 4.1 mL/min/kg in patients with Class C liver cirrhosis (with ascites), and mean t was 22, 32 and 59 min, respectively [10]. The Austrian SPC recommends that the starting dosage of sodium oxybate be halved in patients with hepatic impairment, and that the response to dosage increases be monitored closely [10]. No dosage adjustment is recommended in patients with renal impairment (although such patients should be advised to reduce their sodium intake) [10].

4 Potential Drug Interactions In vitro, sodium oxybate at concentrations of up to 378 lg/mL (i.e. higher than therapeutic concentrations) did not significantly inhibit the cytochrome P450 (CYP) enzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A [10]. In healthy adults, no pharmacokinetic interactions were observed when a single dose of sodium oxybate 2.25 g was coadministered with a single dose of lorazepam 2 mg or zolpidem 5 mg [10]. Although pharmacodynamic

G. M. Keating

interactions between sodium oxybate and zolpidem were not assessed, increased sleepiness was seen when sodium oxybate and lorazepam were coadministered [10]. No pharmacokinetic or pharmacodynamic interactions were seen when a single dose of sodium oxybate 2.25 g was coadministered with a single dose of tramadol 100 mg to healthy adults [10]. Pharmacodynamic interactions resulting in CNS and/or respiratory depression cannot be excluded when higher dosages of sodium oxybate (up to 9 g/day) are coadministered with higher dosages of hypnotics or opioids [10]. Coadministration of a single dose of sodium oxybate 2.25 g with protriptyline 10 mg (single dose) or duloxetine 60 mg (at steady state) was not associated with pharmacokinetic interactions in healthy adults [10]. In addition, no additive effect on sleepiness was seen when sodium oxybate and duloxetine were coadministered, compared with sodium oxybate alone. However, a possible additive effect between sodium oxybate and antidepressants cannot be excluded and an increased incidence of adverse events was seen when sodium oxybate was coadministered with tricyclic antidepressants [10]. No pharmacokinetic interaction was seen between a single dose of sodium oxybate 4.5 g and a single dose of modafinil 200 mg in healthy adults [10]. Omeprazole did not affect the pharmacokinetics of sodium oxybate to a clinically significant extent [10]. Sodium oxybate is metabolized by GHB dehydrogenase, meaning there is a potential for interactions between sodium oxybate and drugs that induce or inhibit this enzyme (e.g. valproate, phenytoin, ethosuximide), although no human studies examining this potential interaction have been conducted to date [10]. No significant pharmacokinetic interaction between sodium oxybate 50 mg/kg and alcohol was seen in healthy volunteers [38]. In terms of significant pharmacodynamic interactions, increased alertness and stimulation and decreased sedation were seen in healthy volunteers 15 min after administration of a solid formulation of sodium oxybate 2.25 g (&30 mg/ kg) plus alcohol (study available as an abstract) [46, 47]. Sodium oxybate alone was associated with less pronounced subjective and objective sedation than alcohol alone, 165 min post dose. No significant changes in oxygen saturation (assessed noninvasively) were seen with sodium oxybate alone, alcohol alone, sodium oxybate plus alcohol or placebo [46, 47]. In a second study, oxygen saturation (assessed noninvasively using pulse oximetry) was reduced to a significantly (p \ 0.05) greater extent with sodium oxybate 50 mg/kg (liquid formulation) plus alcohol, sodium oxybate 50 mg/kg alone or alcohol alone than with placebo [38]. Although the greatest observed reduction in oxygen


saturation seen with sodium oxybate plus alcohol was only modest (reduction of 2.12 % seen at 90 min), it was significantly (p \ 0.05) greater than that seen with sodium oxybate alone, alcohol alone or placebo [38].

5 Therapeutic Efficacy The efficacy of oral sodium oxybate has been examined in the treatment of alcohol withdrawal syndrome (Sect. 5.1) and for the maintenance of abstinence (Sect. 5.2) in alcohol-dependent patients. Most studies diagnosed alcohol dependence or alcohol withdrawal syndrome using Diagnostic and Statistical Manual of Mental Disorders (DSM)III-R [48], DSM-IV [49] or DSM-IV-TR [50] criteria, with some studies also using the WHO International Classification of Diseases, 10th revision (ICD-10) [51]. 5.1 Alcohol Withdrawal Syndrome Four randomized, double-blind [52, 53], single-blind [54] or open-label [43] trials compared the efficacy of oral sodium oxybate with that of placebo [52], diazepam [43, 54] or clomethiazole [53] in patients with acute alcohol withdrawal syndrome. The trials were of relatively small size (n = 23–98) and were of multicentre [43] or singlecentre [52–54] design. These studies assessed the effects of treatment on alcohol withdrawal syndrome for up to 7 h [52], or 8 [53], 18 [54] or 21 [43] days. Three studies did not specify a primary endpoint [43, 52, 54]; in the fourth study, the total Clinical Institute Withdrawal Assessment for Alcohol-revised scale (CIWA-Ar) score was the primary endpoint [53]. Two noncomparative studies examining the efficacy of oral sodium oxybate in alcohol withdrawal syndrome are also briefly discussed (Sect. 5.1.4) [55, 56]; one of these articles also reported the results of a separate randomized, double-blind, placebo-controlled study examining the use of sodium oxybate for the maintenance of abstinence (Sect. 5.2.1) [56]. Where specified, patients were treated as inpatients and the intake of sodium oxybate was supervised [43, 53, 55, 56]. The efficacy of intravenous sodium oxybate was also compared with that of oral clomethiazole for the treatment of severe alcohol withdrawal syndrome in an intensive care unit setting [57]. However, this trial is beyond the scope of this review and is not discussed further. 5.1.1 Comparison with Placebo The placebo-controlled trial included alcohol-dependent patients with alcohol withdrawal syndrome (DSM-III-R

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criteria) who were randomized to receive a single dose of sodium oxybate 50 mg/kg (n = 11) or placebo (n = 12) [52]. Six withdrawal symptoms (tremor, sweating, nausea, depression, anxiety, restlessness) were each scored on a 4-point scale (ranging from 0 = not present to 3 = severe), giving a maximum possible score of 18 [52]. Sodium oxybate 50 mg/kg was more effective than placebo in alcohol withdrawal syndrome [52]. The mean withdrawal symptom score was significantly lower with sodium oxybate than with placebo 1 h after treatment (7.2 vs. 11.8; p \ 0.05). Among sodium oxybate recipients, mean withdrawal symptom scores were significantly (p \ 0.05) reduced from baseline at all time points (12.6 at baseline vs. 7.2, 4.2, 2.1, 1.5 and 2.6 at 1, 2, 3, 5 and 7 h, respectively, after treatment). By contrast, mean withdrawal symptom scores in placebo recipients were significantly higher at 7 h than at baseline (14.7 vs. 11.8; p \ 0.05), with no significant difference versus baseline seen at other time points (11.8, 11.3, 12.6 and 13.6 at 1, 2, 3 and 5 h, respectively, after treatment) [52]. At the end of the double-blind phase, patients assigned to sodium oxybate continued to receive open-label treatment with 50 mg/kg every 8 h up to day 3, after which the dosage was tapered, with discontinuation on day 7 [52]. The mean withdrawal symptom score remained \2 throughout this open-label phase [52]. 5.1.2 Comparisons with Diazepam The two trials comparing sodium oxybate with diazepam included patients aged 18–65 [54] or C18 [43] years who had alcohol dependence and/or abuse (DSM-IV criteria) [54] or alcohol dependence (DSM-IV-TR criteria) [43], with alcohol consumption of [80 g/day in the past 24 h [54]. Patients also had a CIWA-Ar score of C10 points (indicating moderate to severe withdrawal) [54] or C20 points (indicating severe withdrawal) [43]. In one trial, the median duration of addiction was 15 years and mean alcohol intake was 238.8 g/day [54]. Sodium oxybate 50 mg/kg/day was at least as effective as diazepam 0.5–0.75 [54] or 0.5 [43] mg/kg/day in the treatment of alcohol withdrawal syndrome. Mean total CIWA-Ar scores improved over time in both treatment groups in both studies (Table 1) [43, 54]. In patients with severe withdrawal symptoms, mean total CIWA-Ar scores were significantly (p \ 0.01) lower in sodium oxybate recipients than in diazepam recipients after 1, 2 and 3 weeks of therapy [43]. However, in patients with moderate to severe withdrawal symptoms, there was no significant difference between sodium oxybate and diazepam recipients in the mean total CIWA-Ar score at any time point (assessed on days 1, 2, 3, 4, 5 and 10 and after study drug discontinuation on day 18) [54]. In both treatment

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G. M. Keating

Table 1 Efficacy of oral sodium oxybate in alcohol withdrawal syndrome. Results of trials comparing sodium oxybate with diazepam or clomethiazole Study (study design)

Treatment (no. of pts)

Time point

Mean CIWA-Ar scorea Total

Paroxysmal sweats

Tremor

Anxiety

Comparisons with DIA Addolorato et al. [54] (r, sb)

SOX 50 mg/kg/dayb (26)

DIA 0.5–0.75 mg/kg/dayc (22)

Nava et al. [43] (r, ol, mc)

SOX 50 mg/kg/dayd (21) DIA 0.5 mg/kg/dayd (21)

Day 1

13.7

2.1

4.4

3.5

Day 10 Day 18

2.59 1.55

0.4 0.4

1.5 0.8

0.5 0.5

Day 1

14.41

2.1

3.8

3.4

Day 10

3.17

0.7

1.7

0.4

Day 18

2.88

0.4

1.2

0.1

Day 1

&28e

5.38

3.71

5.42

Day 21

&0**e

0.33*

0.05*

0.67*

Day 1

&28e

5.19

3.67

5.33

Day 21

&2e

0.90

0.95

0.85

Comparison with CLO Nimmerrichter et al. [53] (r, db, sc)

SOX 50 mg/kg/dayf (33)

SOX 100 mg/kg/dayf (32)

CLO 1 g/dayf (33)

Baseline

27.1

4.4

4.5

4.1

Day 2

16.3

2.0

2.7

2.1

Day 8

11.7

1.3

1.3

1.1

Baseline

27.2

4.4

4.8

4.2

Day 2

16.7

2.2

2.5

2.1

Day 8 Baseline

12.4 27.2

1.4 4.5

1.5 4.6

1.4 3.9

Day 2

16.9

2.2

2.6

2.2

Day 8

12.8

1.3

1.5

1.5

CIWA-Ar Clinical Institute Withdrawal Assessment for Alcohol-revised scale, CLO clomethiazole, db double-blind, DIA diazepam, mc multicentre, ol open-label, pts patients, r randomized, sb single-blind, sc single-centre, SOX sodium oxybate * p \ 0.05, ** p \ 0.01 vs. DIA a

The CIWA-Ar rates ten withdrawal symptoms (nausea and vomiting, tremor, paroxysmal sweats, anxiety, agitation, tactile disturbances, auditory disturbances, visual disturbances, headache/fullness in head [each rated from 0 to 7] and orientation/clouding of sensorium [rated from 0 to 4]), with higher scores indicating more severe symptom (maximum total score of 67). The total CIWA-Ar score was the primary endpoint in one study [53]

b

Administered in three divided doses each day for 10 days

c

Administered in six divided doses each day for 6 days, and then tapered down to day 10

d

Administered in four divided doses each day for 21 days, with gradual tapering starting from the second week

e

Value estimated from graph

f

Administered in four divided doses each day for 5 days, followed by half the daily dose on day 6 and placebo on days 7 and 8

groups, most of the reduction in total CIWA-Ar scores was seen on days 2 and 3 [54]. The improvements over time in mean CIWA-Ar scores for three key withdrawal symptoms (paroxysmal sweats, tremor, anxiety) are also shown in Table 1. In patients with severe withdrawal symptoms, mean CIWA-Ar scores for paroxysmal sweats, tremor and anxiety were significantly (p \ 0.05) lower with sodium oxybate than with diazepam for all time points from day 2 onwards [43]. In patients with moderate to severe withdrawal symptoms, the mean CIWA-Ar score for anxiety was significantly (p \ 0.02) lower with sodium oxybate than with diazepam on day 4,

with no significant between-group differences seen at other time points or for the symptoms of paroxysmal sweats or tremor at any time point [54]. Significant differences favouring sodium oxybate were seen for all other withdrawal symptoms at certain time points in patients with severe withdrawal symptoms [43]. For example, significantly (p \ 0.05) lower mean CIWAAr scores were seen with sodium oxybate versus diazepam for nausea and vomiting on days 5, 6 and 7; for agitation on all assessed time points from day 2 to 21; for tactile disturbances on days 3, 5, 6, 7 and 14; for auditory disturbances on days 2, 5, 7, 14 and 21; for visual disturbances


on days 2, 3, 4, 5, 7, 14 and 21; for headache/fullness in head on days 3, 5, 7, 14 and 21; and for orientation/ clouding of sensorium on days 4, 5, 6 and 7 [43]. In patients with moderate to severe withdrawal symptoms, the mean CIWA-Ar score for agitation was significantly (p \ 0.02) lower with sodium oxybate than with diazepam on day 4 [54]. In this study, mean scores on the State Anxiety Inventory (assessing anxiety) or the SDS Zung self-rating depression scale (assessing depression) declined in both treatment groups (indicating improvement), with no significant differences seen between sodium oxybate and diazepam recipients at any time point [54]. 5.1.3 Comparison with Clomethiazole In the trial comparing sodium oxybate with clomethiazole, patients had alcohol dependence (DSM-IV and ICD-10 criteria), with a CIWA-Ar score of C20 points (i.e. severe withdrawal), a c-glutamyltransferase (GGT) level C1.3 9 the upper limit of normal (ULN) and/or mean corpuscular volume (MCV) of C95 fL and/or a relative carbohydrate-deficient transferrin level (%CDT) of C2.5 % [53]. Across treatment groups at baseline, the mean blood alcohol level was 1.01–1.99 %, mean GGT was 187–204 IU/L, mean MCV was 94.9–99.3 fL, and mean %CDT was 4.8–5.9 % [53]. Mean total CIWA-Ar scores improved over time in both sodium oxybate 50 or 100 mg/kg/day and clomethiazole 1 g/day recipients, with the main treatment effect seen within the first 48 h [53]. No significant between-group difference in the mean total CIWA-Ar score was seen on day 2 (primary endpoint) (Table 1) [53]. No rebound effect was seen when the study drugs were completely tapered off, as shown by the mean total CIWAAr scores on day 8 (Table 1) [53]. 5.1.4 Noncomparative Studies Two noncomparative, multicentre [55] or single-centre [56] studies examined the efficacy of sodium oxybate in the treatment of patients with alcohol withdrawal syndrome (n = 299 [55] and 22 [56]). In an Austrian study, patients hospitalized for reasons primarily unrelated to their alcohol dependence received sodium oxybate 50–100 mg/kg/day [55]. In an Italian study, patients with severe alcohol dependence and alcohol withdrawal syndrome were hospitalized and treated with oral sodium oxybate 50–150 mg/ kg/day for 6 days; two patients were treated until day 10 because withdrawal symptoms were still present on day 6 [56]. Eight withdrawal symptoms were scored on an alcohol withdrawal scale with a maximum total score of 38 [56]. In terms of amelioration/suppression of the symptoms of alcohol withdrawal syndrome, sodium oxybate was

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considered to be excellent, good, fair and insufficient in 57, 34, 6 and 3 % of patients, respectively, in the Austrian study [55]. In the Italian study, the mean alcohol withdrawal scale score was 16.3 at baseline, with mean scores of 4.9, 2.0, 0.9, 0.6, 0.4, 0.1, 0.1, 0.06 and 0 reported 1–2, 3, 4, 5, 6, 7, 8, 9 and 10 days after starting sodium oxybate therapy [56]. 5.2 Maintenance of Abstinence The main focus of this section is randomized, double-blind [56, 58, 59] or open-label [60–63] trials comparing sodium oxybate with placebo [56, 58, 59], naltrexone [60, 61, 63] or disulfiram [60], or examining the efficacy of sodium oxybate in combination with naltrexone [63], escitalopram [62], or naltrexone plus escitalopram [62] for the maintenance of abstinence in patients with alcohol dependence. Apart from the GATE 2 trial (n = 314) [59], the trials were of relatively small size (n = 17–86) and, where specified, were of multicentre [59–61, 63] or single-centre [56, 62] design. These studies examined the effect of treatment on the maintenance of abstinence for up to 3 [58, 61, 63], 6 [56, 62] or 12 [59, 60] months. Most of these randomized, controlled trials did not specify a primary endpoint [56, 58, 60–63]. However, in the GATE 2 trial (available as an abstract and poster), the primary endpoint was the cumulative abstinence duration at 6 months [59]. Results of several additional studies are also briefly discussed, including a large noncomparative study [64] (Sect. 5.2.4.1), a study examining the use of greater dose fractioning of sodium oxybate [65] (Sect. 5.2.4.2), studies in patients with chronic, treatment-resistant alcohol dependence [66, 67] (Sect. 5.2.4.3), a study in patients with psychiatric co-morbidities [68] (Sect. 5.2.4.4) and a pilot study examining the efficacy of sodium oxybate according to Lesch alcoholism typology [69] (Sect. 5.2.4.5). Where specified, sodium oxybate and its administration were entrusted to a designated family member [60–65, 67– 69]. 5.2.1 Comparisons with Placebo Three trials compared the efficacy of sodium oxybate 50 mg/kg/day with that of placebo in the maintenance of abstinence. GATE 2 included alcohol-dependent patients (DSM-IV and ICD-10 criteria) who were willing to stop drinking alcohol and maintain complete abstinence [59]. Patients received treatment with sodium oxybate or placebo for 6 months, after which they were followed for another 6 months without treatment [59]. In the second study, patients had a C5-year history of alcoholism

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G. M. Keating

Table 2 Efficacy of sodium oxybate in the maintenance of abstinence in alcohol-dependent patients. Results of randomized, double-blind, placebo-controlled trials Study (study duration)

Cacciaglia et al. [59]c (12 months) Gallimberti et al. [58] (3 months) Moncini et al. [56]g (6 months)

Mean no. of daily drinks (baselinea)

Mean % of abstinent days (baselinea)

Abstinent pts (% of pts) [no. of pts]

SOX 50 mg/ kg/dayf (36)

4.7** (12.1)

25.9*** (5.6)

30.6 [11/36]

PL (35)

9.3 (11.4)

8.4 (4.9)

5.7 [2/35]


Mean cumulative abstinence duration (days) At 6 months

At 12 months

SOXd (154)

90.4e

136.0

PL (160)

73.9e

108.9

Relapsed pts (% of pts) [no. of pts]

Retention rate (% of pts)

Mean craving scoreb (baseline)

3.1***   (8.9) 7.6 (8.5)

SOX 50 mg/ kg/day (9)

66.7 [6/9]

11.1 [1/9]

44.0*

1.5* h (7.5h)

PL (8)

50.0 [4/8]

25.0 [2/8]

37.0

2.7h (6.6h)

PL placebo, pts patients, SOX sodium oxybate * p \ 0.05, ** p \ 0.01, *** p \ 0.001 vs. PL; a

p \ 0.05,



p \ 0.001 vs. baseline

Baseline was the 3 months prior to treatment [58]

b

Craving was assessed using an 11-item questionnaire (maximum score of 11) [58], or the 14-item Alcohol Craving Scale (maximum score of 14) [56]

c

Available as an abstract and poster. Pts received SOX or PL for 6 months, and were then followed for another 6 months without treatment

d

The SOX dosage was 3.06 g/day in pts weighing B65 kg and 3.50 g/day in pts weighing [65 kg, administered in three divided doses each day

e

Primary endpoint

f

Administered in three divided doses each day

g

The abstinence rate was reported at the end of the programme (mean duration of 24.9 weeks for SOX and 16.6 weeks for PL), and relapse and retention rates were assessed at 6 months

h


(DSM-III-R criteria) with an average alcohol intake of [150 g/day for C2 years [58]. In this study, patients were initially assessed and received their first dose of sodium oxybate or placebo in a day hospital, and were then monitored as outpatients for 3 months [58]. The third study included patients with severe alcohol dependence (DSMIV criteria) and an average alcohol intake of C150 mL/day of pure ethanol [56]. Patients had undergone a 30-day inpatient detoxification; they received their first dose of sodium oxybate or placebo in hospital, and were then monitored as outpatients for 6 months [56]. In the GATE 2 trial, the difference between sodium oxybate and placebo in the mean cumulative abstinence duration at 6 months (primary endpoint) was of borderline statistical significance (p = 0.05) (Table 2) [59]. After a further 6 months’ follow-up (without treatment), the cumulative abstinence duration did not significantly differ between sodium oxybate and placebo recipients (Table 2). The median time to first relapse did not significantly differ between sodium oxybate and placebo recipients (77 vs. 46 days) [59]. In the second study, the mean number of daily drinks and the proportion of abstinent days was significantly lower in patients receiving sodium oxybate than in those receiving placebo after 3 months’ treatment (Table 2) [58]. The proportion of sodium oxybate and placebo recipients who

were abstinent was 30.6 and 5.7 %, respectively (Table 2), with controlled drinking seen in 41.7 and 17.1 % of patients, and excessive drinking seen in 27.8 and 77.1 % of patients [58]. In the third, 6-month study, the proportion of abstinent patients at the end of the programme and the proportion of relapsed patients did not significantly differ between sodium oxybate and placebo recipients (Table 2) [56]. However, the 6-month retention rate was significantly higher in sodium oxybate recipients than in placebo recipients (Table 2). There was no significant difference between sodium oxybate and placebo recipients in terms of the mean stay in the programme (24.9 vs. 16.6 weeks) [56]. In two studies, alcohol craving scores were significantly lower in sodium oxybate recipients than in placebo recipients by study end (Table 2) [56, 58]. However, in GATE 2, alcohol craving (assessed using the Lu¨becker Craving Risiko Ru¨ckfall questionnaire) did not significantly differ between sodium oxybate and placebo recipients (quantitative data not reported) [59]. 5.2.2 Comparisons with Naltrexone or Disulfiram Three trials compared the efficacy of sodium oxybate with that of naltrexone [60, 61, 63] or disulfiram [60]. One trial also included a treatment arm in which patients received


sodium oxybate in combination with naltrexone; results pertaining to this treatment arm are discussed in Sect. 5.2.3 [63]. The trials included patients aged C18 years [60] who were alcohol dependent (DSM-IV [61] or DSM-IV-TR [60, 63] criteria). In addition, patients had to be recently detoxified [61, 63], completely abstinent for 7 [63] or C14 [60] days and/or free of withdrawal symptoms [60]. At baseline, patients had a mean duration of alcohol dependence of &4 [60], &14.6 [61] or &15 [63] years, had a mean alcohol intake of &10 drinks per day [60] and had been abstinent for a mean 2.4 [60] or 5.1 [61] days. Sodium oxybate 50 mg/kg/day was at least as effective as naltrexone 50 mg/day in maintaining abstinence. In two 3-month trials, patients receiving sodium oxybate were significantly more likely to remain abstinent than patients receiving naltrexone [61, 63], with sodium oxybate recipients in one trial also significantly less likely than naltrexone recipients to fail to maintain abstinence [63] (Table 3). In the 12-month trial, no significant differences were seen between sodium oxybate and naltrexone recipients in the rates of abstinence, failure to maintain abstinence or relapse (Table 3) [60]. The mean number of daily drinks was significantly reduced from baseline in both sodium oxybate and naltrexone recipients in the 12-month study [60], with no significant difference seen between sodium oxybate and naltrexone recipients in the mean number of alcohol units consumed per day in one 3-month study [63] (Table 3). Statistical analysis of this endpoint was not conducted in the second 3-month study because of the low number of evaluable patients (Table 3) [61]. Craving scores were significantly reduced from baseline in both sodium oxybate and naltrexone recipients [60, 61], with significantly lower scores seen with sodium oxybate than with naltrexone seen in the 12-month study [60] (Table 3). At study end, GGT, ALT and AST levels were significantly (p \ 0.05) reduced from baseline in sodium oxybate and naltrexone recipients [60, 61], and were significantly (p \ 0.05) lower in patients receiving sodium oxybate than in those receiving naltrexone in one study [60]. After 12 months’ follow-up, the mean number of daily drinks was significantly reduced from baseline in both sodium oxybate and disulfiram recipients, with no significant between-group differences in the percentage of patients who were abstinent, failed to maintain abstinence or relapsed (Table 3) [60]. Mean Alcohol Craving Scale scores were significantly lower with sodium oxybate than with disulfiram (Table 3) [60]. At study end, GGT, ALT and AST levels were significantly (p \ 0.05) reduced from baseline in sodium oxybate and disulfiram recipients, and were significantly (p \ 0.05)

71

lower in patients receiving sodium oxybate than in those receiving disulfiram [60]. 5.2.3 In Combination with Naltrexone and/or Escitalopram The efficacy of combination therapy in maintaining abstinence was examined in a 6-month trial in which patients received sodium oxybate plus naltrexone and escitalopram, sodium oxybate plus escitalopram, naltrexone plus escitalopram, or escitalopram alone [62] and in a 3-month trial comparing sodium oxybate plus naltrexone with sodium oxybate or naltrexone alone [63]. Patients were alcohol dependent (DSM-IV [62] or DSMIV-TR [63] criteria) and had completed detoxification [62, 63] (with no evidence of alcohol withdrawal syndrome and negative urine tests [62]). At baseline, the mean duration of alcohol dependence was &12 [62] or &15 [63] years. After 6 months’ follow-up, significant reductions from baseline in alcohol consumption and alcohol craving were seen in patients receiving combination therapy with sodium oxybate plus naltrexone and escitalopram, sodium oxybate plus escitalopram or naltrexone plus escitalopram, but not in those receiving escitalopram alone (Table 3) [62]. In addition, alcohol consumption and alcohol craving were reduced to a significantly greater extent in patients receiving sodium oxybate plus naltrexone and escitalopram than in the other three treatment arms (Table 3). Abstinence and relapse rates are shown in Table 3 [62]. During the study, the mean percentage of positive urine tests was significantly (p \ 0.01) lower in patients receiving sodium oxybate plus naltrexone and escitalopram than in patients receiving sodium oxybate plus escitalopram, naltrexone plus escitalopram, or escitalopram alone (18.5 vs. 41.4, 63.1 and 89.2 %) [62]. The difference between patients receiving sodium oxybate plus escitalopram or naltrexone plus escitalopram and those receiving escitalopram alone was also significant (p \ 0.05) [62]. GGT, ALT and AST levels were significantly (p \ 0.05) reduced from baseline in patients receiving sodium oxybate plus naltrexone and escitalopram, sodium oxybate plus escitalopram or naltrexone plus escitalopram after both 60 and 180 days of follow-up, and in patients receiving escitalopram alone after 180 days of follow-up [62]. In addition, at both 90 and 180 days of follow-up, Hamilton Depression Rating Scale scores were significantly (p \ 0.01) reduced from baseline in all four treatment groups [62]. In the 3-month study, patients receiving sodium oxybate plus naltrexone were significantly more likely to remain abstinent, and significantly less likely to fail to remain abstinent, than patients receiving sodium oxybate or naltrexone alone (Table 3) [63]. Rates of relapse into heavy

2.2

ESC 20 mg/day (11)

g

1,300 (1,600 )

g

900*g (1,700g)

NAL 50 mg/day ? ESC 20 mg/day (12)

(1,650 )

100**

SOX 75 mg/kg/day ? NAL 50 mg/day ? ESC 20 mg/day (12)

g

f

e

d

c

b

a

p \ 0.05,



p \ 0.001,



p = 0.0001 vs. NAL;

à

p \ 0.05 vs. DIS;

§

p \ 0.05,

§§

/

81.8 [9/11]

66.7 [8/12]

16.7 [2/12]

50.0 [6/12]

0 [0/18]

5.9 [1/17]

15.0 [3/20]

p = 0.01 vs. SOX,

11.1   §§ [2/18]

70.6 [12/17]

0 [0/17]

10 [3/31] 11.1 [2/18]

26 [7/27]

14 [4/28]

83.3 [15/18]

76.5 [13/17]

90.0 [18/20]

76.5 [13/17]

61 [19/31] 77.8 [14/18]

67 [18/27]

79 [22/28]

Completed study (% of pts) [no. of pts]

20g (23g)

14*g (22g)

5**/g (23g)

11*g (24g)

2.0* (8.5)

3.1* (7.8) 1.9* (9.4)

3.6* (7.3)

1.7* à (8.2)

Mean craving scored (baseline)

p \ 0.05 vs. all other comparators

Relapse ratec (% of pts) [no. of pts]


Administered in five divided doses each day

Administered in three divided doses each day

Craving was assessed using a 10 cm visual analogue scale [60], the 14-item Alcohol Craving Scale (maximum score of 14) [61] or the Obsessive Compulsive Drinking Scale [62]

Defined as relapse into heavy drinking [60–63], resulting in withdrawal [60]

Defined as the failure to maintain abstinence, but without relapse into heavy drinking [60, 61, 63]

Mean no. of daily drinks [60], mean units of alcohol per day [61, 63] or mean g/week of alcohol [62]

* p \ 0.05, ** p \ 0.01 vs. baseline;

18.1 [2/11]

33.3 [4/12]

83.3 [10/12]

50.0 [6/12]

550*g (1,750g)

SOX 75 mg/kg/dayf ? ESC 20 mg/day (12) g

0.5  §

SOX 50 mg/kg/daye ? NAL 50 mg/day (18) /g

72.2   § [13/18]

2.0

f

5.9 [1/17]

2.0

SOX 50 mg/kg/day (20) 50.0 [10/20]

40.0 [8/20]

41.2 [7/17]

23 [7/31] 0 [0/18]

19 [5/27]

14 [4/28]

Failure to maintain abstinenceb (% of pts) [no. of pts]

35.3 [6/17]

39 [12/31] 66.7 [12/18]

48 [13/27]

64 [18/28]

Abstinence rate (% of pts) [no. of pts]

NAL 50 mg/day (17)

e

NAL 50 mg/day (17)

DIS disulfiram, ESC escitalopram, NAL naltrexone, pts patients, SOX sodium oxybate

Stella et al. [62] (6 months)

Caputo et al. [63] (3 months)

Caputo et al. [61] (3 months)

0.8* (10.5) 0.9* (10.5) 2.5

DIS 200 mg/day (31) SOX 50 mg/kg/daye (18)

0.6* (11.3)

SOX 50 mg/kg/daye (28)

Nava et al. [60] (12 months)

NAL 50 mg/day (27)

Alcohol consumptiona (baseline)


Study (study duration)

Table 3 Efficacy of sodium oxybate in the maintenance of abstinence in alcohol-dependent patients. Results of randomized, open-label, active comparator trials

72 G. M. Keating


drinking did not significantly differ between the three treatment arms (Table 3) [63]. Alcohol consumption at study end was also significantly lower in patients receiving sodium oxybate plus naltrexone than in those receiving sodium oxybate or naltrexone alone (Table 3) [63]. Among patients who maintained abstinence, Alcohol Craving Scale scores were significantly (p = 0.01) reduced from baseline both in sodium oxybate plus naltrexone recipients (from 9.8 at baseline to 1.9) and in those receiving sodium oxybate alone (from 9.1 at baseline to 1.4) [63]. In addition, among patients who maintained abstinence, GGT, ALT and AST levels at study end were significantly (p = 0.01) reduced from baseline both in patients receiving sodium oxybate plus naltrexone and in those receiving sodium oxybate alone [63].

73

the subgroup of abstinent patients and 11 in the subgroup of nonabstinent patients [65]. Among the 78 patients who responded to sodium oxybate administered in three divided doses, the median Alcohol Craving Score was significantly (p \ 0.001) reduced from baseline to a score of 2 at the end of phase 1, with a score of 1 reported at the end of phase 2 [65]. At the end of phase 1, the median Alcohol Craving Score was also significantly (p \ 0.01) reduced from baseline in nonabstinent patients to a score of 6, although this score was significantly (p \ 0.001) higher than that seen among patients who were abstinent. Following the change in treatment regimen to six divided doses per day, 26 of the 37 nonresponders (70 %) achieved and maintained abstinence during phase 2, and the median Alcohol Craving Score was significantly (p \ 0.005) reduced from the end of phase 1 to a score of 2 [65].

5.2.4 Additional Trials 5.2.4.1 Noncomparative Study A large (n = 179) noncomparative, multicentre study enrolled patients with mild to severe alcohol dependence (DSM-III-R criteria) [64]. Patients received sodium oxybate 50 mg/kg/day in three divided doses for 24 weeks [64]. Of the 109 evaluable patients, 84 (77 %) became abstinent and maintained abstinence throughout the study [64]. Abstinence was maintained 6 months and 1 year after discontinuation of sodium oxybate in 43 and 30 patients, respectively [64]. Mean Alcohol Craving Scale scores were significantly (p \ 0.001) reduced from baseline to study end in the entire study group (from 9.01 at baseline to 3.72 at study end), in the subgroup of abstinent patients (from 9.16 to 3.09) and in the subgroup of patients who achieved, but did not maintain, abstinence (from 8.51 to 5.75) [64]. However, at study end, mean Alcohol Craving Scale scores were significantly (p \ 0.01) higher in patients who did not maintain abstinence than in abstinent patients [64]. 5.2.4.2 Effects of Greater Dose Fractioning Greater fractioning of the sodium oxybate dosage appeared to improve abstinence rates in patients who did not respond to the conventional fractioning regimen, according to the results of an open-label study [65]. The study included 115 patients with alcohol dependence (DSM-III-R criteria) who received sodium oxybate 50 mg/kg in three divided doses for 8 weeks (phase 1) [65]. Patients who were abstinent continued to receive this sodium oxybate regimen for a further 8 weeks (n = 78), whereas nonabstinent patients (n = 37) received sodium oxybate 50 mg/kg in six divided doses for 8 weeks (phase 2). The baseline median Alcohol Craving Score was 10 in

5.2.4.3 In Patients with Chronic, Treatment-Resistant Alcohol Dependence Two studies examined the use of long-term treatment with sodium oxybate alone (n = 35) [66] and in combination with disulfiram (n = 52) [67] in patients with chronic, treatment-resistant alcohol dependence. Patients had alcohol dependence (DSM-IV [66] or DSM-IV-TR [67] criteria) [with or without psychiatric comorbidity] and were resistant to treatment [66] or specifically to treatment with sodium oxybate [67]. Treatment resistance was defined as at least two periods of treatment in the preceding 2 years with relapse into alcohol abuse during the last treatment period, and the presence of multiple psychosocial or environmental problems within the past 2 years [66, 67]. Patients initially received sodium oxybate 50 mg/kg/day (in three divided doses) for 7 days (to facilitate cessation of alcohol consumption and relieve alcohol withdrawal symptoms) [66, 67]. The sodium oxybate dosage was then adjusted up to a maximum dosage of 100 mg/kg/day (in either three or six divided doses) [66, 67], with disulfiram 400 mg/day coadministered in the combination therapy study [67]. Patients were followed for up to 6 months [67] or 1 year [66]. Of the 35 patients receiving sodium oxybate alone, 21 (60 %) completed the treatment protocol and were considered responders [66]. Of these 21 responders, 4 were full responders (i.e. they had complete abstinence and good social adjustment) and 5 were partial responders (i.e. they reduced their alcohol intake but did not achieve abstinence). After 1 year of follow-up, 12 of the 35 patients (34 %) were still receiving sodium oxybate therapy [66]. Of 52 patients receiving combination therapy with sodium oxybate and disulfiram, 34 patients (65.4 %) completed the treatment programme and were considered responders [67]. The remaining 18 patients (34.6 %) left

74

the treatment programme and were considered nonresponders. Patients stayed in treatment significantly (p \ 0.001) longer when they were treated with sodium oxybate plus disulfiram than during their last unsuccessful treatment with sodium oxybate alone. When the number of days of complete abstinence was considered, 36, 12 and 4 patients stayed in treatment for a longer time, for a shorter time and for the same time, respectively, with combination therapy than during their last unsuccessful treatment with sodium oxybate alone (p \ 0.0001) [67]. 5.2.4.4 In Patients with Psychiatric Co-Morbidities The efficacy of sodium oxybate was examined in alcoholdependent patients with (n = 28) or without (n = 20) a psychiatric co-morbidity (DSM-IV-TR criteria) [68]. Psychiatric co-morbidities included borderline personality disorder (n = 9), anxiety disorder (n = 6), major depressive disorder (n = 6), bipolar disorder (n = 3), narcissistic personality disorder (n = 3) and obsessive compulsive disorder (n = 1). Patients received sodium oxybate 50 mg/ kg/day in three divided doses for 12 weeks. The primary endpoint was the maintenance of abstinence [68]. At the end of the study, abstinence had been maintained by 50 % of patients with psychiatric co-morbidities and by 45 % of patients without psychiatric co-morbidities [68]. At the end of treatment, there were no significant differences between patients with and without psychiatric comorbidities in terms of mean daily alcohol intake (2.08 vs. 2.11 U/day) or relapse into heavy drinking (10.7 vs. 10.0 % of patients). However, 11 patients with a psychiatric co-morbidity developed a craving for sodium oxybate at the end of treatment (see Sect. 6.2) [68]. 5.2.4.5 According to Lesch Alcoholism Typology An open-label, multicentre, pilot study included 48 alcoholdependent patients (DSM-IV-TR criteria) who had completed detoxification and had been abstinent for at least 2 days and no more than 7 days; patients with a previously diagnosed psychiatric disorder (DSM-IV-TR criteria) could not be receiving long-term treatment for the disorder [69]. Patients were classified into Lesch type I (n = 11), II (n = 12), III (n = 14) or IV (n = 11) groups and received sodium oxybate 50 mg/kg/day in three divided doses for 12 weeks. The primary endpoint was the maintenance of abstinence [69]. After 12 weeks of sodium oxybate treatment, continuous abstinence had been maintained in 54.5, 50.0, 57.1 and 27.3 % of patients in Lesch type I, II, III and IV groups, respectively, nonabstinence was seen in 45.5, 25.0, 35.7 and 63.6 % of patients, and a relapse into heavy drinking was seen in 9.1, 8.3, 14.3 and 9.1 % of patients [69]. No significant differences were seen between the Lesch groups in terms of these results [69].

G. M. Keating

Alcohol Craving Scale scores were significantly (p \ 0.05) reduced from baseline in all four Lesch groups, regardless of whether patients were abstinent or not, although no such reduction was seen in patients in Lesch group II who were not abstinent [69].

6 Tolerability and Safety Data regarding the tolerability and safety of oral sodium oxybate were obtained from the clinical trials discussed in Sect. 5. Results of an additional open-label study examining the risk of craving or abuse in different populations of alcohol-dependent patients are also discussed [70]. Data were also obtained from pooled analyses of phase III and IV study data in 368 inpatients being treated for alcohol withdrawal syndrome with sodium oxybate 50–150 mg/kg/ day for a mean 7.09 days and 732 outpatients with alcohol dependence who received sodium oxybate 50–100 mg/kg/ day for a mean 132.2 days for the maintenance of abstinence [37]. 6.1 General Tolerability Profile Oral sodium oxybate was generally well tolerated when used for the treatment of alcohol withdrawal syndrome or for the maintenance of abstinence. Among patients with alcohol withdrawal syndrome who received short courses of sodium oxybate, the most commonly reported adverse events included dizziness [52, 55], vertigo [53, 54], drowsiness [54], nausea [53, 55], diarrhoea [53, 55, 56] and gastric upset [56]. Adverse events generally occurred after the first dose of study drug [52, 54, 56], were of mild severity [52, 56] and resolved quickly [52, 54, 56]. In the active comparator trials, vertigo and/or drowsiness occurred in 19 % of sodium oxybate 50 mg/kg/day recipients and in 36 % of diazepam recipients [54], and vertigo was reported by 9 of 33 sodium oxybate 50 mg/kg/ day recipients (17 episodes), 17 of 32 sodium oxybate 100 mg/kg/day recipients (32 episodes) and 7 of 33 clomethiazole recipients (9 episodes) [53]. Seizures were reported in one sodium oxybate 100 mg/kg/day recipient (on day 3) and in one clomethiazole recipient (on day 1) [53]. In this study, one sodium oxybate 100 mg/kg/day recipient discontinued the study on day 4 and was found in the street 12 h later disoriented to place and situation [53]. In the pooled analysis of patients with alcohol withdrawal syndrome, transient, mild vertigo was reported in 16.0 % of sodium oxybate recipients, particularly after the first dose [37]. Other adverse events included diarrhoea (1.4 % of patients), rhinitis (0.8 %), nausea (0.5 %), headache (0.5 %), dry mouth (0.3 %) and seizures (0.3 %) [37].


Among alcohol-dependent patients who received longer-term sodium oxybate to maintain abstinence, the most commonly reported adverse events included dizziness [56, 58, 59], vertigo [58, 60, 61, 63, 64], headache [58, 59, 63], sleepiness/somnolence [59, 64], a ‘sense of drunkenness’ [63] and tiredness [61, 64]. Adverse events were usually reported after the first morning dose of sodium oxybate on the first few days of treatment [56, 58] and were transient [56, 58, 61, 63]. For example, dizziness usually occurred following administration of the first dose of sodium oxybate, and resolved spontaneously within 15–30 min [10]. Among sodium oxybate recipients who did not maintain abstinence, additional sedative effects, which would reflect an interaction between sodium oxybate and alcohol, were not reported [63, 68]. In the large, placebo-controlled GATE 2 trial, treatmentrelated adverse events were reported in 9.1 % of sodium oxybate recipients and in 6.9 % of placebo recipients; adverse events were mainly of mild to moderate severity [59]. There was no significant difference between sodium oxybate and placebo recipients in the incidence of the most commonly reported treatment-related adverse events, including dizziness (5.2 vs. 4.4 %), nausea (1.3 vs. 2.5 %), vomiting (1.3 vs. 0.6 %), somnolence (1.3 vs. 0 %), flatulence (0.6 vs. 0.6 %), headache (0.6 vs. 0.6 %), upper abdominal pain (0.6 vs. 0 %), hypoaesthesia (0.6 vs. 0 %), depression/suicidal (0.6 vs. 0 %) and throat irritation (0.6 vs. 0 %). Two serious treatment-related adverse events were reported in sodium oxybate recipients and one serious treatment-related adverse event was reported in placebo recipients. No significant changes in vital signs, ECG recordings, physical examination findings or laboratory parameters, apart from expected reductions in alcohol biomarkers, were seen in sodium oxybate or placebo recipients during the GATE 2 trial [59]. In one of the active comparator trials, adverse effects resulting in withdrawal were reported in 7 % of sodium oxybate recipients (vertigo), 7 % of naltrexone recipients (nausea, vomiting) and 12 % of disulfiram recipients (dizziness, asthenia, somnolence) [60]. The incidence of adverse events was significantly higher among patients receiving combination therapy with sodium oxybate plus naltrexone than in those receiving sodium oxybate alone (50 vs. 10 %; p = 0.009), with adverse events also reported in 23 % of patients receiving naltrexone alone [63]. Among patients receiving sodium oxybate alone, naltrexone alone or sodium oxybate plus naltrexone, vertigo was reported in 10.0, 0 and 27.7 %, respectively, headache was reported in 5.0, 0 and 11.1 %, ‘sense of drunkenness’ was reported in 5.0, 0 and 0 %, nausea was reported in 0, 11.8 and 22.2 %, reduced appetite was reported in 0, 0 and 5.5 %, sweating was reported in 0, 0 and 5.5 %, sedation was

75

reported in 0, 5.9 and 5.5 %, and ‘uncertainty in daily activities’ was reported in 0, 0 and 5.5 % [63]. Treatment was discontinued because of adverse events in 5.0 % of sodium oxybate recipients, 5.9 % of naltrexone recipients and 16.7 % of sodium oxybate plus naltrexone recipients [63]. Panic attacks, anxiety and moderate ‘hyperexcitability’ were reported in patients receiving naltrexone plus escitalopram for the maintenance of abstinence [62]. By contrast, these symptoms were reported as being significantly reduced in patients receiving sodium oxybate plus naltrexone and escitalopram [62]. Other adverse events reported in patients receiving naltrexone plus escitalopram or sodium oxybate plus naltrexone and escitalopram included hyperalgesia (41 vs. 37 % of patients), mild gastrointestinal disorders (4.2 vs. 3.3 %), headache (3.3 vs. 3.1 %) and nonsignificant weight loss (1.8 vs. 1.6 %). In terms of hyperalgesia, scores for present pain intensity (3.7 vs. 0.9) and total pain rating index (33.7 vs. 9.2) were significantly (p \ 0.001) higher in patients receiving sodium oxybate plus naltrexone and escitalopram than in those receiving sodium oxybate plus escitalopram [62]. In the pooled analysis of patients with alcohol dependence, transient, mild vertigo and/or drowsiness was reported in 21.7 % of sodium oxybate recipients, particularly at the beginning of treatment [37]. Other adverse events included headache (0.4 % of sodium oxybate recipients), myalgia (0.3 %) and insomnia (0.1 %) [37]. 6.2 Potential for Abuse, Craving and Withdrawal Symptoms The risk of sodium oxybate abuse appears low when it is administered at the recommended dosage with the supervision of a designated family member under continuous strict medical surveillance. For example, there were no reports of abuse [37] or withdrawal symptoms following the discontinuation of sodium oxybate [37, 54] among patients who received sodium oxybate for the treatment of alcohol withdrawal syndrome. Moreover, no withdrawal symptoms on discontinuation of sodium oxybate were reported in patients receiving sodium oxybate for the maintenance of abstinence in three randomized studies [59, 61, 63]. Among patients receiving sodium oxybate for the maintenance of abstinence, no craving for sodium oxybate was reported in two randomized studies [59, 61], although craving was reported in two sodium oxybate recipients in another study [63]. In a noncomparative study, 11 of 109 sodium oxybate recipients (10.1 %) developed craving for the drug and increased their dosage to 6–7 times the recommended dosage in order to obtain anxiolytic and hypnotic effects [64]. No clinical evidence of sodium oxybate

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addiction (e.g. abuse, misuse, overdosage) was seen in the GATE 2 trial [59]. At the end of sodium oxybate treatment, 11 of 28 patients (39.3 %) with alcohol dependence and a psychiatric co-morbidity developed a craving for sodium oxybate, including 6 of the 14 patients with a psychiatric co-morbidity who had maintained abstinence throughout the study [68]. In isolated episodes, three patients with borderline personality disorder abused sodium oxybate, taking dosages 2–3 times the prescribed dosage and resulting in sedation and sleepiness. None of the patients in this study developed withdrawal symptoms when sodium oxybate was discontinued [68]. In the pilot study examining the use of sodium oxybate according to Lesch Alcoholism Typology, craving for sodium oxybate occurred in 18.2, 25.0, 35.7 and 9.1 % of patients in Lesch type I, II, III and IV groups, respectively [69]. Isolated episodes of sodium oxybate abuse were reported in one patient in the Lesch type 2 group (8.3 %) and in two patients in the Lesch type III group (14.2 %); these patients had diagnoses of borderline personality disorder [69]. The risk of sodium oxybate craving and abuse was also examined in patients with alcohol dependence alone (n = 14), patients with alcohol dependence and sustained full remission from heroin (n = 10) or cocaine (n = 13) or patients with alcohol dependence who were also undergoing methadone maintenance treatment (n = 10) [70]. Patients had completed detoxification treatment from alcohol and received sodium oxybate 50 mg/kg/day in three divided doses for 3 months. Craving for sodium oxybate was reported in significantly more patients in remission from heroin than in patients with alcohol dependence alone, patients in remission from cocaine or patients receiving methadone (90.0 vs. 14.3, 38.5 and 0 %; p B 0.01). None of the patients with alcohol dependence alone or receiving methadone abused sodium oxybate, whereas abuse of sodium oxybate occurred in 60 and 38.5 % of patients in remission from heroin or cocaine, respectively (both p \ 0.05 vs. patients with alcohol dependence alone or receiving methadone). Patients who abused sodium oxybate increased the dosage to 2–3 times the prescribed dosage [70]. The pooled analysis reported that among patients with alcohol dependence, 2.6–10.1 % of patients had craving for sodium oxybate, and increased the dosage up to 6–7 times the recommended dosage [37]. When the correct sodium oxybate dosage was reinstated, some patients reported symptoms of mild anxiety and insomnia, lasting &1 week, [37]. Among patients who adhered to the recommended treatment regimen, no withdrawal symptoms were reported upon discontinuation of sodium oxybate [37].

G. M. Keating

7 Dosage and Administration In Italy, sodium oxybate is approved as an adjuvant therapy for the control of alcohol withdrawal syndrome, for the initial stage of multimodal management of alcohol dependence, and for the prolonged management of alcohol dependence resistant to other therapies [9]. In Austria, sodium oxybate is approved for the treatment of acute alcohol withdrawal syndrome (for up to 7 days) in patients with chronic alcohol abuse, and as part of long-term maintenance therapy under careful medical supervision and in combination with psychosocial support [10]. In Italy, a sodium oxybate dosage of 50 mg/kg/day is recommended for the treatment of acute alcohol withdrawal syndrome and the initial multimodal management of alcohol dependence (i.e. the initial 60 days) [9]. For the prolonged management of alcohol dependence (i.e. after the initial 60 days), the minimum recommended dosage of sodium oxybate is 50 mg/kg/day, with a maximum dosage of 100 mg/kg/day [9]. In Austria, a sodium oxybate dosage of 50 mg/kg/day is recommended, which can be increased up to 100 mg/kg/ day in patients with severe alcohol withdrawal syndrome [10]. It is recommended that sodium oxybate be administered in three divided doses [9, 10], with an interval of C4 h between doses [9]. Sodium oxybate should be used under direct medial surveillance [9, 10]. Elderly patients receiving sodium oxybate should be closely monitored for impaired motor and/or cognitive function [10]. Sodium oxybate is not recommended for use in patients aged B18 years [10]. Contraindications to the use of sodium oxybate include patients with epilepsy or epileptiform seizures or receiving antiepileptic drug therapy [9, 10]. In Italy, sodium oxybate is also contraindicated in patients with severe organic or mental disease, in patients with current or previous opioid addiction and in pregnant or lactating women [9]. In Austria, sodium oxybate is also contraindicated in patients addicted to CNS depressants (e.g. sedatives, hypnotics) [10]. Local prescribing information should be consulted for further information regarding contraindications, warnings and special precautions for use pertaining to sodium oxybate.

8 Place of Sodium Oxybate in the Management of Alcohol Withdrawal Syndrome and in the Maintenance of Abstinence The goals of treatment in alcohol withdrawal syndrome are to decrease symptom severity, prevent the emergence of


more severe withdrawal symptoms (e.g. delirium tremens, seizures) and facilitate patient entry into a treatment programme designed to achieve and maintain long-term abstinence from alcohol [7]. In Europe, benzodiazepines or clomethiazole are often used for the treatment of alcohol withdrawal syndrome [7, 8]. Benzodiazepines are most commonly used to manage alcohol withdrawal in the community, with clomethiazole not recommended for use in community-based assisted withdrawal because of the risk of overdose (which may be associated with fatal respiratory depression [8]) and misuse [5]. Potential drawbacks of benzodiazepines include adverse effects such as excess sedation, memory deficits and respiratory depression in patients with liver impairment, as well as the potential for abuse and dependence [7]. Various other non-benzodiazepine GABAergic compounds have been investigated in the treatment of alcohol withdrawal syndrome, including sodium oxybate, baclofen, carbamazepine and tiagabine [7, 8]. Results of clinical trials indicate that sodium oxybate alleviates the symptoms of alcohol withdrawal syndrome, with a rapid onset of effect (Sect. 5.1). Sodium oxybate 50 mg/kg/day was at least as effective as diazepam and clomethiazole in the treatment of alcohol withdrawal syndrome (Sects. 5.1.2 and 5.1.3). In patients with severe alcohol withdrawal syndrome, sodium oxybate reduced withdrawal symptoms to a greater extent than diazepam at multiple time points, with between-group differences seen as early as day 2 for some symptoms [43]. Preliminary results are also available from a randomized, double-blind, multicentre study (GATE 1) comparing sodium oxybate (n = 61) with oxazepam (n = 65) in alcohol-dependent patients with severe alcohol withdrawal syndrome [71]. Significant reductions in withdrawal symptoms and craving for alcohol were reported in both sodium oxybate and oxazepam recipients, with no significant between-group differences (p-values not reported) [71]. The traditional treatment goal in alcohol dependence is to achieve abstinence and prevent or reduce relapse [5, 72]. Pharmacological agents approved in the EU to support abstinence include naltrexone [73], disulfiram [74] and acamprosate [75]. Naltrexone is an opioid antagonist, disulfiram is an alcohol deterrent compound and acamprosate is a synthetic GABA analogue [73–75]. Nalmefene, an opioid system modulator, was also recently approved in the EU for as-needed use to reduce alcohol consumption in alcoholdependent patients with a high drinking risk level [76]. Sodium oxybate has been used successfully in Italy and Austria to maintain abstinence in alcohol-dependent patients since the 1990s [8, 37]. Indeed, sodium oxybate is the only pharmacological agent currently approved for use in both alcohol withdrawal syndrome and for the maintenance of abstinence.

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The European Medicines Agency guideline on the development of medicinal products for the treatment of alcohol dependence recommends full abstinence as the primary endpoint in clinical trials [72]. Although only one of the randomized controlled trials examining the use of sodium oxybate in the maintenance of abstinence specified a primary endpoint (cumulative abstinence duration in the GATE 2 trial [59]), all of the studies assessed the abstinence duration and/or rate (Sect. 5.2). Mixed results were seen in trials comparing sodium oxybate with placebo for the maintenance of abstinence (Sect. 5.2.1). For example, in the large GATE 2 trial, the difference between sodium oxybate and placebo recipients in the cumulative abstinence duration was of borderline statistical significance [59]. A possible explanation for this result is that mean/median sodium oxybate dosages in this trial were lower than the minimum recommended dosage, with 66 % of patients receiving a sodium oxybate dosage of less than 50 mg/kg/day [59]. Alcohol craving was significantly lower with sodium oxybate than with placebo in two of the placebo-controlled trials, with no significant difference seen between sodium oxybate and placebo recipients in the GATE 2 study. Across individual active comparator trials, sodium oxybate was at least as effective as naltrexone or disulfiram in the maintenance of abstinence (Sect. 5.2.2). Alcohol craving was also significantly lower with sodium oxybate than with naltrexone or disulfiram in one study [60]. It should be noted that these trials were of small size and may be underpowered to detect between-group differences. A recent Cochrane review concluded that sodium oxybate appears better than naltrexone and disulfiram in maintaining abstinence and preventing craving in alcohol-dependent patients [29]. Psychiatric co-morbidities are common in patients with alcohol dependence [68]. The maintenance of abstinence achieved with sodium oxybate appears to be unrelated to the presence of psychiatric co-morbidities (Sect. 5.2.4.4) [68]. However, some patients with alcohol dependence and psychiatric co-morbidities developed craving for sodium oxybate, with sodium oxybate abuse also seen in some patients with Axis II diagnoses such as borderline personality disorder (Sect. 6.2). Given that a proportion of patients (&30–40 % [34]) do not respond to monotherapy with sodium oxybate, the efficacy of combining sodium oxybate with an agent with a differing mechanism of action, such as naltrexone, has been investigated (Sect. 5.2.3). Abstinence rates were higher and alcohol consumption was lower among patients receiving sodium oxybate plus naltrexone than in patients receiving sodium oxybate or naltrexone alone. However, as expected, the incidence of adverse events was higher with sodium oxybate plus naltrexone than with sodium oxybate alone (Sect. 6.1).

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Treatment with sodium oxybate was generally well tolerated both when administered as a short course to patients with alcohol withdrawal syndrome and in the longer term for the maintenance of abstinence (Sect. 6.1). Transient dizziness was the most commonly reported adverse event in the large, placebo-controlled GATE 2 trial. Importantly, no additional sedative effects were seen among sodium oxybate recipients who did not maintain abstinence from alcohol. Withdrawal symptoms were not reported on discontinuation of sodium oxybate among patients receiving the recommended dosage (Sect. 6.2). However, there have been reports of craving for sodium oxybate, leading some patients to increase their sodium oxybate dosage (Sect. 6.2). Indeed, a common concern pertaining to the use of sodium oxybate in alcohol dependence is its potential for abuse, given that in some countries illicit GHB is abused as a recreational drug for its euphorigenic and relaxant properties [15, 34]. Use of illicit GHB to facilitate sexual assault has also been highlighted in the media, although it appears that alcohol and benzodiazepines are associated with sexual assault more commonly than GHB [13, 15, 77]. Despite concerns over abuse potential, it has been demonstrated that when administered with the supervision of a designated family member under continuous strict medical surveillance, without exceeding the recommended dosage of 50–100 mg/kg/day, the risk of sodium oxybate abuse is low [28] (Sect. 6.2). The risk of misuse or diversion of sodium oxybate is also minimized by the fact that in Italy and Austria, sodium oxybate is usually only prescribed to outpatients by centres specializing in alcoholism or addiction [8]. Indeed, the retrospective, multicentre GUM (GHB Use and Misuse) study analysed data from 485 alcohol-dependent patients treated with sodium oxybate by Italian rehabilitation centres between 2005 and 2007 [78]. Preliminary results indicate that sodium oxybate suppressed withdrawal symptoms, with 81 % of patients undergoing successful rehabilitation. At 6 and 12 months, 76 and 78 % of patients were abstinent. Misuse or abuse occurred in 12 % of treatments and cases of intoxication or overdose were very rare [78]. As mentioned previously, cases of sodium oxybate abuse (mostly isolated episodes) were reported in patients with alcohol dependence and borderline personality disorder, and were also reported in alcohol-dependent patients who were in remission from heroin or cocaine addiction (Sect. 6.2), suggesting that these patients may not be suitable candidates for sodium oxybate therapy [68, 70]. Additional placebo-controlled, multicentre studies are needed to confirm these findings [70]. The generally low risk of sodium oxybate abuse in patients being treated for alcohol dependence is supported

G. M. Keating

by the findings of a safety overview of the use of sodium oxybate (XyremÒ) for the treatment of narcolepsy [32] (Sect. 2.3). This safety overview noted that pharmaceutical sodium oxybate can differ from illicit GHB in terms of its accessibility, purity and dosing, and concluded that concern that the risk profile of sodium oxybate may be the same as that of illicit GHB is not supported by the available data [32]. A solid formulation of sodium oxybate is currently under development and has the potential to further reduce the risk of sodium oxybate misuse [8]. A recent pharmacodynamic study in healthy volunteers found that the solid formulation of sodium oxybate is associated with less sedation than alcohol (Sect. 4) [46]. In conclusion, results of randomized controlled trials indicate that sodium oxybate was at least as effective as diazepam and clomethiazole in patients with alcohol withdrawal syndrome, rapidly alleviating symptoms, and was at least as effective as naltrexone or disulfiram in maintaining abstinence in alcohol-dependent patients. Sodium oxybate was generally well tolerated. Although certain patient groups (e.g. alcohol-dependent patients with borderline personality disorder or who are in remission from heroin or cocaine addiction) appear to be at increased risk of abusing sodium oxybate, the risk of sodium oxybate abuse is generally low when it is administered to alcoholdependent patients at its approved dosage, under the supervision of a designated family member and with continuous strict medical surveillance. Thus, sodium oxybate is a useful option for the treatment of alcohol withdrawal syndrome and for the maintenance of abstinence in alcohol-dependence.

Data selection sources: Relevant medical literature (including published and unpublished data) on sodium oxybate was identified by searching databases including MEDLINE (from 1946) and EMBASE (from 1996) [searches last updated 18 November 2013], bibliographies from published literature, clinical trial registries/databases and websites. Additional information was also requested from the company developing the drug. Search terms: Sodium oxybate, sodium hydroxybutyrate, gamma hydroxybutyrate, gamma hydroxybutyric acid, Xyrem, alcohol withdrawal, alcohol dependence, substance withdrawal syndrome, alcoholism. Study selection: Studies in patients with alcohol withdrawal syndrome who received sodium oxybate. When available, large, well designed, comparative trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Disclosure The preparation of this review was not supported by any external funding. During the peer review process, the manufacturer of the agent under review was offered an opportunity to comment on this article. Changes resulting from comments received were made by the author on the basis of scientific and editorial merit.


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