Anton-Proksch-Institute, Vienna and
1 Department of Psychiatry, University Clinic, Vienna, Austria
Received 24 July 2000; in revised form 25 May 2001; accepted 19 July 2001
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ABSTRACT |
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INTRODUCTION |
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-Hydroxybutyrate (GHB) is a neurotransmitter that occurs naturally in the mammalian brain, where it seems to have a role in sleep induction (Van Cauter et al., 1997
). This property was first used in clinical practice over 30 years ago, when GHB was administered as a sedative and anaesthetic. When administered intravenously in the dose range of 50100 mg/kg body wt/day, it is generally well tolerated. GHB has no effect on respiratory function, but it may lead to a slight increase in systolic blood pressure and a decrease in heart rate. Rarely, myoclonia may occur.
GHB has been used in the treatment of alcoholism for withdrawal and in relapse prevention. Oral GHB has been successfully used for the short-term treatment of alcohol withdrawal (Gallimberti et al., 1989; Nimmerrichter et al., 1997
). There is some evidence that it is effective both as an anticraving substance (Maremanni et al., 1996
), and as a support for abstinence during long-term treatment of alcohol-dependent subjects (Addolorato et al., 1996
, 1998
). GHB received regulatory approval for both these indications in Italy in 1993 and has been submitted for similar registration in Austria, Hungary, Portugal and France. The pharmacological profile of GHB with its inhibitory action on the central nervous system, anxiolytic property, and its profound effects on the dopaminergic system is the rationale for using it as treatment for both withdrawal symptoms and controlling ethanol consumption (Cash, 1994
; Maître, 1997
; Agabio et al., 1998
). In the double-blind, placebo-controlled study of Gallimberti et al. (1989), withdrawal symptoms of 11 participants treated with GHB 50 mg/kg body wt were compared to those of 12 participants taking placebo. Di Bello et al. (1995) demonstrated in an open study the effectiveness of GHB in 55% of cases in a dose range from 50 to 150 mg/kg body wt/day. The methodological weaknesses of these studies included the small number of participants, the lack of a control group, and insufficient description of the participants. In the study of Gallimberti et al. (1989) 28% had used illicit drugs in the past. Di Bello et al. (1995) did not describe the previous drug use of their subjects.
The study we report here compares low and high dosage of GHB with clomethiazole (CLO). Both drugs were evaluated for effects on acute withdrawal symptoms, craving for alcohol, and rebound phenomena after treatment discontinuation.
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SUBJECTS AND METHODS |
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Inclusion/exclusion criteria
During the period of the study, 967 patients were admitted to the Anton-Proksch-Institute. Of these, 101 were considered potential participants and were asked for informed consent (all other patients were either already detoxified, pre-medicated, or dependent on substances other than alcohol). Informed consent was given by 98 patients and these were screened. All participants fulfilled at least three DSM-IV (American Psychiatric Association, 1994) and ICD-10 criteria (World Health Organization, 1992
) for the diagnosis of alcohol dependence. The Münchner Alkoholismustest (MALT) (Feuerlein et al., 1979
) was applied to confirm the diagnosis. Only patients with severe alcohol dependence and withdrawal syndrome were eligible for inclusion in the study. The severity of the withdrawal syndrome had to reach
20 points on the Clinical Institute Withdrawal Scale (CIWA-Ar) (Sullivan et al., 1989
; Stuppaeck et al., 1994
), with at least 12 points scored on items 4 (tremor), 5 (sweating), and 11 (nervousness/anxiety), as these were deemed the core symptoms of physical withdrawal, in the following referred to as CIWA-Ar-short. Participants also had to have an elevated
-glutamyltransferase (GGT;
1.3 times the upper normal range) and/or mean corpuscular volume (MCV;
95 fl) and/or relative carbohydrate-deficient transferrin (%CDT) levels (
2.5%) in order to include an objective measure for the severity of the alcohol problem.
Exclusion criteria were: illnesses such as decompensated liver cirrhosis, acute pancreatitis, reduced respiratory function, acute pulmonary or bronchial disease, myocardial infarction during the preceding 6 months and cardiac arrhythmia; dementia, schizophrenia, polysubstance misuse or dependence or use of benzodiazepines and hypnosedatives (all participants underwent urinary drug screening for illegal drugs and sedatives); suspected sleep apnoea syndrome; an allergy to either of the study drugs; epileptic seizures, except those forms occurring exclusively during alcohol withdrawal. A history of delirium associated with alcohol withdrawal was not a reason for exclusion.
Treatments administered
After giving written informed consent, participants were randomized to one of the three treatments by means of a computerized randomization schedule. Patients with severe withdrawal symptoms (20 points on the CIWA-Ar) at admission received the first drug dose after inclusion into the study. In the case of intoxicated participants the first administration was possible after completing screening procedures and only after the blood-alcohol level had dropped to
0.1% (100 mg/dl). At admission and also during the study period, alcohol abstinence was checked by a breathalyser at least once every day. Specially appointed research personnel were responsible for administering the tests and supervising intake of the study medication.
All medications were administered four times a day (at 08.00, 12.00 and 16.00) with double doses in the evening (20.00). Thus, from day 1 (day of admission and start of treatment) to day 5, the daily dosage administered was either 1000 mg of CLO according to the prescribing advice for Austria or 50 mg of GHB/kg body wt (GHB50) or 100 mg of GHB/kg body wt (GHB100). On day 6, participants received only half the daily dose, with the other half of the dose being substituted by placebo. On days 7 and 8, only placebo was given. Placebo was administered either as capsules of identical shape, size, taste and colour, or as a syrup. During the first 5 days, an additional administration of GHB or CLO was allowed at midnight. Participants asking for an additional dose at night were analysed separately, but remained in the study. No other sedative medication was allowed.
Efficacy and safety measures
The primary efficacy variable was reduction of the withdrawal syndrome on the CIWA-Ar compared to the individual baseline level, in the intention-to-treat (ITT) group. We were interested specifically in the main symptoms of physical withdrawal, such as anxiety, sweating and tremor. The severity of the withdrawal syndrome was measured at eight times on day 2, between 07.30 and 14.30, using CIWA-Ar. On days 35, withdrawal symptoms were assessed once, and only the main items constituting withdrawal were assessed, namely items 4 (tremor), 5 (sweating) and 11 (anxiety) of the CIWA-Ar, which we have termed CIWA-Ar-short.
On days 1 and 8, clinical and biological parameters, including electrocardiogram, CDT, MCV, GGT, aspartate aminotransferase (ASAT), and alanine aminotransferase (ALAT) were measured. Side-effects of the study treatment were determined by open questions: the investigator asked the participant how he had been feeling since the last application of the study medication.
Tests administered
The severity of the desire for alcohol was measured using the Lübeck Craving-Risk-Relapse questionnaire (LCRR-1), which includes a visual analogue rating scale for the intensity of craving and verbal information concerning the frequency of craving (Veltrup, 1994). The LCRR-1 craving scale was used to assess a possible increase in craving symptoms during the reduction phase of the study (from day 6 onwards). Details of this analysis will be published elsewhere.
All participants were classified according to Lesch's typology with the Lesch Alcoholism Typology Questionnaire (Lesch et al., 1991) and rated on the Addiction Severity Index (ASI) (McLellan et al., 1980
), which was administered when the patient was recovering from alcohol withdrawal, on day 5.
Additional medication requested was documented daily.
Statistical analyses
A sample size of 30 per group was chosen according to therapeutic experiences with CLO and GHB. Most of the earlier studies with GHB were placebo-controlled without active comparator. In these studies, the coefficient of variation (CV%) in CIWA-Ar scores was ~20%. Thus, it was concluded that, when using 20% CV%, an of 0.05 and a power of 0.8, a difference between treatment groups of 1.5 points according to the CIWA-Ar scale would yield a significant result, if 30 participants per group were evaluated. The primary parameter for the evaluation of efficacy was the effect of the study treatments on the symptoms of withdrawal measured on the morning of day 6 and the detection of possible rebound phenomena after discontinuation of the study treatments on day 8 (measured as an increase in the CIWA-Ar score compared with that of day 6). A statistical analysis was performed using analysis of variance based on the ITT group. The ITT group was defined as those who received at least one dose of the trial medication, and had at least one post-baseline assessment on the primary efficacy variable (CIWA-Ar scale). If the data were not normally distributed or variances were not homogeneous, the non-parametric KruskalWallis H-test was used. For between-group comparisons, multiple comparisons by Nemenyi were used. Two-tailed tests were used throughout, testing for levels of significance at
= 0.05. The secondary parameters were number of drop-outs, additional administration of GHB or CLO in the evening, and sedation. LOCF (last observation carried forward) was used for the primary criterion in the ITT group. Patients diagnosed as Type IV alcoholics according to Lesch et al. (1991) were excluded from the per protocol (PP) group, but not from the ITT group.
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RESULTS |
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All participants showed signs of severe withdrawal (Table 2). The time of the first drug administration was considered as the baseline. At baseline, the participants showed a mean total score (sum of all items of the CIWA-Ar) of 27.1 ± 4.4 SD with no difference between the treatment groups. In the CIWA-Ar-short scale, the mean sum of items (tremor, sweating, and anxiety) (± SD) was 13.0 ± 1.1 in the GHB50 group, 13.4 ± 1.7 in the GHB100 group, and 13.1 ± 1.3 in the CLO group (Table 2
). The differences between groups were non-significant.
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Statistical analysis revealed no differences between either GHB dosages as compared to CLO, nor between the two dosages of GHB, so that the results obtained with these treatment schemes can be considered as equal.
Premature discontinuation.
Six participants in the CLO group discontinued the study (Table 2): one suffered a seizure on day 1, another withdrew his consent also on day 1, one did not respond adequately to therapy and discontinued on day 1, and three discontinued for other non-medical reasons (on days 2, 4 and 5). One patient from the GHB50 group dropped out because of insufficient treatment response on day 4. Four from the GHB100 group discontinued prematurely, two because of insufficient treatment response on day 2, one because of a grand mal seizure on day 3 and one for medical reasons other than withdrawal symptoms on day 4 (Table 2
).
Additional medication. Additional study medication had to be given 25 times; five participants in the CLO group (total of 10 requests), four participants in the GHB50 group (nine requests), and four participants in the GHB100 group (six requests). Thus, administration of GHB at the lower dosage regimen did not lead to more requests for additional administration of medication than in the higher dosage group. Furthermore, there was no increased need for additional medication in either GHB groups, compared to CLO, despite GHB's half-life of 20 min.
Adverse events
Fifty-five participants complained of adverse events (Table 3). The most frequently reported adverse event was vertigo. Here, nine participants in the GHB50 group suffered from 17 attacks of vertigo, 17 participants in the GHB100 group reported 32 attacks and seven participants in the CLO group suffered from nine attacks. Rhinitis, a frequent side-effect of CLO treatment, was reported by four participants in the CLO group, three participants in the GHB100 group and two participants in the GHB50 group. With regard to the time when adverse events occurred, an unequal distribution was identified. More than two-thirds of the events were reported between 20.00 and 24.00 after administration of the evening dose (which was twice as high as the doses administered during daytime). During this 4-h period, 61% of the adverse events in the CLO group were reported, whereas at the same time 63% of all adverse events in the GHB50 group, and 75% of the events in the GHB100 group were reported. Therefore, it is reasonable to assume that the higher rate of adverse events was related to the higher evening dose.
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One participant of the GHB100 group discontinued the study on day 4. After leaving the department, he was found in the street 12 h later, disoriented in place and situation. This patient seemed to respond well to the treatment as the CIWA-Ar score dropped from 32 (maximum score on day 1) to 15 (maximum score on day 2). On the last evaluation on day 4, he scored 2 points (on 6 possible points) on tremor and 2 points on sweating. At this evaluation, he did not show symptoms of anxiety.
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DISCUSSION |
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Pharmacotherapy is only one part of the therapeutic strategy in the treatment of alcoholism. Successful detoxification improves the motivation for further treatment and is an important precondition for relapse prevention (Lesch et al., 1996; Nimmerrichter et al., 1997
). It can also reduce the length of withdrawal and thus the length of hospitalization (Poldrugo, 1997
). A successful pharmacotherapeutic management of withdrawal will therefore promote a patient's active participation in the treatment programme (Lesch, 1992
).
GHB, a putative neurotransmitter or neuromodulator in the mammalian brain, produces a variety of neuropharmacological effects (Cash, 1994; Maître, 1997
; Poldrugo and Addolorato, 1999
), including reduction of ethanol consumption in animals (Agabio et al., 1998
) and in humans (Gallimberti et al., 1992
; Addolorato et al., 1997
, 1998
). Furthermore, it has been shown to be effective in the treatment of alcohol withdrawal in rats (Poldrugo and Snead, 1984
; Agabio et al., 1998
) and in humans (Gallimberti et al., 1989
; Nimmerrichter et al., 1997
). GHB exerts its effects via its own receptor which may be a target of ethanol action (Agabio et al., 1998
; Colombo et al., 1998
).
All participants included in our study had a severe alcohol withdrawal syndrome at baseline, with a CIWA score of 20 points. We showed that GHB at two dose levels (50 and 100 mg/kg body wt) is as effective as CLO in the dose we used (which is lower than the recommended dosage for the treatment of delirium tremens in some other countries). Sedatives administered in doses necessary to treat the alcohol withdrawal syndrome often induce cognitive dysfunction, which can prolong short-term treatment of withdrawal and impair the patient's chances for a subsequent successful long-term treatment of addiction (Lesch and Nimmerrichter, 1993
). In this respect, the use of less impairing substances like GHB may be an advantage (Lesch et al., 1996
).
In all three treatment groups, the withdrawal syndrome did not last longer than 3 days. At the end of day 2, participants showed no more than one or two mild symptoms (such as tremor, sweating or restlessness). Therefore, we believe that acute withdrawal can be treated within 2 or 3 days with effective medication. Subsequently, the medication should be tapered off, so that the patient does not need any sedative medication after 5 or 6 days. When participants in our study were switched from active medication to placebo on days 7 and 8, no rebound withdrawal symptoms occurred.
A short-acting treatment, such as GHB, may carry risks. The participant receiving the higher GHB dose who developed a delirium had discontinued medication for 12 h. There were no physiological symptoms indicating the development of a delirious state as long as he was under continuous medical treatment. The fact that this adverse event developed so fast could be explained by the short half-life of GHB. A longer-acting medication could have protected him.
A short and effective management of withdrawal symptoms not only reduces the inconvenience for a patient, but also saves costs. Furthermore, a successful withdrawal management with an early start of relapse prevention treatment might improve long-term prognosis.
We found no rebound effect on day 8, which indicates that administration of GHB for 5 days does not lead to drug dependence. Nevertheless, GHB is hotly debated as a drug of potential misuse. Addolorato et al. (1996) reported that 10.1% of patients prescribed GHB increased the dose of GHB to up to 67 times the therapeutic level. In addition, craving for GHB in detoxified subjects was noticeable and resulted in misuse of this drug (Addolorato et al., 1997; Galloway et al., 1997
). For the same reason, the FDA banned the over-the-counter sale of GHB in the USA in November 1990 (Anonymous, 1991
). Despite the ban, GHB is still manufactured and sold clandestinely as a street drug, which supposedly increases the risk of intoxication. Thus, it should be noticed that our data collected over a period of 6 days do not apply to mediumor long-term treatment with GHB. Our observations, as well as other reports (Poldrugo and Addolorato, 1999
), indicate that GHB is a safe substance when used under strict medical supervision. The use of GHB for a longer period than detoxification should only take place under strict medical control.
There was no difference in the frequency of side-effects between CLO and GHB 50 mg/kg body wt. However, at the dosage of 100 mg GHB per kg body wt, 17 participants complained of vertigo, against only nine and seven participants in the GHB50 group and in the CLO group, respectively.
During the clinical trial, two participants suffered seizures, one in the CLO group and one in GHB100 group. GHB has been reported to induce absence-like seizures in rats (Aizawa et al., 1997). In man, it is still debatable whether GHB can provoke EEG changes, which clinically resemble non-convulsive epilepsy (Cash, 1994
). In our sample of 98 alcohol-dependent participants, no such petit mal seizures occurred.
It proved unnecessary to administer GHB at higher dosages. GHB showed considerably more side-effects, especially vertigo, at the larger dose of 100 mg/kg body wt. It seems that, for an average adult, single doses of GHB need not exceed 700 mg.
We conclude that GHB is equivalent in efficacy and tolerability to CLO used according to Austrian prescribing advice. In view of the equivalent efficacy of both dosages of GHB and the higher frequency of adverse events after administration of higher dosages, the lower dosage of 50 mg/kg body wt/day has proved sufficient for treating even severe symptoms of alcohol withdrawal.
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ACKNOWLEDGEMENTS |
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FOOTNOTES |
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