CNS Drugs (2018) 32:437–442 https://doi.org/10.1007/s40263-018-0516-6 SHORT COMMUNICATION Baclofen to Prevent Relapse in Gamma-Hydroxybutyrate (GHB)- Dependent Patients: A Multicentre, Open-Label, Non- Randomized, Controlled Trial 1,2 3 2 • • • Harmen Beurmanjer Rama M. Kamal Cor A. J. de Jong 1,2 2,4 Boukje A. G. Dijkstra Arnt F. A. Schellekens Published online: 12 April 2018 The Author(s) 2018 Abstract square analyses, with both per-protocol (PP) and intention- Background Gamma-hydroxybutyrate (GHB) dependence to-treat (ITT) analyses. is associated with a severe, potentially lethal, withdrawal Results GHB-dependent patients treated with baclofen syndrome and relapse rates as high as 60% within 3 months after detoxiﬁcation showed no reduced lapse rates, but of detoxiﬁcation. Baclofen has been shown to decrease reduced relapse and dropout rates, compared with patients self-administration of GHB in mice and reduce relapse in a receiving TAU only (24 vs 50%). While both ITT and PP case series of GHB-dependent patients. Controlled studies analyses revealed similar results, the effectiveness of on the effectiveness of baclofen to prevent relapse in GHB- baclofen prescribed PP was slightly higher than in ITT dependent patients are lacking. analysis. Patients reported overall limited side effects, with Aim The aim of this study was to assess effectiveness of the most frequently reported being feeling tired (28%), baclofen in preventing relapse in GHB-dependent patients. sleepiness (14%) and feeling depressed (14%). No serious Methods This was an out-patient, multicentre, open-label, adverse events were reported. non-randomized, controlled trial in GHB-dependent Conclusions This study showed potential effectiveness of patients (n = 107) in the Netherlands. Treatment as usual baclofen in preventing relapse in patients with GHB (TAU, n = 70) was compared with TAU plus baclofen dependence after detoxiﬁcation. Though promising, future 45–60 mg/day for 3 months (n = 37). Outcome measures studies with longer follow-up and a randomized double- were rates of lapse (any use) and relapse (using GHB on blind design should conﬁrm these ﬁndings before recom- average once a week or more), based on self-report. Side mendations for clinical practice can be made. effects were monitored with a baclofen side-effects ques- Clinical trial registration Netherlands Trial Register with tionnaire. Treatment groups were compared using Chi number NTR4528. Electronic supplementary material The online version of this Key Points article (https://doi.org/10.1007/s40263-018-0516-6) contains supple- mentary material, which is available to authorized users. Baclofen up to 60 mg daily might be effective in preventing relapse and increasing treatment & Harmen Beurmanjer email@example.com adherence in patients with GHB use disorder. Novadic-Kentron, Vught, The Netherlands The use of baclofen up to 60 mg daily in patients 2 with GHB use disorder seems safe, when prescribed Nijmegen Institute for Scientist-Practitioners in Addiction according to the protocol. (NISPA), Nijmegen, The Netherlands GGZE, Eindhoven, The Netherlands Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboudumc, Nijmegen, The Netherlands 438 H. Beurmanjer et al. 1 Introduction 2 Methods In Europe, misuse of gamma-hydroxybutyrate (GHB) has 2.1 Study Design increased over the past decade, particularly in the Nether- lands, Norway, Spain and the UK . GHB originally The effectiveness of baclofen was assessed in a multicen- emerged in the 1990s as an innocent party drug, but later tre, open-label, non-randomized, controlled clinical trial proved to be highly addictive. Precise prevalence rates are (see protocol publication ). After detoxiﬁcation from unknown due to a lack of systematic surveillance on GHB GHB, patients received TAU or TAU combined with use . Physical dependence on GHB can develop within baclofen, based on patient preference. Participants pro- weeks, when used daily . GHB dependence is associated vided written informed consent. The study was approved with a severe, potentially lethal withdrawal syndrome and by the Medical Ethics Committee, Twente Medical School high relapse rates of 60% within 3 months of detoxiﬁcation (METC/14015.am) study number NL40321.044.13. The . However, studies on relapse prevention in GHB study was registered in the Netherlands Trial Register with dependence are lacking. number NTR4528. GHB is a short-chain fatty acid, which is biosyntheti- cally derived from the inhibitory neurotransmitter GABA 2.2 Participants . It occurs naturally in the brain, predominantly in the hypothalamus and basal ganglia [6, 7]. GHB binds to GHB-dependent patients (according to DSM-IV criteria of GABA-A receptors, GABA-B receptors and GHB recep- substance dependence) were recruited at six addiction care tors . It has a rapid onset of action after ingestion, facilities (IrisZorg, Mondriaan, Novadic-Kentron, Tactus, reaching maximum concentration (C ) in a short period Victas and VNN) in the Netherlands, when admitted for max (T = 20–60 min), and a short half-life (T detoxiﬁcation. Inclusion criteria comprised completed max - = 30–60 min). The clinical effects of GHB include seda- GHB detoxiﬁcation, wish for abstinence, continuing out- tion, euphoria and, in higher doses, hypoventilation and patient treatment after detoxiﬁcation, age between 18 and coma; see  for further details. 40 years, and comprehension of Dutch. Exclusion criteria Baclofen might be an adequate substitute for GHB. It is comprised physical contra-indications for baclofen (e.g. a high-afﬁnity GABA-B receptor agonist, similar to GHB liver problems, renal impairment, hypertension, diabetes [10, 11], but with a longer half-life (T = 2–6 h). This has mellitus, seizure disorder and pregnancy), severe psychi- the theoretical advantage of more stable drug-plasma atric conditions (e.g. bipolar disorder, major depression, levels, and subsequent GABA-B activation, with less fre- psychotic disorders and suicidal ideations), use of anxi- quent dosing (i.e. 3 times daily, instead of 12) . Indeed, olytics, stimulants or hypnotics after detoxiﬁcation, or one animal study in mice showed that baclofen reduced previous misuse of baclofen. Of 137 GHB-dependent GHB self-administration . To date, only one case series patients admitted for detoxiﬁcation, 107 were eligible for on baclofen treatment (30–60 mg/day) in GHB dependence participation. Thirty-seven patients received baclofen on has been reported, showing 3-month abstinence in nine out top of TAU; 70 received TAU only. During admission, a of eleven cases . Baclofen has also been shown to physician informed patients about the baclofen study. A increase abstinence rates and reduce craving and anxiety in ﬂowchart is shown in Fig. 1. alcohol-dependent patients [14–18]. However, several studies failed to replicate these effects [19, 20]. These ﬁndings warrant further studies on the potential efﬁcacy of baclofen in the treatment of GHB use disorders. To our knowledge, no clinical studies on the effects of baclofen in GHB use disorders have been published. Here, we investigated the effectiveness of baclofen in recently detoxiﬁed GHB-dependent patients to prevent relapse in an open-label, non-randomized, controlled clinical trial. Speciﬁcally, we tested the hypothesis that patients receiv- ing baclofen on top of treatment as usual (TAU) after GHB detoxiﬁcation have decreased relapse rates compared with patients receiving TAU. Fig. 1 Flowchart of participants included in the study. ITT intention to treat, PP per protocol, TAU treatment as usual Baclofen for GHB-Dependent Patients 439 2.3 Sample Size Calculation 0 = never to 4 = always). Examples are vomiting, nausea and diarrhoea. See Supplementary Table 1 in the electronic Sample size calculation was based on the effectiveness of supplementary material for the complete list. baclofen in alcohol use disorders. Though the literature on baclofen’s efﬁcacy in alcohol use disorders is contradic- 2.6 Analysis tory, several studies do suggest a beneﬁcial response of baclofen versus placebo (abstinence rates 70% vs 20–30%) Demographics were calculated using descriptive statistics [18, 22]. Anticipating a smaller effectiveness in GHB and compared between groups using univariate analysis of dependence (3-month abstinence rates 60 vs 40%) based on variance (ANOVA) and Chi square analyses. Lapse, our previous studies , approximately 30 patients per relapse and relapse including drop-out rates in each group group are needed in order to detect any signiﬁcant effects were compared using Chi square analyses. In contrast to of baclofen, with a = 0.05 and b = 0.80 . the original protocol publication , we only analysed primary outcomes using both intention to treat (ITT) and 2.4 Treatment Intervention per protocol (PP) analyses due to the limited inﬂux of patients receiving baclofen after a prolonged inclusion 2.4.1 Baclofen period (n = 37 instead of n = 80). In the more conservative ITT analyses, all participants receiving baclofen were Participants initially received 15 mg per day, divided over compared with TAU. In the PP analyses, only those par- three doses, which was gradually increased over a period of ticipants receiving baclofen according to the protocol were 10 days to 45 mg daily. When patients reported no or compared with TAU. limited effects of baclofen on anxiety and craving after Though a historical control group was available for 2 weeks without side effects, the dose was increased to a comparison , only the current control group was maximum of 60 mg daily. This dose was maintained for included in the analyses. First, the current control group is 10 weeks. In case of relapse or adverse events, immediate substantially larger than the intervention group, making cessation of treatment was considered to avoid intoxication addition of an extra control group redundant. Second, hazards. Compliance was assessed during weekly meetings relapse rates in the current control group were substantially between the prescribing physician and the patient. lower compared with our historical control group (50 vs 65%, respectively). Finally, the current control group was 2.4.2 Treatment as Usual (TAU) more comparable to the baclofen group in terms of received TAU. Therefore, adding a historical control group All participants received TAU as provided by their addic- to the analyses was considered of no added value. tion treatment centre, including cognitive behavioural All analyses were carried out in SPSS version 21, with therapy with additional treatment for social, psychiatric a \ 0.05 considered signiﬁcant. and medical problems if necessary. 2.5 Outcome Measures 3 Results 2.5.1 Lapse and Relapse 3.1 Demographics Lapse and relapse were measured by self-report on a Patients in the baclofen group were more often male than in questionnaire at 3 months’ follow-up. Lapse was deﬁned as the TAU group, but gender was not related to treatment any use of GHB and relapse as weekly use of GHB during outcome. There were no other differences in demographics, the past 3 months. Patients who were no longer in care at GHB use or psychiatric comorbidity, see Table 1. Of the follow-up were contacted via telephone and e-mail. Those 37 patients receiving baclofen (included in ITT analysis), unavailable for follow-up were considered relapsed. 13 received baclofen according to protocol (included in PP analysis). 2.5.2 Side Effects 3.2 Effectiveness Safety of baclofen was monitored using a baclofen side effects questionnaire, both self-monitored and observed by ITT analysis showed no difference in lapse rates treating physicians. This questionnaire was based on the (v = 0.20, p = 0.885) and relapse rates excluding drop-out side effects of baclofen reported in the literature , (v = 3.29, p = 0.069) in the baclofen-treated group com- containing 21 items with a ﬁve-point Likert scale (range: pared with TAU, see Table 2. In the baclofen group, 440 H. Beurmanjer et al. Table 1 Demographics and GHB use per sub group Treatment as usual (N = 70) Baclofen ? treatment as usual (N = 37) Test statistic p value Male (%) 54 74 v = 4.68 0.030 Age, mean (SD) 28.9 (7.8) 29.5 (7.0) F (1.98) = 0.014 0.905 Employment (%) 31 32 v = 0.01 0.916 GHB use, mean (SD) Months using GHB 58.3 (42.2) 63.5 (43.0) F (1.85) = 0.285 0.595 Months using daily GHB 27.4 (28.2) 41.2 (43.0) F (1.79) = 2.958 0.089 GHB gram daily 55.6 (53.8) 46.1 (40.9) F (1.93) = 0.797 0.374 Interval between doses (h) 1.8 (0.73) 1.84 (0.64) F (1.85) = 0.114 0.736 GHB Gamma-hydroxybutyrate Table 2 Comparison of TAU Baclofen ? TAU Test statistic p value (re)lapse in GHB use in the 3 months after detoxiﬁcation Patient completed follow-up 55 35 between patients prescribed Lapse (any use) 47% (n = 26) 46% (n = 16) v = 0.20 0.885 baclofen (ITT) and patients who Relapse (weekly use) 38% (n = 21) 20% (n =7) v = 3.29 0.069 received treatment as usual Patients including drop-out 70 37 a 2 Relapse 50% (n = 35) 24% (n =9) v = 6.59 0.010 GHB Gamma-hydroxybutyrate, ITT intention to treat, TAU treatment as usual Drop-out is considered relapse in GHB-dependent patients, therefore only relapse is mentioned relapse rates including drop-out as relapse were lower 4 Discussion compared with TAU (v = 6.59, p = 0.010). PP analysis showed no difference in lapse rates (v = 1.99. p = 0.158), This is the ﬁrst case–control study evaluating the effec- but lower relapse rates in the baclofen group when drop-out tiveness of baclofen to prevent relapse in GHB-dependent rates were not included (v = 3.97, p = 0.046) and inclu- patients. Patients receiving baclofen per protocol after ded as relapse (v = 5.31, p = 0.021) compared with TAU, detoxiﬁcation showed reduced relapse rates compared with see Table 3. patients receiving TAU, supported by a similar trend towards beneﬁcial effects of baclofen in the ITT analysis. 3.3 Side Effects Mild tiredness, sleepiness and depressed feelings were reported in the baclofen group as the most relevant side Patients reported overall limited side effects, with the most effects of baclofen. frequently reported being feeling tired (28%), sleepiness These results are comparable with an earlier case series (14%) and feeling depressed (14%). No serious adverse (n = 11) on baclofen treatment in GHB-dependent patients, events were reported. showing 81% abstinence rates during 3 months’ follow-up, without signiﬁcant side effects . Similarly, Fattore et al.  showed prevention of self-administration of GHB in Table 3 Comparison of TAU Baclofen ? TAU Test statistic p value (re)lapse in GHB use in the 3 months after detoxiﬁcation Patient completed follow-up 55 12 between patients prescribed Lapse (any use) 47% (n = 26) 25% (n =3) v = 1.99 0.158 baclofen according to the study Relapse 38% (n = 21) 8% (n =1) v = 3.97 0.046 protocol (PP) and patients who receive treatment as usual Patients including drop-out 70 13 a 2 Relapse 50% (n = 35) 15% (n =2) v = 5.31 0.021 GHB Gamma-hydroxybutyrate, PP per protocol, TAU treatment as usual Drop-out is considered relapse in GHB dependent patients, therefore only relapse is mentioned Baclofen for GHB-Dependent Patients 441 mice when treated with baclofen (0.625 and 1.25 mg/kg). which GHB can be detected as a result of its short half-life Importantly, a lower dosage of baclofen (0.312 mg/kg) did . We relied on self-report measures, with potential not prevent GHB self-administration. There is currently no recall bias, particularly given the open-label design of the consensus on the most appropriate dose of baclofen in study. Compliance with the baclofen treatment was also addiction treatment. In line with the previous case series, assessed by self-report, during weekly meetings between we prescribed a relatively low dosage of baclofen the prescribing physician and the patient. Pill count was not (45–60 mg daily) in comparison with studies on alcohol used. This is a potential confounder of the data, since dependence (up to 300 mg daily ). As higher doses of compliance is considered highly relevant for the effec- baclofen might be more effective, future studies on tiveness of baclofen. Finally, follow-up duration was baclofen effectiveness in GHB dependence should also 3 months after detoxiﬁcation, which makes drawing con- study higher doses of baclofen. However, caution is war- clusions about long-term effects impossible. Fourth, side ranted as data about safety of high-dose baclofen are effects were not measured in the TAU group, therefore limited. reported side effects cannot be solely attributed to baclo- GHB, baclofen and alcohol share a similar pharmaco- fen. Many of the reported side effects are common in GHB- logical proﬁle. Studies on alcohol dependence have shown dependent patients in general after detoxiﬁcation . that GHB is effective in reducing alcohol craving and Future studies should address long-term efﬁcacy of intake . Therefore, it is conceivable that baclofen baclofen in GHB dependence, using placebo-controlled, should be effective in reducing GHB dependence in view randomized designs in substantially large samples. of its efﬁcacy in reducing alcohol dependence . In light of the longer half-life of baclofen compared with GHB, it can also be speculated that baclofen might be considered a 5 Conclusion substitute for GHB . The currently poor prognosis in GHB dependence and severity of complications might This study showed that baclofen could be a potential can- justify a substitution therapy approach . Recently, didate for preventing relapse in GHB-dependent patients baclofen gained attention for its potential effectiveness in after detoxiﬁcation, particularly when administered strictly the detoxiﬁcation of GHB . One could also suggest according to the protocol. Though promising, future studies using baclofen to ameliorate GHB withdrawal during with longer follow-up and a randomized double-blind detoxiﬁcation, without tapering off completely, in order to design should be conducted to conﬁrm these ﬁndings, prevent relapse. This would likely increase treatment before recommendations for clinical practice can be made. adherence in some patients, preventing them from dropping Compliance with Ethical Standards out of treatment and relapse in GHB use. Given the explorative, non-randomized, open-label Conﬂict of interest Harmen Beurmanjer, Rama M. Kamal, Cor A. J. design of our study, the results need to be interpreted with de Jong, Boukje A. G. Dijkstra and Arnt F. A. Schellekens declare no caution and further studies are needed in order to conﬁrm conﬂicts of interest. our ﬁndings. Several limitations should be considered Funding The Ministry of Health of The Netherlands provided when interpreting the results. First, sample size was limited funding for this study. The funding for open access is provided by the and lower than anticipated. Moreover, patients who chose Radboud University Nijmegen. baclofen treatment might have been more motivated to Informed consent Participants provided written informed consent. achieve full abstinence, adding to the chance of good outcome at follow-up. However, we did observe similar Ethical approval The study was approved by the Medical Ethics ﬁndings to previous animal work and a case series of GHB- Committee, Twente Medical School (METC/14015.am) study num- dependent patients [12, 13]. The observed effectiveness of ber NL40321.044.13. All procedures performed in studies involving human participants were in accordance with the ethical standards of baclofen, despite a limited sample size, does suggest the institutional and/or national research committee and with the 1964 treatment potential of baclofen in patients with GHB use Helsinki declaration and its later amendments, or comparable ethical disorders. Second, TAU was not speciﬁed in the current standards. study. Any variation in TAU between groups might con- found the results. While we have no such indication when Open Access This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International it comes to psychosocial treatment, it is, however, possible License (http://creativecommons.org/licenses/by-nc/4.0/), which per- that some patients in the TAU group were prescribed mits any noncommercial use, distribution, and reproduction in any benzodiazepines on top of their psychosocial treatment. medium, provided you give appropriate credit to the original Therefore, a potential confounding effect cannot be fully author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. ruled out. Third, abstinence was not conﬁrmed using sys- tematic urine or blood tests, due to the narrow timeframe in 442 H. Beurmanjer et al. intake: a preliminary double-blind randomized controlled study. References Alcohol Alcohol. 2002;37(5):504–8. 18. 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