Share on
INTRODUCTION
Alcohol consumption is responsible for 5.9% of all deaths (3.3 million), accounting for 5.1% of the global disease burden [1]. Alcohol Use Disorder (AUD) has a European and US adult population prevalence of 7-10% [1]. Currently, disulfiram, acamprosate (ACM), and naltrexone are medications approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA), while nalmefene has been approved only by EMA for the treatment of AUD [2]. In addition, baclofen has been authorized by the French agency for the treatment of AUD [2, 3], and sodium oxybate (SO) has been approved by the Italian agency for the treatment of alcohol withdrawal syndrome [4]. The actual efficacy of these combined pharmacological therapies raised debate among experts as these drugs yielded contrasting results [5].
SO, or the sodium salt of gamma-hydroxybutyrate, acts directly on the gamma-aminobutyric acid (GABA) system as a GABAB agonist and indirectly through SO-derived GABA [4, 6, 7], and exhibits an alcohol-mimicking effect. Compared to placebo, SO was effective in the treatment of alcohol withdrawal syndrome and in preventing relapses in previously detoxified participants [8].
ACM shows a neuroprotective effect, which can be explained through the antagonistic activity on the N-methyl-D-aspartate (NMDA) glutamate receptor, and subsequent reduction of the excessive intracellular calcium flow [9]. This mechanism improves dysphoria, often identifiable in patients affected by AUD, and indirectly reduces alcohol craving and consumption [10].
So far, the few published studies involving SO in combination with other drugs showed positive results in the maintenance of alcohol abstinence and the prevention of relapse [11-14]. Similarly, limited evidence has been produced about ACM in association with other drugs [10]. However, no study examined the possible efficacy of the combination SO with ACM in patients with AUD. Therefore, our case series aimed to evaluate the outcomes of a combined therapy of SO plus ACM in maintaining alcohol abstinence in a cohort of patients with AUD.
METHODS
We enrolled 48 AUD patients consecutively admitted over 24 months to the Unit of Alcohol Addiction Treatment, SerD, Caserta and in the Centre for the Study and Treatment of Alcohol-Related Diseases, SS. Annunziata Hospital, Cento, Ferrara. AUD was defined according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) criteria [15]. Patients with severe liver and/or renal failure were excluded. After the resolution of the acute phase of alcohol withdrawal syndrome [16], only patients with the persistence of symptoms of alcohol withdrawal were recruited. All recruited patients were treated with oral doses of SO (50-100 mg/kg of body weight, tid), and they needed the treatment with SO for at least 12 weeks. In addition, ACM (666 mg three times daily, reduced in those patients with a body weight <60 kg) was combined with SO for 12 weeks too. Each subject underwent weekly outpatient visits for 12 weeks, recording the degree of abstinence from alcohol and the amount of daily alcohol intake (expressed as standard US drinks; one standard US drink = 12 g of absolute alcohol) [1]. Complete abstinence was assessed based on interviews with patients and their relatives, and by measuring ethyl glucuronide in urine [17]. Laboratory parameters related to alcohol abuse – aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyl transpeptidase (GGT), and mean red blood cell volume (MCV) – were assessed at the beginning and after three months of treatment. An accurate investigation on the amount of abused SO was carried out with the assistance of patients and their family members to whom the SO had been entrusted. In addition to weekly counseling sessions and pharmacological therapy, self-help groups, such as Alcoholics Anonymous and social services, were recommended.
The study was performed in accordance with the ethical standards of the 1975 Declaration of Helsinki, as revised in 2013, and all participants gave verbal informed consent.
Statistical analysis
The characteristics of the study participants were expressed as median and interquartile range (IQR) for quantitative variables (due to the non-normal distribution) and as count and percentages for categorical variables. Sociodemographic and treatment-related variables were compared between participants who were abstinent vs those who were not abstinent at the end of the observation period using the Mann-Whitney U test and the Chi-square or Fisher test, as appropriate. Intra-individual changes in laboratory parameters from the start of treatment to the 12-week visit within the groups of abstinent and not abstinent individuals were assessed through the non-parametric Wilcoxon test for paired samples. All analyses were performed using the IBM SPSS version 25.0 statistical software. All analyses were two-tails, and a p-value <0.05 was defined as statistically significant.
RESULTS
The sample included 48 AUD patients (34 males and 14 females) with a median age of 47.5 years, whose clinical and demographic characteristics are shown in Table 1. Patients who resulted abstinent and those who were not abstinent at the 3-month visit did not differ in terms of age, education, baseline units of alcohol intake, duration of alcohol consumption, and laboratory markers of alcohol misuse, while the former group was more likely to use illegal drugs at the first visit (Table 1).
At the 3-month visit, continuous abstinence from alcohol was maintained by 34 patients (70.8%). During the observation period, all laboratory markers of alcohol misuse significantly decreased both in abstinent and not abstinent patients (Table 2). Concerning side effects (Table 3), 15 (31.3%) patients reported mainly nausea (20.8%), dizziness (8.3%), and abdominal pain (2.1%), without significant differences between abstinent and not abstinent patients. A significantly higher dropout rate was observed in patients who were not abstinent than abstinent (50% vs 5.9%). At the end of treatment, no patient developed cravings or episodes of abuse of SO, and none showed withdrawal symptoms at SO discontinuation. No additional sedative effects due to alcohol/SO interaction were observed in patients failing to maintain abstinence.
DISCUSSION
To our knowledge, this is the first case series that evaluated the outcomes of the combined therapy with SO and ACM for AUD. In particular, the present study suggests that the association of these drugs may be effective in maintaining complete alcohol abstinence in almost 70% of AUD patients. These results align with previous experiences of SO combined with other compounds. Indeed, we previously showed that the degree of abstinence ranged from 68% to 72% in patients treated with SO plus DF [12] and SO plus NTX [11], respectively. Moreover, the therapeutic combination between SO and ACM seems more promising than other pharmacological regimens. For instance, recent studies found that the abstinence rate was about 50% in patients treated with ACM plus NTX, while considering therapies with SO or ACM alone, it did not overcome 40% [18]. Of note, the high number of patients (almost two-thirds of the sample) achieving complete abstinence at the end of treatment exhibited a significant reduction of all laboratory markers of alcohol misuse. In the not abstinent group, we also observed a significant decrease in all laboratory markers of alcohol misuse confirming that the reduction of alcohol intake improved liver function too.
The high potential of the efficacy of this treatment is likely ascribable to the different actions of SO and ACM. These medications affect the two major signaling systems, i.e. GABA and NMDA both involved in AUD. SO has an alcohol-mimicking effect on GABA receptors and acts as a replacement therapy, while ACM is an antagonist of glutamate and modulates the upregulation of the NMDA system.
An important issue to be considered is craving and the potential abuse of SO [6, 7]. In our study none of the treated patients showed craving for SO. It is well known that both abuse of and craving for SO may limit the use of this drug, although clinical trials suggested that these effects are relatively rare at therapeutic doses [7, 19, 20]. Craving and the abuse of SO are more frequent in patients with psychiatric comorbidities or poly-drug use [19, 20]. In the case series herein reported, conversely to previous experience [19], craving and abuse were not documented although about one-third of patients experienced previous or current substance abuse.
A further aspect that needs to be considered is the prescription of SO. In Italy, SO has been used for over 30 years for the treatment of AUD in the absence of specific indications [21]. In 2018 the Italian Drug Agency (Agenzia Italiana del Farmaco, AIFA) modified the clinical prescription of SO leaving only the indication for the treatment of alcohol withdrawal syndrome, removing the indication for maintaining abstinence from alcohol and the prevention of relapse. For this reason, in the guidelines of the treatment of AUD recently published on the Italian National Guidelines System, SO has been included only with the indication for the treatment of alcohol withdrawal syndrome since it is an off-label medication for the maintenance of alcohol abstinence and the prevention of relapse [21]. Indeed, after the resolution of the acute phase of alcohol withdrawal syndrome [16], all reported patients in our case series showed the persistence of symptoms of alcohol withdrawal which allowed the treating physicians to use SO for at least 12 weeks. In favor of the safety and efficacy outside the specifically authorized use for the treatment of alcohol withdrawal syndrome, essential data on the use of SO for maintaining alcohol abstinence and relapse prevention have been recently published. At this regard, a meta-regression analysis showed that SO was more effective in AUD patients with higher severity, and undergone longer treatments [22].
In conclusion, this case series suggests that SO and ACM are safe and may be effective in patients with AUD. Well-designed, controlled clinical trials are needed to establish whether the combination of drugs might become a key step in the therapeutic approach to AUD.
Other Information
Funding
The Authors report no involvement in the research by the sponsor that could have influenced the outcome of this work. FC and RDG receive constant support from the University of Ferrara (FAR 2024 and FIRD 2024 funds).
Conflict of interest statement
The Authors declare no conflict of interest.
Address for correspondence: Fabio Caputo, Centro Universitario per lo Studio ed il Trattamento delle Patologie Alcol-Correlate (PACC), Dipartimento di Medicina Traslazionale, Università degli Studi di Ferrara, Via Luigi Borsari 46, 44121 Ferrara, Italy. E-mail: fabio.caputo@unife.it
Figures and tables
| Characteristics | All (n=48) | Not abstinent (n=14, 29.2%) | Abstinent (n=34, 70.8%) | p-value |
|---|---|---|---|---|
| Age | 47.5 (41.25-54) | 47.5 (41.25-53) | 47.5 (40.75-54.5) | 0.81 |
| Sex (male) | 34 (70.8) | 9 (64.3) | 25 (73.5) | 0.52 |
| Scholarity | 0.11 | |||
| Primary | 19 (39.6) | 4 (28.6) | 15 (44.1) | |
| Secondary | 24(50) | 10 (71.4) | 14 (41.2) | |
| Degree or above | 5 (0.4) | 0 (0 ) | 5 (14.7) | |
| Pre-treatment UA/day | 11.5 (8.25-16) | 11 (8-16) | 11.5 (9-16) | 0.75 |
| Duration of addiction (months) | 18 (10-26.5) | 16.5 (10.75-28.25) | 18 (10-25) | 0.75 |
| Current or past substances use | 0.02 | |||
| Current | 3 (6.3) | 3 (21.4) | 0 (0.0) | |
| Past | 12(25) | 3 (21.4) | 9 (26.5) | |
| Type of substance used | 0.96 | |||
| Heroin | 3 (6.3) | 1 (7.1) | 2 (5.9) | |
| Cocaine | 5 (10.4) | 2 (14.3) | 3 (8.8) | |
| Cannabis | 7 (14.6) | 3 (21.4) | 4 (11.8) | |
| Psychiatric comorbidities | 16 (33.3) | 6 (42.9) | 10 (29.4) | 0.37 |
| Biochemical parameters | ||||
| GGT | 97.5 (55.75-188.75) | 162.5 (59.5-573) | 90.5 (54.5-167) | 0.21 |
| GPT | 39.5 (23.25-78.25) | 46 (30-77.75) | 32 (22-81.5) | 0.11 |
| GOT | 31 (22-78.25) | 51 (29.75-80.75) | 25.5 (20.75-82) | 0.10 |
| MCV | 95.5 (92-102) | 102 (94.75-107.25) | 94.5 (91.8-100) | 0.02 |
| UA: unit of alcohol; GGT: γ-glutamyl transpeptidase; GPT: glutamic pyruvic transaminase; GOT: glutamic oxaloacetic transaminase; MCV: mean red blood cell volume | ||||
| Time 0 | Time 1 | ΔT1-T0 | p-value | ||
|---|---|---|---|---|---|
| GOT | |||||
| Abstinent | 25.5 (20.75-82.0) | 16.5 (14.75-21.5) | -11.5 (- 56.75, -3) | <0.001 | |
| Not abstinent | 51 (29.75-80.75) | 22 (20-36) | -28 (- 44.25, -9.50) | 0.001 | |
| GPT | |||||
| Abstinent | 32 (22-81.5) | 16.0 (13-22.25) | -14.5 (-49, -7) | <0.001 | |
| Not abstinent | 46 (30-77.75) | 26.5 (18.50-36.5) | -19 (-48, -12.5) | 0.001 | |
| GGT | |||||
| Abstinent | 90.5 (54.5-167) | 28 (18.75-33) | -66 (-141.5, -27.25) | <0.001 | |
| Not abstinent | 162.5 (59.5-573) | 56 (28-112.75) | -60 (-468.25, -29.5) | 0.001 | |
| MCV | |||||
| Abstinent | 94.50 (91.75-100) | 88 (86.75-91.25) | -5.50 (-8.25,-4) | <0.001 | |
| Not abstinent | 102 (94.75-107.25) | 95 (90.50-99) | -5.50 (-12.75,-3) | 0.001 | |
| Alcohol (Unit/day) | |||||
| Abstinent | 11.50 (9-16) | 0 (0.0) | -11.5 (-16, -9) | <0.001 | |
| Not abstinent | 11 (8-16) | 2.00 (1.75-3.25) | -9.5 (-13.25, -6) | 0.001 | |
| GGT: γ-glutamyl transpeptidase; GPT: glutamic pyruvic transaminase; GOT: glutamic oxaloacetic transaminase; MCV: mean red blood cell volume. | |||||
| Treatment outcomes | All (n=48) | Not abstinent (n=14, 29.2%) | Abstinent (n=34, 70.8%) | p-value |
|---|---|---|---|---|
| Drop-out | 9 (18.8) | 7(50) | 2 (5.9) | <0.001 |
| Side effects | 15 (31.3) | 5 (35.7) | 10 (29.4) | 0.669 |
| Type of effects | 0.662 | |||
| Nausea | 10 (20.8) | 4 (28.6) | 6 (17.6) | |
| Abdominal pain | 1 (2.1) | 0 (0) | 1 (2.9) | |
| Dizziness | 4 (8.3) | 1 (7.1) | 3 (8.8) |
pdf
