The present retrospective observational study described the use of GHB for the treatment of AWS in hospitalized AUD patients diagnosed with liver cirrhosis, thus representing valuable new insights into the pharmacological management of AWS in a clinically frail subgroup.

Long-acting BZDs are known to be the gold standard therapy for AWS [12]. Drugs with shorter half-life, such as short-acting BZDs or GHB, should be chosen in case of hepatic impairment to avoid drug accumulation and potentially life-threatening AEs [13,14,15]. The utility of GHB as a treatment for AWS is largely demonstrated by many studies [7, 16,17,18, 18,19,20,21,22], nevertheless none of them focused the attention on the use of this drug in AUD patients affected by liver cirrhosis. In fact, in the scientific literature, only one case report is described evaluating the use of GHB in a patient affected by liver cirrhosis and concurrent AWS [23]. In their anecdotal description, Caputo et al. concluded that physicians should always consider GHB as a valuable non-BZD GABA-ergic pharmacological option for the treatment of AWS even in AUD patients with a severe liver disease, especially those with alcohol dependence who experienced AWS in the hospital setting. On this regard, a study published in 1996 analyzed the pharmacokinetics changes of GHB in patients affected by moderate and severe hepatic impairment [24], confirming that liver failure can cause many alterations in GHB pharmacokinetics, such as half-life prolongation and clearance reduction, but none of those are sufficient to induce an accumulation of the drug when administered in repeated doses.

Considering the clinical setting of AWS, the efficacy and the safety of GHB were already evaluated in several Italian and Austrian studies. In particular, a single-blind trial comparing GHB versus diazepam did not show a significantly different efficacy of these drugs in suppressing AWS [17], even though GHB reduced anxiety, agitation and current depression more rapidly than diazepam. Other investigations, however, demonstrated that GHB was even more effective than diazepam in treating AWS [25], and equally efficient as clomethiazole [26]. GHB efficacy was further confirmed by treating AWS in almost 300 hospitalized AUD patients affected by different clinical conditions [27]. Nevertheless, these conditions did not include liver impairment. Compared to our sample, in all these studies, GHB was administered at the dose of 50–100 mg/kg divided into three or four daily administrations, and no safety issues were observed. In 2010, a Cochrane systematic review was performed to evaluate the efficacy and safety of GHB for treatment of AWS [7]. Authors included randomized controlled trials and controlled prospective studies evaluating GHB vs placebo or other pharmacological treatments (including diazepam). Of note, there was insufficient randomized evidence to be confident that the effects of GHB and placebo were different, or to determine reliably if GHB was more or less effective than other drugs for the treatment of AWS. In fact, comparing GHB 50 mg with diazepam, the CIWA‐Ar scores for tremor, anxiety and agitation were more often lower for GHB, but the difference was usually not statistically significant. No significant differences were found between the drugs for AEs. To date, despite this cluster of evidence, studies are still limited and investigations including a larger number of patients are needed. In addition, some safety concerns, such as potential development of GHB dependence, have to be more investigated [28]. According to recent literature reviews concerning the management of AUD in patients with alcohol-associated liver disease, GHB may be considered a treatment option when other drugs are deemed as not appropriate but, as confirmed by our evidence, results regarding its use in clinical practice are promising [29, 30]. Additionally, its usefulness has also been demonstrated in maintaining abstinence. In fact, abstinence rates have increased by up to 34% and pharmacovigilance analyses have reported very few adverse side effects and only a few cases of abuse [31].

Based on our clinical practice routine, the use of GHB is influenced by AWS severity, alcohol tolerance and the presence, concomitant or previous, of other substances of abuse, in particular opioids. Similarly, AUD patients diagnosed with liver cirrhosis, affected by more severe AWS and with a higher alcohol tolerance, are more frequently treated with GHB. In particular, we observed that AUD patients who presented higher values of liver impairment were more likely to be treated with GHB. Regarding the use of GHB in patients known to be poly-abusers, concern has been raised regarding the risk of developing GHB addiction, misuse or abuse [32]. Thus, it is important to underline that GHB must always be used in a controlled environment (hospital), under the strict supervision of specialist doctors (clinical toxicologists). In addition, continuous monitoring of clinical parameters, such as CIWA-Ar, MELD, and CPT scores, as well as the severity of AWS, plays a pivotal role in guiding the management of GHB therapy. Ensuring strict control and regular assessment of these parameters is essential for optimizing treatment outcomes and minimizing potential risks associated with GHB administration. In our sample, although with a slightly longer hospital stay, all AUD patients with cirrhosis treated with GHB went through a complete resolution of withdrawal symptoms. However, it is already described in the scientific literature that the early administration of GHB can prevent the worsening of the syndrome [7]. In light of these considerations, the timing of GHB administration can be considered a relevant key point for an appropriate management of AWS. In fact, among the patients managed at our Medical Toxicology Unit who were administered with GHB early during the first day of hospitalization, we observed a significantly lower probability of AWS worsening. The duration of AWS was slightly longer for AUD patients treated with GHB and it is probably due to the more severe syndrome at arrival that required a more intensive and prolonged treatment. Moreover, these patients also had a longer period of stay (> 36 h) in our Medical Toxicology Unit, and this could be related to the necessity to gradually taper the dosage of GHB until complete discontinuation before discharge. From our analysis, in a small percentage of AUD patients, GHB is associated with lower efficacy when it is not administered promptly on the first day of hospitalization. However, in abuser or poly-abuser patients in the presence of pathological cirrhosis, GHB still guarantees good results both in terms of manageability and safety for patients.

Excessive sedation (i.e., drowsiness) is the only AE related to drug administration that occurred in our sample. The onset of this AE required the reduction or the discontinuation of one or more drugs to achieve the complete resolution of the symptom. We tried to identify the risk factors for the onset of excessive sedation. Analyzing our data, we found out that GHB therapy was not related to a higher risk of drowsiness. The data analysis confirmed that the dosage of GHB (mg/Kg/die) was not related to the onset of excessive sedation, not even when the dosage used was higher than the recommended one (50–100 mg/Kg/die). On the contrary, it appeared that the administration of drugs acting on the CNS, such as neuroleptics, methadone, and opioids, was related to a higher risk of excessive sedation. This safety evidence confirms that, if administered in a hospital setting, GHB can be considered a safe therapeutic option, also for frail AUD patients, such as those affected by liver impairments.

We also tried to assess if the administration of withdrawal therapy had any negative impact on liver function. All patients went through an improvement of both scores. This result shows that AWS treatments did not cause liver cirrhosis worsening in both groups. The improvement of MELD values was probably due to the complete alcohol abstention during the hospital stay.

This study has several limitations. The main one is represented by the small sample size and the retrospective nature of the study design. Both these aspects may have led to a poor characterization and an underestimation of GHB usefulness for AWS treatment, both in terms of effectiveness and safety. Moreover, the concomitant use of GHB with other drugs, including benzodiazepines and phenobarbital, does not allow us to draw firm conclusions on GHB efficacy. Furthermore, it was not possible to address if, compared to patients treated with standard therapy (i.e., BZDs), those administered with GHB had a higher decrease of cirrhosis severity scores. Finally, the limited follow-up did not allow to asses if GHB-treated AUD patients were more likely to experience a relapse compared to those treated with standard therapy.

On the other hand, this is the first real-world analysis performed in AUD patients affected by cirrhosis, describing the effect of time and dose of administration of GHB in AWS on several relevant outcomes that may support clinicians in their clinical practice.