Letter: Pharmacotherapy for Alcohol Dependence in Cirrhosis—By Addressing One Issue Do We Create Another? Authors' Reply

We thank the authors for their thoughtful comments [1] and their careful appraisal of our study [2].

We agree that altered mental status in patients receiving baclofen may not always represent classical hepatic encephalopathy. As the authors note, baclofen itself can cause neurocognitive adverse effects, particularly in susceptible individuals. In patients with cirrhosis, however, distinguishing hepatic encephalopathy from baclofen‐associated encephalopathy in routine clinical practice remains challenging because these conditions often share overlapping clinical manifestations. Furthermore, studies relying on electronic health records and diagnostic codes cannot definitively differentiate between these entities. Even in prospective studies, adjudication may be challenging in the absence of objective biomarkers capable of distinguishing the underlying cause of encephalopathy. We acknowledged this limitation in our manuscript and agree that some degree of outcome misclassification is possible.

We also agree that residual confounding cannot be fully eliminated in observational studies. Important factors such as alcohol consumption, medication adherence, participation in relapse prevention programs and clinician prescribing preferences were not directly captured. Although we employed an active‐comparator design, target trial emulation and extensive propensity score matching to reduce bias, our findings should be interpreted as associations rather than evidence of causality. We agree that adequately powered multicenter randomized trials are needed to further clarify the comparative safety of baclofen and acamprosate in patients with cirrhosis. Until such data become available, carefully designed real‐world studies may provide valuable evidence to inform clinical decision‐making.

Importantly, our intention was not to discourage the use of baclofen in patients with alcohol‐associated cirrhosis. Baclofen remains an important therapeutic option and is supported by randomized trial data in this population. Rather, we sought to identify potential safety signals that may inform individualized treatment decisions. Our findings suggest that clinicians should exercise caution when prescribing baclofen to patients at increased risk of neurocognitive complications, particularly those with a history of hepatic encephalopathy or those receiving concomitant neuroactive medications such as gabapentin.

Ultimately, we share the authors' view that achieving and maintaining abstinence remains the most important modifiable determinant of prognosis in alcohol‐associated cirrhosis. Expanding access to both pharmacologic and psychosocial interventions should remain a priority. Additional prospective studies incorporating detailed alcohol use measures and careful phenotyping of neurocognitive events will be important to further define the role of baclofen and other medications for alcohol use disorder in patients with cirrhosis.

The authors' declarations of personal and financial interests are unchanged from those in the original article [2].

Author Contributions

Yee Hui Yeo: writing – original draft, writing – review and editing. Lorenzo Leggio: writing – review and editing. Juan Pablo Arab: writing – review and editing.

Funding

The authors have nothing to report.

Linked Articles

This article is linked to Yeo et al. papers. To view these articles, https://doi.org/10.1111/apt.70763 and https://doi.org/10.1111/apt.70619.

Yeo Y. H., Leggio L., and Arab J. P., “Letter: Pharmacotherapy for Alcohol Dependence in Cirrhosis—By Addressing One Issue Do We Create Another? Authors' Reply,” Alimentary Pharmacology & Therapeutics 64, no. 4 (2026): 568–569, 10.1111/apt.70784.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.