Background: Opioids are essential for pain management in liver transplant (LT) patients but may cause adverse outcomes. Further research is needed to optimize their use and improve post-transplant prognosis.

Objectives: This study examines the impact of high-dose opioid use on post-transplant outcomes.

Methods: This retrospective cohort study analyzed 12,414 adult LT patients (2011–2021) to examine the correlation between opioid use and graft failure. Subgroup analyses identified risk factors, including the impact of hepatocellular carcinoma (HCC) status.

Results: Analysis of the risk of graft failure based on postoperative opioid dosage revealed that, compared to non-users, Level 1 opioid use was not associated with a significantly increased risk (HR, 0.98; 95% CI, 0.63–1.51). However, the risk of graft failure was higher in patients receiving Level 2 (HR, 1.36; 95% CI, 0.91–2.05) and Level 3 opioids (HR, 2.05; 95% CI, 1.40–3.00). Additionally, subgroup analysis based on HCC status demonstrated that, compared to non-users, patients receiving Level 3 opioids had a higher risk of graft failure in the HCC group (HR, 2.55; 95% CI, 1.47–4.42) than in the non-HCC group (HR, 1.69; 95% CI, 1.00–2.86).

Conclusion: High-dose opioid use after LT increases the risk of graft failure in a dose-dependent manner. Effective pain management should include careful opioid dosing and alternative strategies. This approach can help minimize adverse outcomes.