The Emerging Role of Ketamine and Esketamine in the Concurrent Management of Pain and Depression in Cancer Patients: Evidence and Implications for Practice

Cancer patients frequently experience pain and depression, yet current guidelines address these conditions separately and do not recommend a single agent for concurrent management. Ketamine and its S-enantiomer esketamine, through N-methyl-D-aspartate receptor antagonism and glutamate modulation, may offer dual benefit. This paper examined ten clinical studies published between 2018 and 2024 evaluating ketamine and esketamine for concurrent cancer-related pain and depression. Evidence was heterogeneous but promising. Two randomized controlled trials in post-surgical breast and cervical cancer patients demonstrated that intravenous (IV) esketamine and racemic ketamine improved both pain and depression, with esketamine showing greater, longer-lasting benefit. When pain was the primary outcome, results were mixed: IV esketamine provided dual benefit in one trial, whereas racemic ketamine produced variable or nonsignificant effects across IV, intranasal (IN), and oral routes. In depression-focused studies, IV and IN administration consistently improved mood, even without pain relief. Dose-response relationships were observed, with esketamine outperforming ketamine and higher IN dosing yielding stronger antidepressant effects. Adverse effects were generally mild and transient, though cardiovascular, urinary, and cognitive risks remain concerns. With rapid dual action, ketamine and esketamine may serve as valuable adjunctive therapies in palliative care. Further studies should clarify optimal dosing, route, and long-term safety.