Effectiveness and safety of pharmacologic agents for postoperative delirium: a narrative review

Postoperative delirium (POD) is a common and distressing neuropsychiatric complication following major surgery, linked to prolonged hospitalization, increased mortality, and long-term cognitive decline. Despite its widespread clinical use, evidence supporting pharmacologic treatments for established POD remains limited and inconsistent. Recent large-scale studies and clinical guidelines published between 2018 and 2025 reveal that neither traditional antipsychotics like haloperidol nor second-generation atypical antipsychotics like quetiapine, olanzapine, and risperidone significantly improve delirium duration, cognitive recovery, survival, or length of stay compared to a placebo. While these medications do not alter the clinical course of delirium, they may help manage severe agitation when immediate safety is compromised. Other pharmacologic agents also show limited utility. Dexmedetomidine demonstrates minimal benefit, restricted primarily to mechanically ventilated or highly agitated patients. Meanwhile, medications such as melatonin, ramelteon, orexin receptor antagonists, and ketamine have been evaluated mostly for delirium prevention rather than treatment, leaving insufficient evidence to support their use in established POD. Consequently, current international guidelines strongly emphasize supportive, non-pharmacologic care as the primary approach. Pharmacologic interventions should be strictly reserved for short-term behavioral control when severe agitation threatens the safety of the patient or staff. To move forward, future research must utilize standardized definitions, clearer phenotype characterizations, and long-term neurocognitive outcomes to successfully identify specific patient populations that might truly benefit from targeted pharmacologic therapies.