Multimodal Pharmacologic Strategies for Chronic Cancer Pain: A Systematic Review

Cancer pain remains inadequately controlled in some patients despite opioid therapy, particularly when neuropathic or mixed pain mechanisms are present. This systematic review evaluated the efficacy and safety of non-opioid or adjuvant analgesics used alongside opioids in adults with chronic cancer pain. MEDLINE, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched for English-language randomized controlled trials published from January 2010 to August 2025. Two reviewers independently selected studies, extracted data, and assessed risk of bias using Cochrane Risk of Bias 2 (RoB 2). Ten trials involving 1,344 participants were included. In one trial, duloxetine was associated with clinically meaningful pain-response rates, although its primary mean pain-score analysis was not statistically significant. Low-dose gabapentin plus imipramine reduced pain and rescue-morphine use. Pregabalin reduced the morphine dose required to maintain pain control in one crossover trial, while other pregabalin studies showed numerical or non-significant benefits. Neither nabiximols trial met its primary efficacy endpoint, and nefopam did not significantly improve pain response or morphine consumption. Risk of bias was low in two trials, raised some concerns in one, and was high in seven. Overall, the evidence remains heterogeneous and insufficient to support a standard multimodal pharmacological regimen. Selected antidepressant and gabapentinoid strategies, particularly in neuropathic cancer pain, may benefit selected patients.