OBJECTIVE: The present study aimed to compare the effects of suppository diclofenac (an example of NSAIDs) and oral administration of the combination of oxycodone (an example of an opioid) and acetaminophen in managing pain in patients with renal colic after SWL treatment. METHOD: The current study is a double-blind clinical trial involving individuals scheduled to receive elective SWL therapy for kidney and ureteral stones. Participants were randomly assigned to one of two groups using the block randomization technique: suppository Diclofenac (100 mg) or a combination of 325 mg Acetaminophen + 5 mg oxycodone administered orally for pain relief following SWL. Pain intensity was measured immediately after the SWL procedure, and analgesics were then given to the patients. After 30 min, pain severity was reassessed. The severity of pain in patients was documented before and after drug administration at 24, 48, and 72 h after the SWL intervention. RESULTS: 154 renal stone patients (63 females) underwent SWL with a mean age of 41.52 ± 10.52 years. The two groups were similar in terms of age ( CONCLUSION: The combination of oxycodone and acetaminophen, including a multimodal analgesic approach, can be considered a preferred option in the clinical setting for pain management of patients undergoing SWL. It provides relief for patients as effectively as NSAIDs, with the same safety profile, leading to high patient satisfaction.