Background: Individuals waking from general anesthesia frequently experience disagreeable symptoms of catheter-related bladder discomfort (CRBD) due to intraoperative catheterization. Objective: Comparing efficacy of nefopam versus tramadol to prevent (CRBD) after percutaneous nephrolithotomy (PCNL) surgery. Patients and methods: This was a prospective double-blind study conducted on a total of 150 adult patients between the ages of 18 and 60, of both sexes, who were undergoing percutaneous nephrolithotomy (PCNL) for a renal upper ureteric stone. They were divided into three groups; Tramadol group, Nefopam group and Control group. Results: The demographic data showed no statistically significant differences between the three groups (P value >0.05). Average fentanyl use after surgery was much higher in the control group (326.50±35.14 mcg/24 hours) compared with both tramadol (165.00±15.15 mcg/24 hours) and nefopam groups (183.00±21.69 mcg/24 hours) (P value <0.001). The severity of CRBD, when comparing the control group to the tramadol and nefopam groups, the control group had significantly higher post-operative pain and rescue analgesic use throughout all study timeframes (P value <0.05). Sedation, an increase in the number of patients reporting post-operative nausea and vomiting (PONV), and dry mouth were all significantly more common in the tramadol group than in the nefopam or control groups (P value<0.05). Conclusions: Intra-operative administration of both tramadol and nefopam significantly reduced post-operative CRBD, pain together with reduced consumption of post-operative fentanyl requirements in patients undergoing PCNL. However, nefopam was superior to tramadol as it was not associated with post-operative sedation and had lesser incidence of post-operative adverse events.