Background: Postoperative pain management remains a critical challenge in high-risk patients undergoing laparotomy. This study compared the analgesic effectiveness and safety profiles of Nefopam and Tramadol in this specific patient population. Methods: In this prospective, randomized trial, 50 high-risk post-laparotomy patients were randomized into two groups. Group A (n=25) received intravenous Nefopam 20mg once daily for 3 days followed by oral Nefopam 30mg three times daily. Group B (n=25) received intravenous Tramadol 100mg over 24 hours followed by oral Tramadol 100mg once daily. Pain assessment was conducted using the FLACC scale and Visual Analog Scale (VAS) on Days 3, 7, and 21 postoperatively. Results: Mean FLACC scores were significantly lower in the Nefopam group compared to the Tramadol group across all time points (Day 3: 2.5 ± 0.8 vs 4.0 ± 1.2; Day 7: 1.8 ± 0.6 vs 3.2 ± 1.0; Day 21: 1.2 ± 0.4 vs 2.0 ± 0.6; p<0.05). Analgesic consumption was also lower in the Nefopam group. Adverse effects were less frequent with Nefopam, particularly for nausea (16% vs 32%) and vomiting (8% vs 24%). Conclusions: Nefopam demonstrated superior analgesic efficacy and a more favourable safety profile compared to Tramadol in high-risk post-laparotomy patients. These findings suggest Nefopam may be preferable for postoperative pain management in this population.