Background Postoperative pain management is a challenge in opioid-dependent patients as this patient group is often undertreated for pain. An appropriate dose of an appropriate opioid should be administered to these patients to control the pain and prevent the development of withdrawal symptoms. Objectives The aim of this study was to evaluate the analgesic and adverse effects of pethidine versus morphine in postoperative pain relief in opioid-dependent patients after major surgery. Methods Eighty opioid-dependent patients undergoing major surgical operations were included in our study. Forty patients received intravenous morphine (up to 0.15 mg/kg) or intramuscular pethidine (up to 1.5 mg/kg) for 48 h postoperatively. Withdrawal symptoms were recorded using the Clinical Opioid Withdrawal Scale (COWS) at 30 and 60 min after drug administration. The effectiveness and tolerability profile of pethidine was compared with that of morphine at 6, 12, 24 and 48 h after the initiation of treatment. Analgesic efficacy was recorded using a visual analogue scale (VAS), and drug safety was estimated using sedation scores and adverse drug reactions. Results Pethidine and morphine had similar analgesic effects at 6 and 12 h postoperatively, but morphine had better analgesic effects at 24 and 48 h. Morphine was associated with fewer adverse reactions and less prominent withdrawal symptoms than pethidine. Conclusion Morphine is a more effective and better tolerated analgesic than pethidine in the management of postoperative pain in opioid-dependent patients.