Abstract Introduction: In laparoscopic surgery, insufflation of CO2 gas into the peritoneal cavity creates referred postoperative pain and diffuse abdominal pain. Referred pain is sometimes more intensive than incisional and abdominal pain. Objective: To determine the efficacy of acetazolamide by increasing pH and reducing acidity in the abdomen and to compare the analgesic effects of paracetamol and acetazolamide with a control group in laparoscopic surgery. Methods: This randomized, double-blind, parallel-controlled clinical trial was conducted on ASA1 (American Society of Anesthesiologists Class 1) patients, who were candidates for laparoscopic cholecystectomy in teaching hospitals affiliated with Mashhad University of Medical Sciences during 2016-2017. One hundred fourteen patients were allocated equally into two study groups and one control group (receiving acetazolamide, paracetamol, or placebo). In the acetazolamide group, 250 mg acetazolamide was administered one hour before anesthesia. In the paracetamol group, 1 g paracetamol was infused over a 15-min postanesthesia induction. Incision site, diffuse abdominal, and shoulder pains were evaluated at the recovery room the day after surgery and upon hospital discharge using a numeric rating scale (NRS). Data were analyzed by SPSS 16.0, using Chi-square for trend test, Fisher\\\'s exact test, paired-samples t-test, Wilcoxon signed-rank test, two-way repeated measure analysis of variance (ANOVA), and Mann-Whitney U test. Results: There were no significant differences between groups regarding their demographic characteristics. The acetazolamide group exhibited a lower frequency of shoulder pain than the paracetamol and control groups at recovery (p=0.03), 24 hours later (p=0.001), and before discharge (p=0.014). Incisional and diffuse abdominal pains were lower in the paracetamol group (p=0.012). Conclusion: In the patients undergoing laparoscopic cholecystectomy, acetazolamide was effective in the reduction of shoulder pain and paracetamol was effective in postoperative incisional and abdominal pain control. Registration: This study was registered In the Iranian Registry of Clinical Trials under registration number IRCT201206108384N2. Funding: Research Vice-chancellor, Mashhad University of Medical Sciences (Ref: 900337). Keywords: Acetazolamide, Paracetamol, Laparoscopic surgery, Referred pain

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