Premedication with Oral Alprazolam and Melatonin Combination: A Comparison with Either Alone—A Randomized Controlled Factorial Trial

Randomized controlled factorial trial with four parallel groups in adults 18 to 65 years old, ASA I-II, with preoperative anxiety (VAS score >=3) undergoing elective laparoscopic cholecystectomy. The active intervention arms each included 20 participants and were allocated in a 1:1:1:1 ratio across the four study groups.

Oral premedication given 90 minutes before surgery. The active combination regimen was alprazolam 0.5 mg plus melatonin 3 mg, taken as one tablet; comparator active arms received alprazolam 0.5 mg alone or melatonin 3 mg alone.

The alprazolam plus melatonin combination was more effective for preoperative anxiolysis than either agent alone or placebo. At 60 minutes, anxiety reduction from baseline in the combination arm was 3 (1.0-4.3) cm versus 0 (0-1.7) cm with placebo (P = 0.008). Sedation at 60 minutes was also greater with the combination than placebo, 1 (1.0-1.75) versus 0 (0-1) (P = 0.008), and greater than melatonin alone, 1 (1.0-1.75) versus 0.5 (0-1) (P = 0.001). Amnesia for the picture task at 60 minutes favored the combination and alprazolam alone over melatonin and placebo, and 19 of 20 participants in the combination arm said they would prefer the same premedication in the future. Adverse events such as nausea, vomiting, dizziness, headache, and restlessness were similar across groups.

Small per-arm sample size and short perioperative follow-up limit precision and longer-term interpretation. The trial was restricted to relatively healthy ASA I-II adults undergoing laparoscopic cholecystectomy, which narrows generalizability, and several demographic details such as sex and ethnicity were not reported by arm.