Phase III Trial Finds No Significant Difference Between Melatonin, Diazepam, and Placebo for Preoperative Anxiety

Exploring New Paths in Preoperative Anxiolysis

Preoperative anxiety is a persistent clinical challenge, affecting patient wellbeing and perioperative outcomes. While benzodiazepines such as diazepam are widely used as anxiolytics, alternatives like melatonin have garnered attention for their sedative properties and favorable safety profiles. This Phase III, randomized, triple-blind, placebo-controlled trial, sponsored by the University of Jordan and led by Dr. Omar Ismail, rigorously examined melatonin versus diazepam and placebo in adult surgical candidates.

Design and Methods

The study enrolled 87 adults (aged 18–65, ASA I or II) scheduled for elective surgery under general anesthesia at Jordan University Hospital. Randomized in parallel arms, participants received either a 5mg melatonin pill, 5mg diazepam tablet, or placebo (vitamin B12 5mg) one hour before surgery. The trial implemented quadruple masking (participants, care providers, investigators, and outcome assessors) to minimize bias. Anxiety levels were assessed before and one hour after medication using the Visual Analogue Score for Anxiety (VAS-A) and the Amsterdam Preoperative Anxiety and Information Scale (APAIS). Secondary outcomes included effects on sedation (Ramsay Sedation Scale) and cognitive orientation.

Outcomes and Endpoints Quantifying Anxiety and Sedation

The primary endpoints focused on the changes in anxiety, as measured by both the VAS-A and APAIS scales, between the three treatment groups. Secondary endpoints evaluated sedation and orientation scores before and after premedication. Exploratory analyses also compared these outcomes between genders.

Population and Baseline Characteristics

Of 87 randomized patients, 76 completed the trial (melatonin n=28, diazepam n=23, placebo n=25). Baseline anxiety, sedation, and orientation scores were comparable across groups, ensuring balanced comparability for outcome assessment. Median ages ranged from 36 to 43 years, and sex distribution was similar (39 females, 37 males).

No Evidence of Superiority for Melatonin or Diazepam

For the primary endpoint, median changes in the VAS-A after one hour were zero across all arms (melatonin: 0 [IQR -5, 5]; diazepam: 0 [IQR -5, 5]; placebo: 0 [IQR -7.5, 7.5]). APAIS total score change was also minimal across groups (melatonin: -0.5 [IQR -2, 1]; diazepam: -1 [IQR -3, 1]; placebo: 0 [IQR -1, 1]), with similar findings on anxiety and information subscales. No meaningful differences were observed in Ramsay sedation or orientation scores, either between groups or by gender. Additionally, no adverse events were reported.

Implications for Preoperative Anxiety Management

This rigorously executed, well-controlled trial did not demonstrate a significant benefit of either melatonin or diazepam over placebo for reducing preoperative anxiety within one hour of administration in this surgical population. Both active agents and placebo resulted in negligible shifts in subjective anxiety and sedation scores, challenging assumptions about the necessity and acute efficacy of routine pharmacologic anxiolysis in low- to moderate-risk surgical patients.

Reflections and Future Directions

These findings raise important questions about the clinical rationale for preoperative sedative-anxiolytics, the role of non-pharmacologic interventions, and the value of tailoring premedication strategies. Could future studies, perhaps with larger or higher-anxiety cohorts, reveal subgroup benefits or longer-term effects? Might expanded endpoints—patient satisfaction, recovery trajectories, or perioperative complications—clarify the true impact of anxiolytic premedication? Finally, what regulatory or institutional changes could be prompted by this demonstration of equivalence between widely used interventions and placebo?

The landscape of perioperative anxiety management may be due for a shift—how will research and practice respond?