Tramadol is one of the most commonly used analgesics worldwide, classified as having a low abuse potential by U.S. Drug Enforcement Agency, and often recommended in pain management guidelines. Its pain-relieving mechanism of action is attributed to mild μ-opioid receptor agonism, serotonin and norepinephrine mediated nociception modulation, and N-methyl-D-aspartate receptor, NMDAR, antagonism. However, recent case reports and case-control studies have shown an association between tramadol use and hypoglycemia. The growing concern over increasing tramadol use and unexpected side effects warranted a further comparative and quantitative analysis of tramadol adverse reactions. In this study we analyzed over twelve million reports from United States Food and Drug Administration Adverse Event Reporting System and provided evidence of increased propensity for hypoglycemia in patients taking tramadol when compared to patients taking other opioids, serotonin-norepinephrine reuptake inhibitors, and drugs affecting NMDAR activity. Additionally, we identified that only methadone from the opioid cohort behaves similarly to tramadol and has an association with hypoglycemia.