Abstract
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.
Highlights
Tramadol, a synthetic centrally acting weak opioid analgesic approved in 1995, has gradually gained increased worldwide use for acute and chronic pain management due to its low risk of respiratory depression, compared to other opioids[1,2]
In this study we posed two questions: (1) is tramadol use significantly associated with an elevation of hypoglycemia reports in non-diabetic patients, (2) is hypoglycemia associated with any other opioids, serotonin and norepinephrine reuptake inhibition (SNRI), or N-methyl-D-aspartate receptors (NMDARs) modulators
Frequencies of hypoglycemia reports were initially calculated for opioids, SNRIs and NMDAR antagonists as a class, for comparison with hypoglycemia reports in the tramadol cohort (Fig. 2a)
Summary
A synthetic centrally acting weak opioid analgesic approved in 1995, has gradually gained increased worldwide use for acute and chronic pain management due to its low risk of respiratory depression, compared to other opioids[1,2]. Tramadol’s analgesic effect originates from two distinct mechanisms It increases the pain threshold by acting on serotonergic and noradrenergic nociception via serotonin and norepinephrine reuptake inhibition (SNRI), and its metabolite, O-desmethyltramadol, acts as a μ-opioid receptor agonist (MOR)[7,8,9]. Based on previous evidence from animal studies, tramadol induced hypoglycemia has been attributed to MOR agonism or serotonin modulation. Another possible etiology of hypoglycemia could be related to NMDAR antagonism[10,24,25,26,27,28,29,30]. In this study we posed two questions: (1) is tramadol use significantly associated with an elevation of hypoglycemia reports in non-diabetic patients, (2) is hypoglycemia associated with any other opioids, SNRIs, or NMDAR modulators. SNRI and NMDAR modulators were selected as comparison patient treatment categories because they represent two non-opioid activities of tramadol
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