Tramadol Use Linked to Increase Hypoglycemia

Investigators from the University of California San Diego has found that a common opioid, often prescribed due to its potential for fewer side effects, could increase a patient’s risk of developing hypoglycemia.

A review of reports from the United States Food and Drug Administration (FDA) Adverse Effect Reporting System and Adverse Event Reporting System databases revealed patients receiving tramadol were at a 10-fold greater risk of developing hypoglycemia than almost every other opioid except methadone.

To determine whether tramadol increased hypoglycemia in non-diabetic patients and if hypoglycemia was associated with any other opioids, serotonin and norepinephrine reuptake inhibitors (SNRI), or N-Methyl-D-aspartate receptor (NMDAR) modulators, investigators examined 12,004,552 reports from the FDA databases dated between January 2004 and March 2019. Tigran Makunts, PharmD, researcher at Skaggs School of Pharmacy and Pharmaceutical Sciences at UC San Diego, points to the jump in tramadol prescribing as the driving force behind the study. 



"The impetus was the recent dramatic surge in tramadol popularity and prescriptions," Makunts said. "We wanted to have an objective data-driven look at its adverse effects and bumped into a dangerous, unlisted and unexpected hypoglycemia."



Investigators grouped reports related to tramadol, codeine, hydrocodone, oxycodone, oxymorphone, hydromorphone, morphine, fentanyl, methadone, dextropropoxyphene, and tapentadol into separate groups for the current analysis. Investigators also analyzed SNRIs including duloxetine, venlafaxine, desvenlafaxine, and milnacipran used as monotherapy, and drugs with NMDAR activity such as minocycline, atomoxetine, ketamine, dextromethorphan, and memantine.

Additionally, investigators noted the frequency of hypoglycemia reports were calculated for opioids, SNRIs, and NMDARs as a class for comparison with reports in the tramadol cohort. The investigators’ analyses revealed a significant increase in frequency of hypoglycemia reports in the tramadol cohort when compared to opioids-class (Report-Odds-Ratio (ROR) 11.36; 95% CI; (8.23, 15.66)), SNRIs-class (ROR 10.14 (7.08, 14.54), and NMDAR-class (ROR 14.57 (8.07, 26.31)).

Upon analysis, investigators found that the frequency of hypoglycemia reports was 0.10 for the codine cohort, 0.04 for fentanyl, 0.07 for hydrocodone, 0.19 for hydropmorphone, 0.04 for morphine, 0.09 for oxycodone, 0.87 for methadone, and 1.13 for tramadol. No reports were found for tapentadol, oxymorphone, or dextropropoxyphene. 



In a related release, lead investigator Ruben Abagyan, PhD, professor of pharmacy at UC San Diego, said physicians should be cognizant of these potential effects as they could pose a serious threat to certain patient populations.

"The takeaway message is to warn physicians about the likelihood of low blood sugar (and/or high insulin content), in particular if the patient is predisposed to diabetes,” Abagyan explained. "And to motivate research about the unique molecular mechanism leading to that side effect. It is particularly important for tramadol or methadone that are used widely and, often, chronically."

This study, “Retrospective analysis reveals significant association of hypoglycemia with tramadol and methadone in contrast to other opioids,” was abolished online in Scientific Reports.