One of the five most popularly prescribed opioid analgesics in the United States for chronic pain conditions, tramadol, has proven to cause a tenfold risk of hypoglycemia in nondiabetic patients. There is a need to study the link of opioids to hypoglycemia since it indicates an early sign of diabetes, when blood sugar levels drop due to the production of excess insulin. 

Researchers at the Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, studied two aspects of tramadol related to hypoglycemia. They did not only researched the elevated levels of hypoglycemia in nondiabetic patients, but they also tried to find an association between hypoglycemia and the consumptions of eleven other opioids.

To study the association further, they analyzed four serotonin and norepinephrine reuptake inhibitors (SNRIs) and five NDMA receptor antagonists. Results and analysis were published in Scientific Reports on Wednesday. 


12 million adverse reaction reports from Food and Drug Administration’s Adverse Event Reporting System (FAERS) were analyzed to conclude that tramadol consumption was significantly linked to hypoglycemia. This finding validated studies done in the recent past on the same association between tramadol and development of hypoglycemia. . 

Researchers therefore accessed 145,404 monotherapy reports and compared the odd ratios of hypoglycemia association with other opioids from 2004 to 2019. Only one drug, methadone, was confirmed to have high risk, just like tramadol. However, two highly addictive opioids, oxycodone and codeine, had a poor link. Even the SNRI and NMDAR categories of drugs were ruled out. 

opioids Oxycodone pain pills prescribed for a patient with chronic pain lie on display on March 23, 2016 in Norwich, CT. Photo Courtesy John Moore/Getty Images

“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 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,” Ruben Abagyan, PhD and one of the senior authors said in the press release. 

Risk Factors

The researchers investigated the side effects of this common opioid sold under the ConZip and Ultram brands. They found that ,tramadol, not only has common adverse drug reactions that occur after consuming all opioids, it also has serious side effects such as serotonin syndrome and increased seizure risks. 

The impetus for the study was the insurmountable increase in prescriptions. Between 2008 and 2013, an 88 percent increase in prescriptions for tramadol and other opioids was noted by Centers for Disease Control and Prevention (CDC) Census Report. The usage of the tramadol was considered relatively harmless and less addictive than oxycodone.   

But the records suggest otherwise. Hospital visits due to adverse reactions to tramadol has doubled since 2005 and the majority of patients are female. As a safety precaution, the Drug Enforcement Agency (DEA), moved tramadol from Schedule V of the Controlled Substance Act in 2014 to Schedule IV, which lists drugs that could have a chance to be misused.