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The mild opioid tramadol was associated with an increased risk of hospitalization for hypoglycemia, researchers reported.

In a case-control study, the use of tramadol was associated with a 52% higher risk of hospitalization for hypoglycemia compared with codeine, , of McGill University in Montreal, and colleagues

Risk was highest within the first 30 days of use, they reported -- nearly three times as high as that seen with codeine.

Tramadol is seen as a lower-risk alternative to other opioids and its prescriptions have increased in recent years. In August, the opioid became a schedule IV controlled substance.

Suissa and colleagues wrote that three recent case reports have described tramadol-induced hypoglycemia, which included patients with and without diabetes who used the drug at recommended doses.

It's biologically plausible that tramadol may induce hypoglycemia; it activates the mu-opioid receptor and inhibits central serotonin and norepinephrine reuptake. Serotonin pathways are known to have complex effects on peripheral glucose regulation, the researchers wrote, and antidepressants that work via either serotonin or norepinephrine reuptake inhibition both have been tied to hypoglycemia risk.

They conducted a nested case-control analysis within the U.K. Clinical Practice Research Datalink and the Hospital Episodes Statistics database of 334,034 patients newly treated with tramadol or codeine for pain between 1998 and 2012.

Among these, 1,105 were hospitalized for hypoglycemia during follow-up, and were subsequently matched with 11,019 controls.

Overall, tramadol use was associated with an increased risk of hospitalization for hypoglycemia compared with codeine use (odds ratio 1.52, 95% CI 1.09 to 2.10).

That risk was particularly elevated in the first 30 days of use, they reported (OR 2.61, 95% CI 1.61 to 4.23).

Suissa and colleagues noted that the 2-day increased risk of hospitalization was confirmed in an propensity score-adjusted model (HR 3.6, 95% CI 1.56 to 8.34) and in cross-over analyses (OR 3.80, 95% CI 2.64 to 5.47).

In an accompanying commentary, , of New York University Medical Center in New York City, and , of Sunnybrook Health Sciences Center in Toronto, noted that hypoglycemia was uncommon in the study, with only eight events in more than 26,000 person-months of tramadol therapy.

It's also unclear why hypoglycemia is less common in patients taking other mu-opioid agonists such as morphine, oxycodone, and hydrocodone, they noted.

Still, since hypoglycemia "can be life threatening, clinicians should remain vigilant for this potential complication of tramadol use, in patients taking the drug as directed, as well as those who abuse it," they wrote. "Whether tramadol therapy should be particularly avoided in patients receiving hypoglycemic drugs is unclear, but given the drug's limited benefit and unpredictable pharmacological properties, it should be handled at least as carefully in these patients as in others."

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