Life-Threatening Hypoglycemia in a Non-Diabetic Patient on Tramadol

Introduction : Tramadol is a commonly used analgesic worldwide to control moderate to severe pain. There has been growing evidence of hypoglycemia with tramadol use, yet hypoglycemia seems to be an underappreciated side effect by many physicians. Even though the percentage of hypoglycemia from tramadol is 1%- 5%, it is a life-threatening side effect. We are presenting this case report to increase awareness of the dangerous side effects of tramadol use.

Case Description : An 86 year old man with a history of coronary artery disease, valve replacement, pacemaker, hypertension, hypercholesterolemia, and diverticulitis with colon resection required EMS attention due to loss of consciousness. His medications included aspirin, atorvastatin, labetalol, losartan, hydrochlorothiazide, warfarin, and tramadol. A point of care (POC) glucose measurement by EMS was 17 mg/dL. After 250 ml of 10% dextrose, he regained consciousness. In the ED, a laboratory blood glucose level was 45 mg/dL. Simultaneous insulin and c-peptide levels were 9.4 mU/mL and 5.7 ng/mL, respectively. Abdominal CT was negative for pancreatic, liver, or retroperitoneal mass. Tramadol was discontinued and he was discharged home after 3 days of observation. There were no further episodes of hypoglycemia. A 24 hour fast was performed in the outpatient setting, during which time hypoglycemia did not occur. Pill identification revealed no antihyperglycemic medications. Laboratory testing at the end of the fast: glucose 88 mg/dL, insulin 2.3 mU/mL, c-peptide 0.75 ng/mL, proinsulin 4.3 pmol/L, and diabetes medication screen was negative. At follow-up 3 months later, no other episodes of hypoglycemia have occurred.

Discussion : Various mechanisms of tramadol induced hypoglycemia have been proposed, including increased insulin sensitivity, mu opioid receptor activation causing a reduction in hepatic gluconeogenesis, and increased utilization of glucose in peripheral tissue. A retrospective study describes a strong association of hypoglycemia with use of tramadol or methadone monotherapy. There have been cases reported in the setting of critically ill patients where tramadol use caused more agitation and restlessness in patients after 60-90 minutes after intravenous tramadol use. This poses an increased risk as symptoms of hypoglycemia would be difficult to identify in the critical care setting. This case illustrates that hypoglycemia can be a presenting symptom with tramadol use in patients with no prior history of diabetes, who are not on any glucose lowering agent. It is critical to recognize hypoglycemia in tramadol treated patients early to promptly initiate treatment.