Methadone Induced Hypoglycemia Occurring During Pregnancy

A 32-year-old female at 33 weeks gestation was referred for evaluation of apparent hypoglycemia.  The patient was receiving methadone for opioid addiction at a 180 mg cumulative daily dose.  Her only other medication was ondansetron.  For approximately four months, the patient had experienced intermittent weakness, headaches, and dizziness that resolved after eating food.  Plasma glucose levels of 40 mg/dL and 43 mg/dL were documented on pregnancy related blood draws during which the patient was symptomatic.  A non-contrast CT scan of the abdomen shortly before pregnancy did not demonstrate any pancreatic masses.  Records showed steady weight gain during second and third trimesters of pregnancy, and 8 AM measurements of cortisol and DHEA-sulfate were unremarkable.  No surreptitious use of sulfonylureas or meglitinides was apparent on a hypoglycemic drugs panel.  A diagnostic fast was deferred due to pregnancy and high suspicion for methadone induced hypoglycemia.  Methadone dose reduction was advised, but the patient was resistant and subsequently lost to follow up.  She delivered a healthy baby four weeks later.

Discussion :

Animal studies have linked the glucose lowering effects of methadone to mu-receptor activity, and the mu-receptor selective antagonist β-funaltrexamine is able to block the glucose lowering effects of the drug. In clinical studies, there is a clear relationship between methadone dose and hypoglycemia risk, with odds of hypoglycemia increased by approximately three-fold at methadone doses of > 80 mg/d.  Methadone and tramadol are the only opioids that significantly increase risk of hypoglycemia in the Food and Drug Administration’s Adverse Events Reporting System.  It is unclear why other opioids (e.g. morphine or fentanyl) do not predispose to hypoglycemia.  Since methadone clearance in pregnancy is increased and physiologic changes during pregnancy predispose to hyperglycemia, pregnancy itself would not be anticipated to increase the likelihood of methadone induced hypoglycemia.  Unfortunately, a PubMed search of “methadone and hypoglycemia and pregnancy” did not yield any publications. This case illustrates the need to be vigilant for hypoglycemia in pregnant woman on methadone maintenance therapy.