Case Presentation: A 66-year-old male with ESRD on dialysis, hepatitis C, hypertension, and opioid use disorder (OUD) on 135 mg of methadone presented with bilateral leg ulcerations and complex pain syndrome that was complicated by recurrent hypoglycemia. His initial blood glucose of 35 was thought to be due to poor insulin clearance with ESRD. He had been unable to tolerate dialysis with an incomplete session the day prior. Despite dextrose administration and inpatient dialysis, hypoglycemia persisted at 42. Chart review revealed chronic episodes of hypoglycemia with negative sulfonylurea panels, inappropriately elevated c-peptide and proinsulin, and MRI and CT in 2022 and 2023 ruling out insulinoma. Methadone-induced hypoglycemia was suspected, so he was transitioned to buprenorphine with a three-day microdose protocol. On the last day of induction, he experienced precipitated opioid withdrawal after numerous doses of PRN oxycodone and hydromorphone. Acute management included 24 mg of buprenorphine and comfort medications for withdrawal symptoms. He has remained free of hypoglycemia since his successful buprenorphine conversion.
Discussion: This case demonstrates hypoglycemia as a lesser-known adverse effect of methadone. The pathophysiology is unclear but is suspected to involve activating μ‐opioid receptors on pancreatic islet cells, suppressing counter‐regulatory hormones, or increasing the serotonergic pathway and raising insulin levels. A retrospective study of hospitalized cancer patients noted that methadone reduced average blood glucose levels by 5.7 mg/dL, and other studies describe instances of hypoglycemia after rapid methadone dose escalations.Although several case reports cite hyperinsulinemia with methadone doses greater than 40 mg daily, limited data highlights this association. As there are no specific guidelines for treating methadone-induced hypoglycemia, clinicians may consider alternative therapy, like inpatient micro-induction of buprenorphine, to minimize this unwanted effect. This approach avoids planned or precipitated withdrawal and allows the patient to remain on a full dose of methadone until the last day of induction. By switching patients in the hospital, physicians can monitor and rapidly address withdrawal symptoms, which establishes a more comfortable method of methadone tapering and overcoming the barriers of buprenorphine initiation. This can be clinically challenging in cases of chronic pain exacerbations, as short-acting opioids used PRN can increase the chances of buprenorphine-induced withdrawal. In these cases, high-dose buprenorphine induction may reduce the risk and facilitate a smoother transition.
Conclusions: There is a critical need for increased awareness of hypoglycemia, the often under-recognized complication of methadone. Physicians should include methadone in their differential for unexplained hypoglycemia and consider transitioning to buprenorphine or adjusting the methadone dosage. Many patients are likely to present on OUD medications given greater public awareness, and complications of those therapies will become more common. While the choice of treatment of OUD is a personal one, this adds to the understanding of clinical situations where switching from methadone to buprenorphine can be advantageous. These nuances will be increasingly important when caring for hospitalized patients with OUD on opioid agonist therapy as they balance hospital management with OUD medication side effects.