Methadone-Induced Hypoglycemia in a Hospitalized Patient

Abstract

Methadone is used as an agent for chronic pain and management of opioid use disorder. While similar pharmacologically to other opioids, methadone does have unique characteristics, including long half-life, low cost, and high oral bioavailability. While advantageous in some ways, methadone is associated with unique adverse effects not seen with other opioids (ie, hypoglycemia). In this case, we describe a patient in his late-60s with opioid use disorder on chronic methadone who presents with symptoms of generalized weakness, fatigue, and decreased appetite for 2 days. The hospital course was complicated by hypoglycemia, without obvious cause other than methadone-induced hypoglycemia. The patient was managed with supportive care to maintain normoglycemia. He was continued on methadone and instructed to follow-up with his opioid treatment program to assess for dose de-escalation to minimize future hypoglycemia risk. While other case reports of methadone-induced hypoglycemia highlight the risk of this adverse effect, our case highlights the importance of assessing methadone as a cause of hypoglycemia and provides discussion around the legality of dose de-escalation at discharge from an acute care setting.

Introduction

Methadone, a full mu-opioid agonist, has been widely used for the treatment of cancer-related pain and non-cancer related pain as well as for detoxification and/or maintenance of opioid use disorder (OUD). ¹ Methadone has some advantages compared to other opioids, including long half-life, low cost, and high oral bioavailability. The safety profile of methadone is similar to other opioids with notable side effects including respiratory depression and constipation; however, there are serious adverse reactions including overdose, QT prolongation, and hypoglycemia at high doses. ² There are no studies that compare the effects of methadone versus other opioids on hypoglycemia. Several reports exist with methadone-induced hypoglycemia and adrenal insufficency.^{3 -7} Despite the previously reported cases, there are limited reports of hospitalized patients with methadone-induced hypoglycemia and appropriate management strategies. Here, we report a case of a hospitalized patient with recurrent hypoglycemia with unknown etiology on chronic methadone for OUD as well as management strategies to mitigate continued hypoglycemia risk.

Case

A 69 years-old male with a past medical history of hypertension, gastrointestinal bleeding (GIB), gastroesophageal reflux disease (GERD), hepatitis C virus (previously treated), and chronic methadone use (125 mg daily for the past 3 years) for OUD presented with symptoms of generalized weakness, fatigue, and decreased appetite for 2 days. In the Emergency Department, patient was hemodynamically stable, afebrile, and only significant laboratory finding was a hemoglobin of 5.8 mg/dl requiring transfusion and serum creatinine of 1.12 mg/dl. All home medications, including methadone, were started on admission. On Day 1, patient was found to be hypoglycemic with a blood glucose (BG) value on 61 mg/dl that was treated with 25 g of 50% dextrose. No obvious reasons for hypoglycemia were noted. Upon chart review, the patient had a previous hospital admission 8 months prior with similar presenting symptoms and was found to be severely hypoglycemic with BG readings of 33, 39, and 43 mg/dl with no identifiable cause. The patient required treatment with 10% dextrose continuous infusion to maintain euglycemia. CT abdomen and pelvis were performed and demonstrated no pathologic abnormalities. The patient has no history of diabetes, no use of any glucose-lowering medications at home, and was not on any insulin during either hospital admission. The patient’s hypoglycemia was managed conservatively with no additional workup pursued during the inpatient admission. Methadone 125 mg daily was continued throughout the hospital admission and the patient was discharged home on the same dose with instructions to follow up at his opioid treatment program (OTP) to report his recent hypoglycemic events.

Discussion

Our case demonstrates a patient with recurrent hypoglycemia with no identifiable cause other than high-dose methadone. Chronic methadone use is often overlooked as a possible cause of hypoglycemia despite several reports indicating the risk.^{3 -5,8 -10} Multiple proposed mechanisms exist for how methadone may cause hypoglycemia including promotion of insulin release (ie, insulinoma mimic), impairment of gluconeogenesis, and suppression of counter-regulatory hormones (ie, glucagon). ⁸ Some data suggests that methadone-induced hypoglycemia is related to adrenal insufficiency via delta or kappa receptors on the hypothalamus, leading to a decrease in adrenocorticotropic hormone (ACTH) and cortisol secretion. ⁴

Methadone-induced hypoglycemia also appears to be a dose-related effect, particularly at doses greater than 40 mg/day. Doses utilized for OUD tend to be higher than those used for chronic pain with American Society of Addiction Medicine (ASAM) guidelines recommending doses of 60 to 120 mg for OUD. ¹¹ In a case series by Moryl et al, ³ 1 in 5 patients undergoing rapid methadone dose escalation inpatient experienced hypoglycemia. These effects were broken down by rates of per-day hypoglycemia for methadone doses: 0 to 15, >15 to 40, >40 to 80, and >80 mg/day were 3.9%, 4.2%, 7.4%, and 8%, respectively. ³ Hypoglycemic events are also time-dependent, with increased risk reported within 24 hours of higher doses (>40 mg/day) in one study, and within 2 days of significant dose increases in another study.^2,3

Hypoglycemia is associated with decreased quality of life and increases mortality. ¹² Patients who experience hypoglycemia while on methadone are at increased risk of additional hypoglycemic episodes (Odds ratio 4.0 [2.3-7.0]) and associated complications. ² In our case, rapid discontinuation of methadone was not considered due to the associated risk of precipitating withdrawal and increased risk of relapse and overdose death with immediate withdrawal of high-dose methadone. ¹³ Current American Society of Addiction Medicine (ASAM) guidelines on OUD recommend long-term treatment when using methadone, for at least 12 months with no fixed length of time to reduce the risk of relapse as long as the benefits outweigh the risks. ¹¹ Typical stabilization doses are at least 60 mg/day to ensure treatment retention. ¹³ All patients should be routinely assessed for dose de-escalation based on response. In this case, our patient had been on methadone 125 mg daily for the past 3 years with no dose changes. It is reasonable in the event of new adverse effects of methadone to slowly taper down the dose. The patient was informed of the need to follow-up with his OTP and ask about slowly de-escalating his dose.

In the setting of methadone-induced hypoglycemia, patients should ideally slowly taper off methadone and consider switching to an alternative medication for OUD (ie, buprenorphine or naltrexone) if continued therapy is indicated. The Substance Abuse and Mental Health Services Administration (SAMHSA) suggests a gradual taper by decreasing methadone dose 5 to 10% every 1 to 2 weeks and tailoring to patient response. ¹³ To transition to buprenorphine, patients should be on 30 to 40 mg for at least a week, and then discontinue methadone for typically 24 to 48 hours before starting buprenorphine. Buprenorphine should be initiated at low doses when patients are in mild withdrawal to decrease the risk of precipitating methadone withdrawal. When transitioning from methadone to naltrexone, patients need to be completely off methadone and other opioids for 7 to 14 days before starting naltrexone to avoid precipitating withdrawal. ¹¹ Another strategy to consider is to split the methadone dose in half (ie, twice daily dosing for the equivalent total daily dose) to minimize the risk of dose-dependent hypoglycemia. ¹⁴

One strategy considered in this case was to decrease the methadone dose at discharge and arrange close follow-up with the methadone clinic. Most clinicians are aware that methadone can be prescribed in acute care settings for management of acute opioid withdrawal or chronic pain. Most hospitalists are unfamiliar with the prescribing rules and regulations when patients are on maintenance methadone and hospitalized for another medical reason that is not withdrawal. Federal law 1306.07 “Administering or dispensing of narcotic drugs” Section (c) states “This section is not intended to impose any limitations on a physician or authorized hospital staff to administer or dispense narcotic drugs in a hospital to maintain or detoxify a person as an incidental adjunct to medical or surgical treatment of conditions other than addiction, or to administer or dispense narcotic drugs to persons with intractable pain in which no relief or cure is possible or none has been found after reasonable efforts.” Thus, dose modifications can be made in the acute care setting by hospital providers based on medical necessity. At discharge, providers should contact the patient’s OTP to discuss dose decreases due to concern for adverse effects. The OTP will ensure the patient can be seen immediately after discharge for assessment and dispensing of the new methadone dose. Recently, the Drug Enforcement Administration (DEA) have created exceptions that allows enhanced access to medication-assisted treatment, including methadone, by allowing hospitals to dispense an emergency supply to patients to bridge follow up with an OTP. ¹⁵ Increasing awareness of this strategy in patients with intolerance to methadone (ie, hypoglycemia) or new medications/diseases states that interfere with methadone use provides patients with a care continuum that increases quality of life and promotes safe use of methadone for OUD.

One limitation in our case was not screening an insulin, c-peptide, proinsulin, β-hydroxybutyrate, or cortisol levels at time of hypoglycemia in order to evaluate possible etiologies of hypoglycemia. Additionally, there was no workup performed for any insulin-producing cancers. Speculation of methadone being the causative agent occurred later in the hospital stay once hypoglycemia had resolved. Additionally, serum methadone levels could have been ordered to assess blood concentrations at the times of hypoglycemia to provide further evidence of a possible cause-effect relationship.

Conclusion

This case highlights the consideration of chronic, high-dose methadone use as a cause of hypoglycemia in hospitalized patients. Dose de-escalations are allowable in acute care settings, but must be communicated to the patient and the patient’s opioid treatment program. Supportive care and adequate follow-up is important in mitigating recurrent hypoglycemic events.