In the United States, opioid use by patients who are pregnant more than quadrupled from 1999 to 2014.1 Opioid use disorder (OUD) in the perinatal period is associated with a higher risk for depression, suicide, malnutrition, domestic violence, and obstetric complications such as spontaneous abortion, preeclampsia, and premature delivery.2 Buprenorphine and methadone are the standard of care for treating OUD in pregnancy.3,4 While a literature review found that maternal treatment with buprenorphine has comparable efficacy to treatment with methadone,5 a small randomized, double-blind study found that compared to buprenorphine, methadone was associated with significantly lower use of additional opioids (P = .047).6 This suggests methadone has therapeutic value for patients who are pregnant.
Despite the benefits of methadone for treating perinatal OUD, the physiological changes that occur in patients who are pregnant—coupled with methadone’s unique pharmacologic properties—may complicate its use. Patients typically take methadone once a day, and the dose is titrated every 3 to 5 days to allow serum levels to reach steady state.7 During pregnancy, there are increases in both the volume of distribution and medication metabolism secondary to increased expression of the cytochrome P450 3A4 enzyme by the liver, intestine, and placenta.8 Additionally, as the pregnancy progresses, the rate of methadone metabolism increases.9 Methadone’s half-life (20 to 35 hours) leads to its accumulation in tissue and slow release into the blood.10 As a result, patients with OUD who are pregnant often require higher doses of methadone or divided dosing, particularly in the second and third trimesters.11
In this article, we provide a strategy for divided dosing of methadone for managing opioid withdrawal symptoms in the acute care setting. We present 2 cases of women with OUD who are pregnant and describe the collaboration of addiction medicine, consultation-liaison psychiatry, and obstetrics services.
CASE 1
Ms. H, age 29, is G3P2 and presents to the emergency department (ED) during her fourth pregnancy at 31 weeks, 1 day gestation. She has a history of opioid, cocaine, and benzodiazepine use disorders and chronic hepatitis C. Ms. H is enrolled in an opioid treatment program and takes methadone 190 mg/d in addition to nonprescribed opioids. In the ED, Ms. H requests medically supervised withdrawal management. Her urine toxicology is positive for cocaine, benzodiazepines, methadone, and opiates. Her laboratory results and electrocardiogram (ECG) are unremarkable. On admission, Ms. H’s Clinical Opiate Withdrawal Scale (COWS) score is 3, indicating minimal symptoms (5 to 12: mild; 13 to 24: moderate; 25 to 36: moderately severe; >36: severe). Fetal monitoring is reassuring.
Ms. H’s withdrawal is monitored with COWS every 4 hours. The treatment team initiates methadone 170 mg/d, with an additional 10 mg/d as needed to keep her COWS score <8, and daily QTc monitoring. Ms. H also receives lorazepam 2 to 4 mg/d as needed for benzodiazepine withdrawal. Despite the increase in her daily methadone dose, Ms. H continues to experience opioid withdrawal in the early evening and overnight. As a result, the treatment team increases Ms. H’s morning methadone dose to 190 mg and schedules an afternoon dose of 30 mg. Despite this adjustment, her COWS scores remain elevated in the afternoon and evening, and she requires additional as-needed doses of methadone. Methadone peak and trough levels are ordered to assess for rapid metabolism. The serum trough level is 190 ng/mL, which is low, and a serum peak level is not reported. Despite titration, Ms. H has a self-directed premature discharge.
Five days later at 32 weeks, 2 days gestation, Ms. H is readmitted after she had resumed use of opioids, benzodiazepines, and cocaine. Her vital signs are stable, and her laboratory results and ECG are unremarkable. Fetal monitoring is reassuring. Given Ms. H’s low methadone serum trough level and overall concern for rapid methadone metabolism, the treatment team decides to divide dosing of methadone. Over 9 days, the team titrates methadone to 170 mg twice daily on the day of discharge, which resolves Ms. H’s withdrawal symptoms.
At 38 weeks, 5 days gestation, Ms. H returns to the ED after experiencing labor contractions and opiate withdrawal symptoms after she resumed use of heroin, cocaine, and benzodiazepines. During this admission, Ms. H’s methadone is increased to 180 mg twice daily with additional as-needed doses for ongoing withdrawal symptoms. At 39 weeks, 2 days gestation, Ms. H has a scheduled cesarean delivery.
Her infant has a normal weight but is transferred to the neonatal intensive care unit (NICU) for management of neonatal opioid withdrawal syndrome (NOWS) and receives morphine. The baby remains in the NICU for 35 days and is discharged home without further treatment. When Ms. H is discharged, her methadone dose is 170 mg twice daily, which resolves her opioid withdrawal symptoms. The treatment team directs her to continue care in her methadone outpatient program and receive treatment for her cocaine and benzodiazepine use disorders. She declines residential or inpatient substance use treatment.
Continue to: CASE 2