Opioid use disorder: Pharmacotherapy with methadone and buprenorphine during pregnancy

INTRODUCTION — Methadone and buprenorphine are used for pharmacotherapy of opioid use disorder (OUD) and medically assisted withdrawal, along with appropriate social and medical services. The comparative advantages and disadvantages of methadone versus buprenorphine pharmacotherapy of OUD are shown in the table (table 1).

This topic will discuss administration and outcomes of methadone and buprenorphine for pharmacotherapy of OUD during pregnancy and postpartum. The use of pharmacotherapy versus medically-assisted withdrawal, choice of drug for pharmacotherapy, candidates for this therapy, maternal and fetal evaluation, labor and delivery management, and postpartum pain control are reviewed separately. (See "Opioid use disorder: Overview of treatment during pregnancy".)

METHADONE PHARMACOTHERAPY

Provider — Regulations regarding provision of methadone for OUD vary by state and/or country [1]. The provider should be aware of all opioid prescribing laws applicable in their area.

Successful pharmacotherapy of OUD depends upon a comprehensive, multidisciplinary, coordinated approach to care [2,3]. Methadone treatment centers usually offer individual and group counseling, and some may provide psychiatric and social services. A few, unique programs also offer health/parenting education and prenatal care.

Pharmacology — Methadone is a synthetic long-acting opioid agonist that binds to and occupies mu-opioid receptors, thus preventing withdrawal symptoms for 24 hours or longer, reducing craving for opioids, and, by maintaining high levels of opioid tolerance, reducing the euphoric effects of subsequent nonprescription opioid use.

It is available as an oral solution, tablet, and injectable solution. The oral solution is used for observed ingestion; the oral solution or tablets are used for take-home doses; the injectable solution is not used for pharmacotherapy of OUD [4]. It is advisable to avoid switching dosage forms, when possible, because withdrawal symptoms sometimes occur when a patient is switched to a different form [5].

The half-life of methadone falls substantially during pregnancy, from an average of 22 to 24 hours in nonpregnant individuals to 8.1 hours in pregnancy, due to changes in pharmacokinetics related to pregnancy [6,7]. Methadone metabolism is consistently accelerated in pregnancy due to significantly increased CYP3A4 expression by a variety of organs, including liver, intestine, and placenta [6,8,9]. Significant genetic diversity in the enzymes that metabolize methadone (CYP3A4, 2D6) result in different individual metabolic rates, and absorption is variable in pregnancy [10]. Metabolism generally increases with advancing gestational age [11-16]; therefore, higher doses or split dosing may be required to maintain therapeutic effects as pregnancy progresses.

Cord blood methadone levels correlate with maternal dose and gestational age, as methadone crosses the placenta in greater amounts in late pregnancy [13].

Initial dosing

●When to start – For pregnant patients desiring methadone pharmacotherapy, the drug should be initiated as early in gestation as possible to get the most maternal, obstetric, and neonatal benefit. For example, some studies have reported that earlier initiation of methadone was associated with improvements in perinatal outcome (eg, longer gestation, greater birth weight) [17-20]. In addition, in a study of 632 pregnant patients with OUD receiving treatment with MOUD, the risk of nonfatal overdose was inversely proportional to treatment duration [21].

In patients with a clear diagnosis of OUD (table 2), there is no requirement that they show signs and symptoms of withdrawal before methadone can be initiated. Signs and symptoms typically appear four to six hours after the last dose of short-acting opioids, peak at one to three days (onset of and peak symptoms may occur later after long-acting opioids) [22], and include one or more of the signs/symptoms in the table (table 3). The severity of each symptom depends on the individual's tolerance to opioids, the continued presence of opioid in the serum and end organs, and the duration of time over which withdrawal has occurred. Withdrawal symptoms generally subside after five to seven days [23]. (See "Opioid withdrawal in the emergency setting", section on 'Clinical features of opioid withdrawal'.)

●Where to start – The optimum setting for initiation of therapy has not been evaluated in the pregnant population. We suggest hospitalization during initiation of treatment because of the potential for serious adverse events, such as overdose and adverse drug interactions. Hospitalization also facilitates daily fetal assessment (fetal heart rate or nonstress test depending on gestational age), which we perform in inpatients until the patient is stabilized (ie, when methadone occupies a sufficient number of opioid receptors to prevent withdrawal). This is also an ideal time for assessment by a social worker and case manager and for initiation of prenatal care. However, some authorities believe hospitalization is not necessary at initiation of therapy.

It is important to emphasize that the approach described below applies to patients who are hospitalized while initiating methadone; initiation and titration of methadone in the outpatient setting must be guided by a different protocol. The dose adjustment recommended below should only be done in the inpatient setting as the upward titration described is too rapid to be safe for all patients in an outpatient setting, where the dose is typically increased no more frequently than every three to five days. Detailed information on dosing in the outpatient setting is available separately. (See "Opioid use disorder: Pharmacologic management".)

Starting dose in hospitalized patients — In most symptomatic patients, we begin therapy with a single oral dose of methadone 20 to 30 mg [11,24-28]. After this dose, incremental doses of 5 to 10 mg are provided every three to six hours as needed to treat withdrawal symptoms (table 3) [24]. In outpatients, United States Federal Regulations limit the initial dose to a maximum of 30 mg and the total first day dose to a maximum of 40 mg if withdrawal symptoms are not fully suppressed by the initial dose, but these restrictions do not apply to patients being treated in the hospital setting. Initiation and titration protocols avoid accumulation and overdose; however, some patients may benefit from more rapid titration. For example, patients who are using nonprescribed fentanyl often have extremely high tolerance and may need rapid titration of methadone to suppress withdrawal symptoms while being carefully monitored for respiratory depression.

For patients with no or only mild symptoms of withdrawal, an alternative approach is to begin with a low initial dose of methadone 10 mg and provide incremental doses of 5 to 10 mg every four to six hours as needed for withdrawal symptoms on the first day of therapy. Mild symptoms of withdrawal can sometimes be managed adequately with counseling, supportive care, and/or clonidine 0.1 mg orally every four to six hours rather than with incremental doses of methadone.

Clinical observation and a structured instrument with a standardized scoring system (eg, Clinical Opiate Withdrawal Scale (table 4)) can be used to assess the progress and severity of withdrawal. (See "Opioid withdrawal: Medically supervised withdrawal during treatment for opioid use disorder", section on 'Monitoring'.)

Dose adjustments in hospitalized patients after the first day of treatment — On the second day of hospital treatment, the total dose of methadone administered over the previous 24 hours is provided as the new morning dose. Patients who initially presented with no or only mild symptoms and were given a low initial dose (10 mg) are provided no less than 30 mg on the second day. Incremental doses are provided as needed.

Daily increments to the morning dose are made until no additional incremental doses are needed to prevent signs and symptoms of withdrawal for at least 24 hours. This is the "stabilization dose" and is achieved when methadone occupies enough opioid receptors to prevent withdrawal [29]. Stabilization may take a week or more, and further adjustments over time may be needed.

Maintenance dosing after initial stabilization — Once the initial stabilization dose has been achieved, the patient is discharged and further dosing adjustments are made at an outpatient treatment center. The dose is not increased for several days even if symptoms occur; we usually wait at least 72 hours before considering an increase in dose [30]. After this 72-hour period, we increase the methadone dose in 5 to 10 mg increments per week, when indicated based on clinical evaluation, to maintain the lowest dose that controls withdrawal symptoms and minimizes cravings. Common discomforts of pregnancy such as nausea, vomiting, and low back pain are similar to some opioid withdrawal symptoms; this possibility should be considered before increasing the daily methadone dose in symptomatic patients [31]. The average patient will require three medication dose increases during the course of pregnancy because of increased metabolism related to the pregnant state [32]. (See 'Pharmacology' above.)

In our experience, the average methadone dose is approximately 120 mg per day. The optimal dose in pregnancy is controversial. The rationale for high-dose therapy is to reach a level sufficiently high that additional doses of nonprescription opioids do not result in euphoria [26,30]. Research from the National Institute on Drug Abuse indicates that methadone doses less than 60 mg are ineffective since they are less likely to prevent drug-seeking behavior. Pregnant patients appear to do better on higher (80 to 120 mg/day) rather than lower methadone doses [33]; doses at these levels are not overly sedating because tolerance develops [30]. Pharmacokinetic changes in methadone metabolism during pregnancy also play a role in the need for high doses. Using pharmacokinetic modeling, at a dose of 90 mg daily, 75 percent of (R-) and 94 percent of (S-) methadone trough levels were below the lower therapeutic window [34].

Awareness of the role of bias in treatment outcomes is particularly important in the OUD population. One study demonstrated that pregnant patients who self-identified as Black or Hispanic received 67 percent of the dose of methadone that white patients received at delivery (mean 105.8 mg versus 144.9 mg) [35]. Use of standardized, objective treatment guidelines may help reduce the disparities in healthcare experienced by patients of color.

Role of twice-daily maintenance dosing — Twice-daily dosing at 12-hour intervals (or rarely, three times daily at 8-hour intervals) results in more sustained plasma levels, fewer withdrawal symptoms, and less nonprescription opioid use than a single high methadone dose [7,36]. Another advantage of split dosing is that it does not suppress fetal movement and breathing as much as single dosing [37,38].

However, split dosing is not possible for all patients because it requires take-home doses. In the US, federal and state regulations list criteria for patients who may have doses of methadone to take home. Eligibility for take-home doses is usually based on adherence to program requirements for counseling and abstinence from nonprescription opioids and other prescription medication misuse (based on urine toxicology testing), as well as absence of recent criminal activity and capacity to store the take-home doses safely in the home environment.

Management of a missed dose — If a patient misses a methadone dose, and this is confirmed with the opioid treatment program, they can resume therapy at the same dose if they have not missed more than three daily doses; after three days of missed doses, they would need restabilization.

If the missed dose cannot be confirmed, methadone should not be provided. The patient should be admitted and assessed for withdrawal using the Clinical Opiate Withdrawal Scale (table 4) [39]. If they are demonstrating signs or symptoms of withdrawal, methadone can be provided in incremental doses up to 50 percent of the reported maintenance dose until additional management can be coordinated with their opioid treatment program.

There is no specific requirement for fetal monitoring due to a missed dose in the absence of standard obstetric indications for fetal surveillance, though some centers routinely obtain a nonstress test or biophysical profile on all patients presenting to the labor and delivery triage unit with pregnancies at or beyond the lower limit of viability.

Role of urine drug testing — After the initial urine drug screening test (UDS) on initiation of care, serial UDS are performed to monitor for continued nonprescription opioid use. Ideally, UDS is performed at weekly visits; in the United States, federal regulations require UDS with a minimum of eight urine tests per year of treatment [40]. UDS is also suggested on admission to the hospital whether for giving birth or other reasons (especially complications possibly associated with nonprescription opioid use [eg, abruption]) if the results will impact maternal or neonatal care. A single positive UDS rarely would lead to discontinuation of medication-assisted treatment. The American Society of Addiction Medicine (ASAM) provides guidelines on the appropriate use of drug testing [41]. Their recommendations are available in multiple forms including an online pocket guide and mobile app [42].

Consent for UDS is not explicitly required; however, a UDS has the same risk of informational harm as other tests that require consent (eg, HIV testing, genetic testing). We agree with the American College of Obstetricians and Gynecologists (ACOG) that consent for UDS should be obtained when possible and in compliance with state laws [43].

One- to two-thirds of patients enrolled in methadone programs continue to use nonprescription opioids and/or misuse other prescription medications or alcohol during pregnancy [44]. Detecting continued polysubstance use is important because it is an indication for additional psychosocial intervention and possibly an increase in methadone dose. In addition, continued polysubstance use may lessen some of the benefits of methadone therapy and increase the incidence and severity of neonatal abstinence syndrome (NAS) [18,45]. For example, use of both benzodiazepines and methadone has been associated with lower birth weight, increased incidence and severity of NAS, and increased risk of maternal respiratory difficulties, coma, or death [27,46,47]. If benzodiazepines are being used, they should be carefully tapered. (See "Benzodiazepine use disorder", section on 'Medically supervised taper'.)

UDS vary with respect to the drugs included in the testing panel. Most panels include naturally occurring opioids and their metabolites, methadone, cocaine, benzodiazepines, barbiturates, amphetamines, and phencyclidine. Testing for synthetic opioids (eg, oxycodone, fentanyl, meperidine, hydromorphone) and buprenorphine may need to be ordered separately. However, an increasing number of commercially available panels test for more substances, including some synthetic opioids (eg, oxycodone, buprenorphine). Providers should be aware of the specific drug tests available to them locally. A detailed discussion of urine drug screening and testing, including interpretation, limitations, validity, and reliability, can be found separately. (See "Testing for drugs of abuse (DOAs)".)

When to check methadone levels — Methadone levels are unnecessary in asymptomatic patients. Determination of a therapeutic dose is based on patient response, which can vary widely among patients [48].

We recommend checking a methadone serum trough level in:

●Patients who remain symptomatic despite increases in methadone dose

●Patients who are excessively sedated two to four hours after dose administration but develop craving or withdrawal symptoms before the next dose is due

However, a single methadone trough level can be difficult to interpret, the number of trough levels for reliable interpretation is unknown, and the turnaround time for the test is typically >7 days, which makes it somewhat impractical. Trough levels should be drawn 24 hours after methadone dose administration [48]. There is no defined therapeutic window, but a methadone trough level of 300 to 400 ng/mL in nonpregnant individuals suggests an adequate total methadone dose and reduced likelihood of heroin use [49] and observations in pregnant patients are consistent with this finding. In a prospective study that evaluated serum trough levels in a cohort of pregnant patients, asymptomatic patients had mean trough levels of 300±160 ng/mL, which was significantly higher than mean trough levels in symptomatic patients (180±110 ng/mL) [50].

If the trough level is <300 ng/mL, management should be guided by symptoms. Withdrawal symptoms in patients with a low trough level suggest that an increased dose may be needed. Excessive sedation with a low trough level often indicates ongoing nonprescription opioid use.

Rapid metabolism of methadone is possible. Rapid metabolizers tend to have a peak to trough ratio >2:1, although peak to trough ratios are not measured clinically. These patients may benefit from split dosing rather than an increase in dose. (See 'Role of twice-daily maintenance dosing' above.)

Note: Drug levels are not useful during induction of methadone because a steady state has not been achieved yet.

Side effects

●Side effects of chronic methadone therapy include constipation, mild drowsiness, excessive sweating, and peripheral edema. (See "Opioid use disorder: Pharmacologic management", section on 'Adverse effects'.)

●Chronic use of methadone and other opioid agonists may result in an increased sensitivity to pain, which may develop within a month of initiating chronic opioid therapy.

●Methadone can prolong the QT interval and cause torsades de pointes and sudden death. Higher methadone doses increase the risk for these events [51]. The confounding influence of other drugs (eg, azithromycin, erythromycin, metronidazole, mifepristone, ondansetron, promethazine, and selective serotonin reuptake inhibitors), a prolonged QT interval at baseline, and hypokalemia also contribute to this risk. An electrocardiogram is recommended before initiation of methadone for patients with significant risk factors [48]. This complication of methadone therapy and approaches to identify patients at high arrhythmic risk are discussed in detail elsewhere. (See "Opioid use disorder: Pharmacologic management", section on 'Adverse effects'.)

Drug interactions — Clinicians should be aware that drug-drug interactions may occur with several common medications and may require the patient's daily methadone dose to be adjusted to prevent complications from such drug-drug interactions. A number of the drug interactions are based on metabolism by the cytochrome P450 isoenzyme system, specifically 3A4. Selected interactions are discussed below and more information is available in the drug interactions program.

●Magnesium sulfate – Though there may be a theoretical risk of additive central nervous system and/or cardiorespiratory depressive effects with combined use of opioids and high doses of magnesium sulfate (as used for prevention of eclamptic seizures or for fetal/neonatal neuroprotection), we have neither observed nor read case reports of such adverse drug interactions and do not alter dosing in patients receiving both drugs during labor.

●Opioid antagonists – Naloxone and other narcotic antagonists may precipitate withdrawal in both the pregnant patient and fetus [6,11,52]. Mixed agonists/antagonist analgesics that are sometimes considered for labor analgesia (eg, nalbuphine, butorphanol, pentazocine) should be avoided. (See "Acute opioid intoxication in adults", section on 'Basic measures and antidotal therapy' and "Prevention of lethal opioid overdose in the community".)

●Rifampin – The antituberculosis drug rifampin induces CYP3A4 and alters P-glycoprotein binding [52,53], which reduces the plasma concentrations of methadone and may lead to opioid withdrawal. Therefore, higher doses of methadone may be required in pregnant patients who are taking rifampin [52].

●Antiseizure medications – The antiseizure medications phenytoin and carbamazepine induce metabolism of methadone. In one study, nonpregnant, methadone-maintained individuals experienced withdrawal symptoms within three to four days of starting phenytoin [54]; a similar response is likely in pregnant patients.

●Antiretroviral drugs – Methadone increases blood levels of zidovudine and may require a 50 percent reduction of the usual dose [6]. Methadone can also decrease concentrations of didanosine and stavudine. Darunavir, efavirenz, nelfinavir, nevirapine, and lopinavir/ritonavir all have the potential to reduce serum methadone concentrations, which could result in methadone withdrawal symptoms and necessitate a methadone dose increase.

●Other – The H2 antagonist cimetidine and the antifungal medication ketoconazole increase methadone levels [28].

Intrapartum and postpartum methadone dosing — The patient's usual oral methadone dose is continued intrapartum (during labor or before scheduled cesarean birth) and postpartum to prevent withdrawal. Intrapartum, some clinicians divide the daily methadone dose into three doses administered every eight hours. (See "Obstetric anesthesia for patients with opioid use disorder or opioid tolerance", section on 'Continue baseline opioid'.)

Although postpartum over-sedation is a theoretic concern since methadone levels may increase as plasma volume and hepatic clearance return to the prepregnant state, we have not observed any cases of oversedation. In a study of 101 methadone-maintained pregnant patients followed for 12 weeks after giving birth, the mean dose change was -3.7 mg (-6.3 to -1.1 mg), 50 percent of patients had either the same or higher methadone doses postpartum, and 5.6 over-sedation events occurred per 10,000 dosing days [55]. Several other studies confirm that most patients will not achieve a significant dose reduction after delivery. The common perception that patients can resume their prepregnancy opioid dose once the metabolic changes of pregnancy resolve postpartum may not be appropriate for feasible [56-58].

Continuing MOUD after discharge is important to support abstinence from other opioids and retention in treatment of OUD. (See "Opioid use disorder: Overview of treatment during pregnancy", section on 'Continue MOUD'.)

Breastfeeding — Breastfeeding should be encouraged in patients who are stable on methadone and not using nonprescription opioids or misusing other prescription drugs, unless other contraindications exist [59]. This recommendation is supported by guidelines from ACOG and the Academy of Breastfeeding Medicine [60] and apply to patients who are enrolled in a methadone program on any dose of methadone. Some of the benefits include improved maternal-infant attachment and favorable effects on NAS [61-64]. It is not clear whether the favorable effects of breastfeeding on NAS are related to breast milk, skin-to-skin contact, or the act of breastfeeding since the amount of methadone in breast milk is small [65]. (See "Infant benefits of breastfeeding" and "Maternal and economic benefits of breastfeeding".)

Neonatal plasma concentrations of methadone are not related to maternal methadone dose [62]. The estimated dose of methadone in breast milk is 1 to 3 percent of the maternal weight-adjusted dose [66]. Infants who were exposed to methadone in utero remain at risk for withdrawal symptoms even while being breastfed by mothers receiving methadone [67]. In very rare cases, infants exposed to methadone in breast milk have experienced serious side effects including severe respiratory depression, heart problems, and death [68,69].

Weaning — In mothers receiving methadone, there is no evidence that the infant is at risk for NAS during gradual reduction of breastfeeding; however, rare reports have described occurrence of NAS when breastfeeding was abruptly discontinued [70]. (See "Prenatal substance exposure and neonatal abstinence syndrome (NAS): Management and outcomes", section on 'Deciding on method'.)

Pregnancy outcome — There is ongoing debate about whether intrauterine exposure to methadone results in long-lasting effects on offspring. The available data, discussed below, are generally reassuring. According to the Substance Abuse and Mental Health Services Administration, the benefits of pharmacotherapy for OUD during pregnancy outweigh the risks of untreated OUD [71].

Neonatal abstinence syndrome — Newborns who withdraw from opioids present with a well-recognized constellation of signs and symptoms known as neonatal abstinence syndrome (NAS). Withdrawal from methadone usually occurs 48 to 72 hours after birth but rarely may be delayed by up to a month [72,73]. The relationship between maternal methadone dose and neonatal withdrawal is controversial and limited by several study design factors. A 2010 meta-analysis concluded that the body of evidence suggests no correlation between methadone dose and severity of neonatal withdrawal at clinically relevant doses [74]. However, a more contemporary single-center retrospective study of 574 methadone-exposed infants, which included a broader range of doses (5 to 610 mg), found a positive correlation between methadone dose and severity of NAS [75]. (See "Prenatal substance exposure and neonatal abstinence syndrome (NAS): Management and outcomes" and "Prenatal substance exposure and neonatal abstinence syndrome (NAS): Clinical features and diagnosis".)

When recognized and managed appropriately, there are no proven long-term sequelae of NAS; however, treatment often requires a lengthy neonatal intensive care unit admission (median length of stay from 13 to 19 days) and results in significant health care costs (totaling USD $1.5 billion in aggregate costs or USD $66,700 per infant with NAS [76,77]). Frequently overlooked are the significant maternal psychologic stress from feelings of guilt and sadness and delayed maternal-fetal bonding when the infant is in an intensive care unit rather than rooming in or at home.

The clinical manifestations and management of neonatal withdrawal are reviewed in detail separately. (See "Prenatal substance exposure and neonatal abstinence syndrome (NAS): Management and outcomes".)

Risk of congenital anomalies — Methadone is not clearly associated with any structural fetal anomalies [71]. In a 2016 systematic review comparing methadone versus buprenorphine treatment of pregnant patients with OUD (one randomized trial [131 neonates] and four observational studies [933 neonates]), there was no significant difference in risk of congenital anomalies between the two treatments, and the overall risk of anomalies was similar to that in the general obstetric population [78].

While some individual studies have described congenital anomalies, there is no clear pattern of anomalies [79]. Additionally, the available information is complicated by multiple confounders including maternal use of nonprescription opioids, use/misuse of other prescription medications, other illicit drug use, high smoking rates, poor nutrition, increased prevalence of infection, poor engagement with antenatal care, and complicated psychosocial circumstances. Other methodologic issues include lack of an appropriate control group, failure to provide adequate details about timing of exposure, and poor characterization of anomalies. Most studies used a cross-sectional study design, which cannot prove causation.

Several studies have reported an association between methadone exposure and Pierre Robin sequence (PRS) [80-82]. The largest of these used data from 12 European Surveillance of Congenital Anomalies (EUROCAT) registries covering nearly four million births [81]. There was an association between methadone exposure and PRS (odds ratio 15.5; 95% CI 6.1-33.3); however, the study was unable to show causation due to potential confounding factors such as alcohol use and smoking, which are similarly associated with PRS. Regardless, the prevalence of PRS is very low (<1/10,000 births), so the possible absolute increase in PRS with methadone exposure is small and should be balanced against the risk of untreated OUD during pregnancy, which has well-described adverse consequences.

Risk of other fetal and neonatal effects

●Thyroid — Enlargement of the fetal thyroid has been reported in methadone-exposed infants, possibly due to changes in monoamine neurotransmitter systems [83]. The functional significance of this enlargement is unclear.

●Prolonged QTc — QTc intervals >450 milliseconds have been reported in 15 to 19 percent of methadone-exposed neonates. All resolved by seven days without cardiac events [51,84].

●Visual development — Several studies have suggested that prenatal exposure to methadone may result in abnormal visual development. In a systematic review of 12 studies that reported visual outcomes in offspring of patients prescribed methadone in pregnancy (275 methadone-exposed versus 128 unexposed), the prevalence of childhood strabismus and nystagmus in the methadone-exposed population was approximately 50 percent, which was higher than expected; differences in visual evoked potentials (VEPs) were also noted [85]. In one of the included studies, the majority (70 percent) of infants with prenatal exposure to methadone demonstrated some type of visual disturbance [86].

Most studies lacked sufficient information to adequately control for other prenatal exposures, thus limiting the ability to make any conclusion about causation. The prevalence of tobacco use among patients with OUD is >90 percent. Like methadone, prenatal exposure to tobacco and other illicit drugs (eg, cocaine, amphetamines) has also been associated with ophthalmic abnormalities [87]. Maternal smoking increases the risk for optic nerve hypoplasia and also results in a significantly thinner retinal nerve fiber layer [88]. Additionally, a study found that strabismus increased proportionally with the number of cigarettes smoked, reaching a relative risk of 1.9 (95% CI 1.57-2.30) at >10 cigarettes/day [89].

The long-term significance of these findings is unclear. In at least one study, differences in VEPs in infants born to patients with OUD-prescribed methadone remained after adjusting for tobacco use [86]. In another study, the findings were transient: In 36-month old children, there was no difference in VEPs between children exposed to methadone and a group of unexposed children [90].

●Size and gestational age at birth — Methadone pharmacotherapy has been associated with an increased risk of adverse neonatal outcomes, such as preterm birth <32 weeks of gestation, small for gestational age infants, low birth weight, decreased head circumference, and sequelae often associated with these outcomes: jaundice, thrombocytosis, and admission to a neonatal intensive care unit [80,91]. However, methadone pharmacotherapy appears to improve birth weight compared with patients using nonprescription opioids, even if not quite to the birth weights seen in the general population (mean difference -295 g).

The association between in utero exposure to methadone and adverse outcome is somewhat explained by confounders such as race, body mass index, gestational weight gain, cigarette smoking, socioeconomic deprivation, maternal age, and parity [80,92-95]. Although some studies have reported that daily doses of 80 to 160 mg adversely affected fetal growth, these findings have not been consistent across studies and could have been due to confounders [19,44,96,97].

●Sudden neonatal death — Opiates have been implicated as a cause of sudden infant death [98]. A retrospective study of sudden death demonstrated an unexpectedly high proportion of neonatal deaths in which there was a maternal history of methadone use (31 percent of 32 neonatal deaths evaluated by autopsy) [99]. Many of these were also complicated by maternal nonprescription opioid use and misuse of other prescription drugs. Whether the deaths were related to methadone (possibly due to QT prolongation) or other factors (eg, exposure to parental smoking or unsafe sleeping practices) is unclear.

While not all factors are easily addressed in the short term, unsafe sleep practices (8 of 32 cases) is an opportunity for harm reduction; patients should be educated about safe sleep before being discharged home, and the message should be reinforced at visits with a medical provider during the postpartum period. (See "Sudden infant death syndrome: Risk factors and risk reduction strategies", section on 'Sleep position and environment'.)

Risk of adverse long-term consequences — Determining the possible long-term consequences of in utero methadone exposure is complicated by a multitude of factors, including concomitant prenatal and postnatal exposures, medical factors, and sociodemographic factors, all of which have potential implications for neurodevelopmental outcome. Another limitation is the high rates of attrition (31 to 70 percent) in many studies [85]. While research attempts to adjust for these variables, confounding by other measurable or unmeasurable differences between groups limits conclusions that can be drawn about prenatal opioid exposure and long-term neurodevelopmental outcome [100]. Therefore, the clear benefits of treatment of OUD with maintenance agonists should be emphasized when counseling patients with OUD about treatment.

●Neurodevelopment – Differences in motor performance, speech and language performance, cognitive performance, and behavior have all been reported in methadone-exposed infants and children. In a 2019 meta-analysis of childhood neurodevelopment after prescription of maintenance methadone for opioid dependency in pregnancy, compared with unexposed infants, methadone exposure was associated with a lower Mental Development Index (MDI; weighted mean difference [WMD] -4.43, 95% CI -7.24 to -1.63) and lower Psychomotor Development Index (PDI; WMD -5.42, 95% CI -10.55 to -0.28) at age two years, but no differences were seen in studies reporting MDI and PDI at age six months [85]. The authors postulated that differences often appear as children grow older. Studies published subsequent to the meta-analysis have demonstrated similar results while controlling for confounding to the extent possible [101,102].

Opioids (and opioid metabolites) freely cross the placenta – Opioid receptors are present in several fetal neurologic structures from a very early gestational age. Studies demonstrating that methadone may alter development of dopaminergic, cholinergic, and serotonergic systems; myelination; and the microstructure of major white matter tracts lend biologic plausibility to the concept that in utero exposure to methadone may have adverse long-term neurodevelopmental consequences [103,104]; however, this probably applies to most, if not all, opioids and is not specific to methadone. Findings from neuroimaging studies also have significant limitations due to failure to account for polysubstance abuse, smoking, nutritional deficiency, and other antenatal and early life exposures.

●Hospitalization – In a registry study from the Czech Republic, hospitalization for infection, gastrointestinal, and skin diseases among children ages 0 to 3 years was higher among offspring of mothers in an opioid maintenance treatment program than those in the general population; in utero methadone exposure was associated with a higher risk of hospitalization and longer hospitalization than in utero buprenorphine exposure [105]. Notably, in the Czech Republic, methadone is available at no cost while buprenorphine may be cost-prohibitive for many patients, which introduces bias based on ability to pay.

BUPRENORPHINE PHARMACOTHERAPY

Provider — In the United States, buprenorphine can be dispensed by an opioid treatment program and can be prescribed by any provider who is licensed under state law and possesses a valid Drug Enforcement Administration (DEA) registration. In 2023 the Consolidated Appropriations Act removed the requirement of obtaining a federally required DATA waiver (X-Waiver). This allows clinicians with schedule III authority on their DEA registration to prescribe buprenorphine for opioid use disorder if permitted by applicable state law [106]. The limits on the number of patients a prescriber may treat for OUD with buprenorphine were also removed.

A directory of providers licensed to prescribe buprenorphine is available online. It is not a complete listing because clinicians can request not to be listed.

Pregnant patients may experience more difficulty compared with nonpregnant patients when attempting access treatment from buprenorphine providers. This may be due to variability in insurances accepted, high out-of-pocket costs, and the provider's comfort level treating pregnant individuals [107].

As with methadone, successful pharmacotherapy depends upon a comprehensive, multidisciplinary, coordinated approach to care [2,3]. In contrast to methadone, which is typically administered at a comprehensive treatment center (ie, availability of pharmacotherapy along with social work and psychiatry), buprenorphine is typically prescribed in the office of the credentialed clinician, unless the patient is admitted for opioid withdrawal and/or to coordinate outpatient treatment. If prenatal care is not available onsite at the office, then these services will need to be arranged separately [26,30,108].

Pharmacology — Buprenorphine acts as a partial agonist at the mu-opioid receptor and has a prolonged duration of action due to its high affinity for the receptor. It is also an antagonist at the kappa opioid receptor. Pharmacologic effects are similar to full opioid agonists (eg, morphine, methadone), but with a "ceiling effect" at high doses across a range of pharmacodynamic measures [109]. This lowers the potential for adverse effects from overdose (eg, respiratory depression), but could also explain why there is greater treatment retention with methadone, especially compared with certain buprenorphine doses/dosing regimens.

Buprenorphine suppresses withdrawal for 24 to 48 hours; typical dosing for OUD is every 24 hours [110,111]. Peak plasma levels occur at approximately 90 minutes and increase linearly with increasing dose. The drug is highly lipophilic, 96 percent bound to plasma proteins, and metabolized by the liver with an active metabolite, norbuprenorphine [111]. It is primarily metabolized by the cytochrome P450 enzyme pathway.

Lower maximum plasma buprenorphine concentrations and total 24-hour plasma levels have been demonstrated during pregnancy compared with the postpartum period [112]. In one study, some patients with OUD excreted a higher percentage of their daily buprenorphine dose during pregnancy than postpartum, indicating possible enhanced renal elimination antenatally [113]. Most of the study participants were prescribed a higher buprenorphine dose as pregnancy progressed.

Buprenorphine and its pharmacologically active metabolites cross the placenta [114,115]. In a study of patients with OUD receiving maintenance doses of buprenorphine, mean cord/maternal ratios for buprenorphine and norbuprenorphine were 0.43 and 0.53, respectively [115]. Transplacental transfer and metabolism do not appear to differ significantly in preterm placentas [116].

Formulations and administration — Buprenorphine is available in a variety of forms and is available with and without naloxone. In the United States, formulations approved by the US Food and Drug Administration include sublingual tablets, film, buccal film (form with naloxone no longer available), and implant. Sublingual, or buccal, formulations have significantly greater bioavailability compared with oral administration and are the most common formulation used during pregnancy.

Proper use of buprenorphine films or tablets is important to ensure absorption; misuse may result in lower bioavailability and consequently lower peak concentrations/effect. Patients should be instructed to drink water to moisten the mouth before taking buprenorphine. Buprenorphine is placed under the tongue (left or right side) or inside the cheek depending on prescribed route of administration and kept in place until completely dissolved, which typically takes 30 minutes. Buprenorphine should not be chewed or swallowed. Eating, drinking, and/or smoking cigarettes should be avoided until the medication has fully dissolved.

Buprenorphine has been available as an implant (Probuphine) since 2016 and a monthly extended-release subcutaneous injection (Sublocade) since 2017. There are no adequate or well-controlled studies of these formulations in pregnant patients; however, the risks should be comparable to buprenorphine in other forms. The implant is an option for nonpregnant patients with sustained clinical stability on no more than 8 mg of buprenorphine. In patients who conceive while using an implant, we recommend not removing it; however, they should be closely monitored for symptoms as a higher dose of buprenorphine may be required during pregnancy and the dose of the implant cannot be changed [117]. The implant can be supplemented with sublingual buprenorphine in these cases.

Initial and maintenance dosing

●When to start – Because it is a partial agonist at the mu-opioid receptor, initiation of buprenorphine may lead to withdrawal symptoms in patients who have recently used opioids. To minimize this risk, it should be initiated when a patient begins to show objective, observable signs of moderate withdrawal (table 3), usually six hours or longer after the last dose of a short-acting opioid, and potentially longer (24 hours to 48 hours) following the use of long-acting opioids [118,119], but before severe withdrawal symptoms occur. Alternatively, microdosing does not require patients to abstain from opioids.

Bothersome mild withdrawal symptoms during this time can be treated with a variety of over-the-counter and prescription medications, such as acetaminophen for aches, antacids for indigestion, loperamide for diarrhea, and hydroxyzine or diphenhydramine for anxiety and restlessness [119]. Alternatively, clonidine can be prescribed. (See "Opioid withdrawal in the emergency setting", section on 'Management' and 'Starting dose in hospitalized patients' above.)

●Initial dosing – There is no consensus on the optimal method of induction of buprenorphine during pregnancy [118-120]. Our approach for initial and subsequent dosing is the same as that in nonpregnant patients: A typical starting dose for buprenorphine is 2 to 4 mg given sublingually. After two hours of observation, if withdrawal symptoms remain, an additional 2 to 8 mg of buprenorphine can be administered.

On the following day, the patient is given a single dose consisting of the total of the doses received the first day (up to 8 mg). Following observation for residual withdrawal symptoms, the dose may be increased in 4 mg increments, up to a maximum of 16 mg total during initial stabilization. Most patients will stabilize on 8 to 16 mg/day [121], so the dose should not be increased above 16 mg for several days to allow time to reach pharmacologic steady state. (See "Opioid use disorder: Pharmacologic management", section on 'Buprenorphine: Opioid agonist'.)

One study observed that buprenorphine is cleared more extensively by pregnant than postpartum patients [122], and some authors have suggested three or four times daily dosing may be required in pregnancy to sustain plasma concentrations [117].

•Role of low-dose initiation – Conventional buprenorphine induction protocols may initiate precipitated withdrawal. This is of particular concern because of the increased prevalence of fentanyl use, which has been associated with a higher risk of precipitated withdrawal attributed to its specific pharmacologic properties (wide interindividual variability in elimination half-life, high affinity for the mu-opioid receptor, and lipophilicity leading to a large volume of distribution) [42,123]. Rather than waiting for moderate withdrawal, an alternative strategy is low-dose initiation ("microinduction" or "microdosing"), which uses small buprenorphine doses (as low as 150 mcg), slowly escalating the dose over the course of several days.

Microdosing may be considered in patients who are unable to tolerate the opioid withdrawal associated with traditional induction, patients transitioning from methadone to buprenorphine, or patients using illicit fentanyl as they may experience greater withdrawal effects [123].

Reports of this approach to treatment of OUD in pregnancy are limited but have reported good outcomes [124-127]. This method of induction should only be used by providers with adequate experience.

●Maintenance dosing – Some authors have suggested that unlike methadone, patients maintained on buprenorphine typically do not require large dose adjustments during pregnancy [118]. However, data from three randomized trials [128-130] demonstrated the need for buprenorphine dose adjustments throughout pregnancy; the average increase was 3 mg [120]. Pharmacokinetic studies confirm increased CYP- and UGT-mediated metabolism providing physiologic evidence to support dose increases [131].

Patients with hepatic or renal insufficiency

●Hepatic dysfunction – Buprenorphine is primarily metabolized by the liver. Severe hepatic dysfunction is a contraindication to use. Lesser degrees of hepatic dysfunction may impair buprenorphine metabolism; in these patients, a reduction in dose or the frequency of administration may be necessary.

Liver function tests are obtained at baseline, but waiting for the results should not delay treatment [132]. The tests should be repeated periodically during treatment. There is no evidence to guide the frequency of monitoring, but testing every six months is adequate for most patients. Prompt additional testing is indicated in those with signs/symptoms of hepatotoxicity (eg, fever, malaise, nausea/vomiting).

Buprenorphine can cause significant elevations in aspartate aminotransferase and alanine aminotransferase [133,134]. In patients with laboratory evidence of hepatotoxicity (transaminase levels >3- to 5-fold higher than normal), all possible causes of liver injury should be evaluated and consideration should be given to lowering the dose or discontinuing buprenorphine [135].

●Renal impairment – Some authors believe that buprenorphine doses do not need to be adjusted in patients with renal impairment [133,134]; however, manufacturers suggest caution when dosing patients with severe renal impairment (creatinine clearance <30 mL/min), or slow titration of doses until dose stabilization [136-138]. In clinical practice, buprenorphine is mainly metabolized in the liver and can be safely tolerated by patients with renal impairment; however, these patients should be monitored for symptoms and dose adjustments made based on clinical assessment.

Management of a missed dose — Patients may present to the labor and delivery unit requesting buprenorphine because of a "lost" or "stolen" dose. In this case, efforts should be made to contact their prescriber to confirm dosing and follow-up. If the provider cannot be reached and assistance from a clinician with experience in this area is not available, the patient should be questioned to detect any suggestion of drug diversion or nonprescription opioid use and examined to assess for signs of intoxication/overdose or withdrawal (eg, using the Clinical Opiate Withdrawal Scale score), and urine should be sent for a toxicology screen. (See "Acute opioid intoxication in adults", section on 'Clinical features of overdose' and "Opioid withdrawal: Medically supervised withdrawal during treatment for opioid use disorder".)

In the absence of evidence of other opioid use, a single missed dose of buprenorphine can be replaced safely and the usual dose resumed. Prescription drug monitoring programs exist in every state except Missouri. Many will include recent prescriptions for controlled substances including buprenorphine, and the dose can often be confirmed this way. If a record of the dose is not available or there is any concern about the patient’s reliability, a 2 mg test dose can be given. If there is no evidence of sedation, then the patient's usual dose can be given two hours later. The patient should only be given a single dose of their usual dose and then referred to their personal buprenorphine provider for further management.

A brief period of maternal observation may be considered before discharging the patient. There is no requirement for fetal assessment in the absence of other indications, though some centers routinely obtain a nonstress test or biophysical profile on all patients presenting to labor and delivery unit triage who are at or beyond the lower limit of viability.

Role of urine drug testing — Urine drug testing for patients on buprenorphine is performed as clinically appropriate, in contrast to those on methadone who are supposed to have at least eight urine drug screening tests (UDS) per year [40]. The frequency of UDS to monitor adherence to therapy and continued nonprescription opioid use varies by phase of treatment. Early in treatment, UDS may be performed every one to two weeks and then at least monthly during maintenance treatment.

A specialized assay can be ordered to detect buprenorphine since it is often not detected by standard UDS, which identifies naturally occurring opiates and their metabolites. However, an increasing number of UDS are able to detect buprenorphine, so providers should be familiar with the tests available at their location.

When to check buprenorphine levels — A quantitative buprenorphine urine level can be obtained to verify buprenorphine use, but can be falsified by adding pieces of buprenorphine tablets to the urine. If tampering is suspected, then the urine should be tested for buprenorphine metabolites (eg, norbuprenorphine).

Buprenorphine levels are not used to guide dosing.

Side effects — Common side effects include chills, fever, abdominal pain, vasodilation, withdrawal, constipation, nausea, vomiting, diarrhea, insomnia, and anxiety. Like other opioids, buprenorphine may cause respiratory depression, particularly when taken with benzodiazepines or other central nervous system depressants [139]. Acute hepatotoxicity has been reported rarely in patients with OUD treated with buprenorphine.

Because it is a partial agonist at the mu-opioid receptor, initiation of buprenorphine may lead to withdrawal symptoms in patients with OUD, particularly if it is given within six hours of opioid use [136].

Drug and chemical interactions — Buprenorphine has fewer drug interactions compared with methadone [140,141]. It does not increase the QT interval to any clinically meaningful degree. A brief synopsis of drug interactions follows; more information is available in the drug interactions program.

●Because it is primarily metabolized by the cytochrome P450 enzyme pathway, close monitoring for withdrawal symptoms is recommended for buprenorphine-maintained patients who are started on CYP3A4 inducers (eg, rifampicin, phenobarbital, carbamazepine), as dose increases may be required. In contrast, dose reduction may be required if CYP3A4 inhibitors (eg, ketoconazole, gestodene, clarithromycin, and some HIV protease inhibitors) are used concomitantly with buprenorphine.

●Although there may be a theoretical risk of additive central nervous system and/or cardiorespiratory depressive effects with combined use of opioids and high doses of magnesium sulfate (as used for prevention of eclampsia or for neuroprotection), we have neither observed nor read case reports of such adverse drug interactions and do not alter dosing in patients receiving both drugs during labor.

●Benzodiazepines, and other sedative hypnotics, may act synergistically with buprenorphine. As with methadone, co-prescribing buprenorphine with benzodiazepines may increase the risk of respiratory difficulties, coma, or death [142]; carefully tapering benzodiazepines is recommended.

Intrapartum and postpartum buprenorphine dosing — Patients admitted in labor or before scheduled cesarean birth should continue to receive their full daily buprenorphine dose. Discontinuation exposes the mother and fetus to the potential risks of withdrawal. Furthermore, discontinuation can precipitate withdrawal symptoms during reintroduction of buprenorphine in postpartum patients receiving opioid analgesics for pain control [143].

Buprenorphine maintenance therapy is usually dosed once daily; patients taking split doses should continue taking their buprenorphine as prescribed. Intrapartum, some clinicians divide the daily buprenorphine dose into three doses administered every eight hours. (See "Obstetric anesthesia for patients with opioid use disorder or opioid tolerance", section on 'Continue baseline opioid'.)

Doses of buprenorphine and other prescribed opioids should be verified when possible, especially on admission to labor and delivery. Verification can be accomplished by querying the prescription monitoring program database; however, when dose verification is not possible, such as in an emergency, the daily opioid dose reported by the patient can be given in two to four divided doses while monitoring for sedation and respiratory depression [144]. This approach may also be useful when there is concern about whether the patient is taking their entire prescribed dose [144].

If the buprenorphine dose was increased during pregnancy, the need to continue this increased dose should be assessed postpartum. Dose adjustments may also be needed in the postpartum period. Overall, during the first year after delivery, one study reported that dose increases were relatively common: zero to four months, 45.3 percent; four to eight months, 33.3 percent; 8 to 12 months, 33.3 percent [145].

Continuing MOUD after discharge is important to support abstinence from other opioids and retention in treatment of OUD. (See "Opioid use disorder: Overview of treatment during pregnancy", section on 'Continue MOUD'.)

Breastfeeding — Several guidelines from national organizations have considered use of buprenorphine pharmacotherapy compatible with breastfeeding [23,70,146-148]. The drug's poor bioavailability when taken orally means it is unlikely that significant absorption will occur from ingestion of breast milk. Based on data from a few small series, a breastfed infant would receive <1 percent of the maternal weight-adjusted dose [148]. The small amounts of buprenorphine in human milk are unlikely to have short-term negative effects on the developing infant [149]. However, breastfed infants should be monitored for respiratory difficulty, sedation, appropriate feeding, and attainment of developmental milestones, especially in younger, exclusively breastfed infants [70,148].

Pregnant patients taking the combination buprenorphine and naloxone can be encouraged to breastfeed; although no human safety data are available, neonatal effects are unlikely based upon the limited bioavailability of naloxone [150]. (See 'Use of combined buprenorphine and naloxone formulation' below.)

Weaning — A single case of infant withdrawal symptoms after sudden cessation of breastfeeding has been reported [151]. Despite the low risk, abrupt cessation of breastfeeding is not recommended [152]. Patients who wish to discontinue breastfeeding are advised to gradually wean the infant from breast milk over a period of two weeks. (See "Prenatal substance exposure and neonatal abstinence syndrome (NAS): Management and outcomes", section on 'Deciding on method'.)

Pregnancy outcome — There is ongoing debate about whether intrauterine exposure to buprenorphine or buprenorphine and naloxone results in long-lasting effects for the infant. The available data, discussed below, are generally reassuring. However, studies assessing the impact of buprenorphine on pregnancy outcomes are limited by a multitude of factors, including concomitant exposures to medications and illicit drugs, comorbidities, nutritional factors, and sociodemographic factors, which may confound any association between buprenorphine and adverse pregnancy outcomes.

According to the Substance Abuse and Mental Health Services Administration, the benefits of pharmacotherapy for OUD during pregnancy outweigh the risks of untreated OUD [71].

Neonatal abstinence syndrome — Interest in buprenorphine as an alternative to methadone stems from data showing a lower rate of neonatal withdrawal (neonatal abstinence syndrome [NAS]), which has been attributed to its lower bioavailability, lower transplacental passage, and greater affinity to binding to the mu-opioid receptor but with less intrinsic activity than methadone [118,120].

Data regarding the relationship between the maternal dose of buprenorphine and need for treatment of NAS remain conflicting [153-155]. Quantification of buprenorphine in meconium samples of 10 infants born to buprenorphine-treated patients demonstrated that neither cumulative nor total third-trimester buprenorphine exposure predicted meconium concentrations or infant outcomes [156]. However, there was a possible relationship between meconium buprenorphine concentrations and the onset of NAS.

In a study with 41 participants entering treatment at a specialized treatment program for pregnant individuals, both maternal buprenorphine dose and prenatal polysubstance exposure to illicit substance use/licit substance misuse were independently associated with NAS expression [154]. Polysubstance exposure was associated with more severe NAS expression after controlling for the effects of buprenorphine dose, but unlike with methadone, severity was not related to either cigarette or selective serotonin reuptake inhibitor use.

Risk of congenital anomalies — Studies of buprenorphine use in pregnancy have not demonstrated an increased risk of congenital anomalies [157].

●A 2016 systematic review including one randomized trial (131 neonates) and four observational studies (933 neonates) comparing methadone versus buprenorphine treatment of pregnant patients with OUD found no significant difference in risk of congenital anomalies between the two treatments, and the overall risk of anomalies was similar to that in the general obstetric population [78]. These data, although reassuring, are insufficient to determine whether either drug is associated with an increased risk of congenital anomalies. Most of the included studies had a medium to high risk of bias, poorly characterized reported defects, failed to describe relevant confounders (maternal use of nonprescription opioids and other substance use, alcohol, and cigarettes; poor maternal nutrition; increased prevalence of maternal infection) or provide adequate details about timing of exposure, and may have missed anomalies not previously known or immediately apparent at birth.

●A study restricted to analysis of congenital anomalies among pregnancies exposed to buprenorphine in the first trimester reported an 8.4 percent rate of anomalies (prevalence ratio compared with no opioid use in pregnancy 2.0, 95% CI 1.2-3.2) [158].

Although concerns about the effects of methadone on the developing visual system have been raised (see 'Risk of other fetal and neonatal effects' above), buprenorphine exposure does not appear to confer this risk [90]. There are no data on the effect on the thyroid in humans.

Birth weight — Compared with neonates born to nonopioid-dependent patients, neonates exposed in utero to buprenorphine appear to have lower birth weight; however, the effect on head circumference is less clear, with at least one study reporting no reduction in head circumference [159]. Several observational and randomized studies have demonstrated longer gestation, increased birth weight, and larger head circumference in buprenorphine-exposed versus methadone-exposed pregnancies [78,160].

These are interrelated variables (ie, larger head circumference may be the result of later gestational age at birth), and most studies were limited in their ability to control for confounding factors (eg, prior obstetric history, smoking, etc). Other large studies have not consistently confirmed a difference in these outcomes [159,161,162].

Risk of adverse long-term consequences — There are few long-term neurodevelopmental studies of buprenorphine-exposed fetuses [162-166]. The lack of such studies documenting absence of adverse long-term effects should be discussed with patients contemplating buprenorphine maintenance therapy [23]. Most of the available data come from small retrospective series lacking comparisons with existing treatments, untreated patients with OUD, or normal controls; therefore, the ability to address confounding factors is limited (especially exposure to other substances). Research on long-term neurodevelopmental outcome is further limited by high rates of attrition, heterogeneity in the methods of assessment, and length of follow-up.

●Cognitive and motor development.

•One study (n = 21 children) reported lower scores on cognitive and language scales at three years of age in children exposed prenatally to maternal buprenorphine use compared with nonexposed controls [163].

•A longitudinal study, which included 73 children evaluated at 24 months (n = 24 buprenorphine exposed, n = 19 methadone exposed, n = 30 nonexposed controls) found no differences between groups in neurologic development or temperament during the first two years of life [162].

•A retrospective study observed that in utero exposure to maternal methadone dose >100 mg/day was associated with a reduction in infant head circumference compared with buprenorphine or lower dose methadone; it also appeared to have a negative impact on motor skill development during early infancy [167], but others have not confirmed this finding [168].

●Brain imaging and EEG.

•A small series reported no structural or signal abnormalities on neonatal magnetic resonance imaging in seven infants exposed in utero to buprenorphine pharmacotherapy [164].

•A small series reported no abnormalities on electroencephalography (n = 9 neonates) or cranial ultrasound (n = 10 neonates) born to patients on buprenorphine pharmacotherapy [165].

●Visual development – Differences in visual development typically have not been noted after in utero buprenorphine exposure. An increase in strabismus was observed in one study (odds ratio [OR] 3.54; 95% CI 1.26-9.94); however, cigarette use was also strongly associated with strabismus and reduced visual acuity [169]. Further study is needed to determine whether the impact on visual development is due to buprenorphine or other co-occurring exposures.

SPECIAL ISSUES

Preconception pharmacotherapy — Conceiving while on methadone has been associated with better drug treatment outcomes compared with individuals who initiate methadone during pregnancy [46].

Switching from methadone to buprenorphine therapy — We agree with the American College of Obstetricians and Gynecologists' recommendation against transitioning patients from methadone to buprenorphine before or during pregnancy [23]. If a patient desires to switch, this should be managed by clinicians with appropriate expertise and preferably prior to conception and following an established protocol [170].

There is no compelling reason to switch patients already on methadone to buprenorphine either before or during pregnancy. Transition from methadone to buprenorphine introduces the possibility for destabilization [119,171]. Transfer from methadone or other long-acting opioids can induce withdrawal symptoms and cause transient dysphoria, although transfer from short-acting opioids appears to be safe [172].

Switching from buprenorphine to methadone therapy — There is no compelling reason to switch patients from buprenorphine to methadone who are stable on treatment and who are trying to conceive or are pregnant. According to the World Health Organization guidelines for pharmacologic treatment of opioid dependence: If patients are being successfully treated with buprenorphine, then the benefit of staying with a treatment that is working should be taken into consideration [173]. However, continued opioid withdrawal symptoms or opioid craving/recidivism may suggest a poor response to buprenorphine. In these patients, switching from buprenorphine to methadone may be reasonable.

Use of combined buprenorphine and naloxone formulation — Buprenorphine is also available in combination with naloxone in a 4:1 ratio. The naloxone combination product is intended to deter intravenous abuse of the sublingual formulation because crushing and injecting the combination formulation causes withdrawal symptoms, which do not occur when the tablet or filmstrip is taken orally or sublingually [174]. However, actual deterrence has not been proven. (See "Opioid use disorder: Pharmacologic management", section on 'Transmucosal formulations'.)

Buprenorphine and naloxone has been the predominant formulation used in the United States because of the perceived benefits of reduced diversion and misuse and limited access to alternative agents in some areas. The available experience with buprenorphine and naloxone use during pregnancy has been reassuring. A few small studies reported no significant differences in maternal or neonatal outcomes compared with use of buprenorphine alone or methadone, but these studies are limited by small sample size and lack of control for confounders such as exposure to other drugs. In a meta-analysis of studies of pregnant patients undergoing treatment for OUD, which included a total of 291 pregnant patients treated with buprenorphine and naloxone, there was no difference in obstetrical or neonatal outcomes between those treated with buprenorphine and naloxone compared with those treated with other medications for OUD [175]. A subgroup analysis showed no difference when treatment with buprenorphine and naloxone was compared with the buprenorphine monoproduct [176]. Long-term follow-up studies of neurodevelopmental outcome are not available. In animal studies naloxone was not associated with an increased risk of congenital anomalies. Naloxone is not detectable in the blood when taken orally and is only detectable at low levels (10 percent) when taken sublingually.

Previous guidelines recommended use of the buprenorphine monoproduct because of theoretical risks of naloxone exposure and withdrawal from misuse, but these risks are not supported by the available data. However, the monoproduct has a higher potential for diversion and misuse, and a higher street value, when compared with the combination product [23]. The American Society of Addiction Medicine (ASAM) issued a focused update to the National Practice Guideline for the Treatment of Opioid Use Disorder, which acknowledged that despite limited data on the use of buprenorphine and naloxone, the consensus of the guideline committee is that the combination product is safe and effective in the pregnant population [177].

There is no reason to preferentially start pregnant patients on the monoproduct, or switch to the monoproduct in patients who were previously stable on the combination product, although switching was advised in the past. Prescribing decisions should be made with the patient's informed consent after review of the risks and benefits [132].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Opioid use disorder and withdrawal" and "Society guideline links: Substance misuse in pregnancy".)

SUMMARY AND RECOMMENDATIONS

●Overview – The advantages and disadvantages of methadone versus buprenorphine pharmacotherapy of opioid use disorder (OUD) are compared in the tables (table 1 and table 5). (See "Opioid use disorder: Overview of treatment during pregnancy", section on 'Methadone or buprenorphine?'.)

●Methadone

•Pharmacology and adverse effects – With advancing gestational age, plasma levels of methadone progressively decrease and clearance increases so that the half-life falls from an average of 22 to 24 hours in nonpregnant patients to eight hours in pregnancy. Methadone can prolong the QT interval and cause torsades de pointes. (See 'Pharmacology' above and 'Side effects' above.)

•Dosing

-We begin methadone therapy in an inpatient setting with a single oral dose of methadone 20 to 30 mg for most symptomatic patients. After the initial methadone dose, incremental doses of 5 to 10 mg are administered every three to six hours as needed to treat withdrawal symptoms. After initial stabilization, the patient is discharged, and the methadone dose is increased in 5 to 10 mg increments per week, if indicated, to maintain the lowest dose that controls withdrawal symptoms and minimizes the desire to use additional opioids. In our experience, the average dose is approximately 120 mg. (See 'Initial dosing' above and 'Maintenance dosing after initial stabilization' above.)

-Twice-daily dosing at 12-hour intervals (or rarely, three times daily at eight-hour intervals) results in more sustained plasma levels, fewer withdrawal symptoms, less illicit drug use, and less effect on fetal behavior than a single high methadone dose. However, split dosing is not possible for all patients because it requires that she is a candidate for take-home doses. (See 'Role of twice-daily maintenance dosing' above.)

-Opioid withdrawal symptoms mimic common discomforts of pregnancy (nausea, vomiting, low back pain), which should be taken into account before increasing the daily methadone dose. (See 'Maintenance dosing after initial stabilization' above.)

-The patient's usual methadone dose should be continued intrapartum. (See 'Intrapartum and postpartum methadone dosing' above.)

•Laboratory monitoring

-Weekly urine drug screens are performed to monitor for continued nonprescription opioid use and prescription medication misuse. (See 'Role of urine drug testing' above.)

-Methadone levels are unnecessary in asymptomatic patients. We check a methadone serum trough level in symptomatic patients with a negative urine drug screen who are excessively sedated or symptomatic despite an increase in methadone dose. These patients may benefit from split dosing. (See 'When to check methadone levels' above and 'Role of twice-daily maintenance dosing' above.)

•Breastfeeding – Patients are encouraged to breastfeed. Those who wish to discontinue breastfeeding should be advised to gradually wean the infant from breast milk over a period of two weeks to reduce the risk of neonatal withdrawal. (See 'Breastfeeding' above and 'Weaning' above.)

●Buprenorphine

•Provider – In the United States, buprenorphine can be dispensed by any provider with schedule III authority on their DEA registration to prescribe buprenorphine for opioid use disorder if permitted by applicable state law. (See 'Provider' above.)

•Candidates – To minimize the risk of buprenorphine-induced withdrawal symptoms, it should only be initiated when a patient shows objective, observable signs of moderate opioid withdrawal (table 3), usually six hours or longer after the last dose of a short-acting opioid, and potentially longer (24 to 48 hours) following the use of long-acting opioids. (See 'Initial and maintenance dosing' above.)

•Dosing

-There is no reason to preferentially start pregnant patients on the buprenorphine monoproduct or switch to the monoproduct in patients who were previously stable on the buprenorphine and naloxone combination formulation, as had been advised in the past. (See 'Use of combined buprenorphine and naloxone formulation' above.)

-Drug dosing for buprenorphine is similar to that in nonpregnant patients. Standard induction protocols, such as the one described above, can be used. Dose adjustments may be needed with advancing gestational age; the average increase appears to be approximately 3 mg. (See 'Initial and maintenance dosing' above.)

-The patient's usual buprenorphine dosing should be maintained intrapartum and postpartum. (See 'Intrapartum and postpartum buprenorphine dosing' above.)

•Breastfeeding – Patients are encouraged to breastfeed. Those who wish to discontinue breastfeeding are advised to gradually wean the infant from breast milk over a period of two weeks to reduce the risk of neonatal withdrawal. (See 'Breastfeeding' above.)