Comprehensive opioid agonist treatment in combination with behavioral and prenatal care has been demonstrated to reduce the risk of obstetric complications [1]. The legal treatment of opioid dependence using opioid agonist medication in the United States is limited to two medications, buprenorphine and methadone. Opioid blocking agents such as naltrexone, and its long-acting injectable form, are also options but not yet widely used during pregnancy. Recommendations on the use of these medications will be discussed later in this chapter. Physicians and other prescribers should be cautioned that it is illegal to prescribe any other opioid agonist medications for the treatment of opioid dependence and should stay fully informed regarding current laws and regulations regarding the use of buprenorphine and methadone.
The History of Opioid Agonist Treatment and Its Use during Pregnancy
The history behind the modern treatment of opioid use disorders, or opioid dependence as it has historically been called, dates back to the 1960s during the heroin epidemic in New York City. At the time, heroin-related mortality was the leading cause of death for young adults between the ages of 15 and 35 [2]. The original research on opioid treatment by Dole and Nyswander in the 1960s demonstrated the efficacy of methadone maintenance [3]. Pregnant women were not included in the initial research; however, treatment was eventually expanded to pregnant women [4]. By the 1970s, methadone maintenance was the recommended treatment for pregnant intravenous (IV) heroin-dependent women.
It was soon recognized, however, that maternal methadone treatment was associated with a longer and more severe neonatal abstinence syndrome (NAS) compared to maternal heroin use due to methadone’s long half-life. Due to concerns regarding NAS, early regulations in 1973 required pregnant women to taper completely from her starting dose to zero milligrams of methadone within 21 days. Later in the 1970s, maintenance methadone treatment was allowed; however, the dose was recommended to be as low as possible, often 20 mg or less, in an attempt to reduce the risk of neonatal withdrawal symptoms. During this time period, it was assumed that likelihood and severity NAS were related to the methadone dose.
In the 1980s–1990s, the attitude toward methadone dosing during pregnancy changed in association with the HIV epidemic and maternal to fetal transmission of HIV among IV drug users. In the early 1990s, mother to child or perinatal rates of HIV transmission in North America and Europe were 16–25 percent [5]. Perinatal transmission was shown to be higher among women continuing to use heroin and cocaine. A retrospective review of 20 years experience of methadone treatment demonstrated that doses greater than 80 mg/day had protective value in HIV transmission [6]. The decrease in perinatal HIV transmission by treating with higher doses of methadone became a higher priority than the attempts to reduce NAS by using low doses.
In 1997, the National Institutes of Health (NIH) recommended methadone maintenance, in combination with counseling and behavioral therapy and support, as the standard of care for opioid dependence during pregnancy. The goal was and remains the treatment of maternal withdrawal symptoms through symptom-based dosing. Symptom-based dosing involves titrating the dose upwards until withdrawal symptoms, which increase the risk of relapse, are eliminated.
In 2002, buprenorphine was approved for office-based opioid treatment (OBOT) of opioid dependence and national guidelines were published in 2004 [7]. Case reports and small studies began to appear suggesting a milder NAS in infants whose mothers were treated with buprenorphine rather than methadone. This milder withdrawal syndrome is likely related to the partial agonist properties of buprenorphine compared to the full agonist properties of methadone.
In 2010, the MOTHER study compared infants whose mothers received buprenorphine to those who received methadone. The buprenorphine group of neonates required less morphine for treatment of NAS and had shorter hospital stays compared to the methadone group [8]. Numerous subsequent studies have confirmed a milder NAS with buprenorphine and no increase in adverse maternal or neonatal outcomes. The use of buprenorphine during pregnancy has become common since publication of the MOTHER study and it has become accepted as an alternative first-line treatment to methadone [9]. Patients who are prescribed buprenorphine should be counseled, however, that there is less long-term safety data available due to the limited history of use in pregnancy. Additionally, other factors in addition to the risk of NAS should be considered when selecting the optimal pharmacologic agent for an individual patient.
Buprenorphine and Methadone Delivery Settings
Methadone maintenance treatment by law may only be prescribed and dispensed by a federally certified opioid treatment program (OTP). The Substance Abuse and Mental Health Services Administration’s (SAMHSA) Division of Pharmacologic Therapies (DPT), which is part of the SAMHSA Center for Substance Abuse Treatment (CSAT), is the agency responsible to certification of OTPs. OTPs must also receive accreditation by an independent, SAMHSA-approved accrediting body to dispense opioid treatment medications and must be licensed by the state in which they operate. All OTPs must register with the Drug Enforcement Administration (DEA), through a local DEA office [10].
Buprenorphine may be prescribed in an office-based setting (office-based opioid treatment or OBOT) or in an OTP and is currently the only opioid approved for the treatment of opioid dependence in an office-based setting [5]. Specific training and a DEA waiver are required to prescribe buprenorphine. Waivers were originally limited to eligible physicians but in 2016 the Comprehensive Addiction and Recovery Act (CARA) expanded buprenorphine prescribing to include nurse practitioner or physician assistants who have also undergone specific training and received a waiver [11]. Nurse–midwives are not currently able to obtain DEA waivers.
Women on Medication Assisted Treatment Prior to Pregnancy
Women who are using methadone or buprenorphine for MAT before they are pregnant will usually continue the same agent. If on methadone she may stay with the same outpatient treatment program or she may transfer to a program for pregnant women. As the pregnancy progresses she may need to adjust her dosing due to physiological changes of pregnancy that alter pharmacokinetics. The need for dose adjustment is most common in the latter half of pregnancy [12]. It is common to need to intermittently increase the daily dose by 5–10 mg as the pregnancy progresses, particularly in the third trimester. Not all women require dose increases during pregnancy, and dosage adjustments should be made on a clinical basis. Rapid metabolism may occur in pregnancy, especially in the third trimester, and split dosing may be indicated if the usual single daily dose does not suppress the development of withdrawal symptoms between doses. Split dosing, or dividing the daily dose into two or more doses, maintains a more stable and therapeutic serum methadone level throughout the day, which prevents withdrawal symptoms and may decrease the likelihood of NAS requiring pharmacological treatment [13].
The maternal methadone dosage does not affect the incidence and duration of neonatal abstinence syndrome based on a systematic literature review and meta-analysis [14]. Attempting to lower the methadone dose is not indicated due to concern about NAS. Women should receive appropriate dose increases to prevent opiate withdrawal and drug cravings (symptom-based dosing). Until 2001, doses above 20 mg/day [15] were deemed a contraindication to breastfeeding by the American Academy of Pediatrics; however, higher doses are no longer a contraindication based on studies demonstrating low concentrations of methadone in breast milk [16, 17].
Pregnant women on methadone may request to be transferred to buprenorphine because they have heard that neonatal abstinence syndrome occurs less frequently and is milder than for methadone exposed neonates. Pregnant women should not transition from methadone to buprenorphine solely for this reason because there is a significant risk of precipitated withdrawal, due to the long-acting property of methadone. The prolonged period of maternal withdrawal required may be accompanied by an intrauterine withdrawal syndrome with unknown fetal effects [18]. If it is determined that a transition from methadone to buprenorphine is needed due to unique circumstances such as lack of methadone provider, distance to treatment or need for residential treatment which cannot accommodate methadone, then a hospital admission may be needed under the supervision of a physician experienced with this process. If she is on more than 60 mg of methadone, the transition may be difficult and the buprenorphine may not address her cravings as well as methadone, which is a risk factor for relapse [19].
Women who become pregnant while already receiving treatment with a stable dose of buprenorphine/naloxone dosage have generally been advised to continue the same buprenorphine dosage but to transition to the single-agent product. However, recent studies evaluating the use of the combination product buprenorphine with naloxone found results are similar when compared with buprenorphine alone [20, 21]. Some women may require small dose increases during the pregnancy, but this is less common than with methadone. Split dosing can also be done in pregnancy to ameliorate withdrawal symptoms.
Women can be transitioned from buprenorphine to methadone during pregnancy, if indicated, because there is no risk of precipitated withdrawal. The potential risk of unrecognized adverse long-term outcomes with buprenorphine use, which is inherent with widespread use of relatively new medications during pregnancy, should always be taken into consideration and thus a woman’s request to change to methadone should be accommodated. Few women typically request transition from buprenorphine to methadone due to the convenience of buprenorphine treatment including less frequent visits along with the potential reduced severity of NAS when compared to methadone. The more likely scenario is that the buprenorphine prescriber or the obstetrician recommends transition from buprenorphine to methadone, commonly due to poor compliance with buprenorphine and the ongoing use of illicit opioids during buprenorphine treatment. The highly structured setting and observed dosing available in methadone clinics may improve compliance with MAT and abstinence.
The Food and Drug Administration approved a long-acting buprenorphine implant that provides low to moderate doses of buprenorphine for up to 6 months for treatment of opioid use disorder in patients stable on the sub-lingual form [22, 23]. The implant has not been studied in pregnant women and if a woman becomes pregnant with the implant she should be counseled regarding the lack of data on use in pregnancy However, since daily buprenorphine dosing also results in chronically elevated serum buprenorphine there is no reason to anticipate maternal or fetal harm from this delivery system. (As this book is going to press, the FDA just approved a depo formulation of buprenorphine. This will provide a greater range of options for the treatment of OUD–editor.)
Naltrexone in Pregnancy
Naltrexone is a nonselective opioid receptor antagonist that in therapeutic doses blocks the euphoric effects of opioids and has been used to help nonpregnant patients with opioid use disorder in their effort to maintain abstinence. While the oral form demonstrates poor adherence, the more recently approved injectable long-acting form is more effective than placebo in maintaining abstinence [24]. To date, information regarding its use in pregnancy is limited to small case series and case reports, with normal birth outcomes reported [25]. However, significant concerns exist regarding unknown fetal effects, as well as risk of relapse and treatment dropout leading to return to opioid use and risk of overdose [24]. Research on naltrexone treatment during gestation poses ethical and logistic challenges but is needed to inform the use of this treatment in pregnant patients. A recent survey among pregnant women enrolled in a comprehensive substance use treatment program demonstrated a strong interest in considering antagonist treatment during pregnancy [26].
The decision whether to continue naltrexone treatment for a woman already using naltrexone prior to conception should involve a careful discussion with the patient, comparing the limited safety data versus the potential risk of relapse with treatment discontinuation. Use in pregnant women not already using naltrexone at the time of pregnancy will likely await a randomized controlled trial or prospective cohort study.
Medically Supervised Withdrawal in Pregnancy
For pregnant women, medication-assisted therapy is the standard of care for moderate to severe opioid use disorders and is preferable to medically supervised withdrawal (MSW) because MSW is associated with high relapse rates [27], ranging from 59 percent to over 90 percent [25]. Relapse poses multiple risks, including nonmedical use of drugs, association with drug culture, accidental overdose, obstetric complications, and lack of prenatal care. However, if a woman refuses methadone or buprenorphine treatment, medically supervised withdrawal can be considered under the care of a physician experienced in perinatal addiction treatment and with the informed consent of the woman. MSW, however, often requires prolonged inpatient care and intensive outpatient treatment to be successful [28].
In some areas, access to medication-assisted treatment is limited, and efforts should be made to improve availability of local resources. Early reports raised concern that withdrawal from opioids during pregnancy could lead to fetal stress and fetal death [29, 30]. More recent studies find no clear evidence of an association between a medically supervised withdrawal and fetal death, but long-term follow-up data is lacking [28, 31, 32]. More research is needed to further assess the safety and efficacy of medically supervised withdrawal and to develop protocols. Any medically supervised withdrawal should preferably be done in the second trimester when the risks of obstetrical complications are lower. Medically supervised withdrawal should be strongly discouraged in the third trimester.
Initiation of MAT during Pregnancy in Outpatient and Inpatient Settings
Due to the different settings in which patients may receive buprenorphine or methadone, the current delivery system often does not offer patients the ideal assessment, decision tree, and selection of medication process to individualize treatment. Although there are some OTPs that offer buprenorphine treatment in addition to methadone treatment, there are often cost considerations that prevent OTPs from doing so. The availability of buprenorphine in OTPs is currently in flux, but likely to increase. Currently, buprenorphine providers are typically clinicians in medical practice, are not licensed as OTPs, and therefore are not allowed to offer methadone treatment. Certainly, a buprenorphine prescriber can refer the patient to an OTP and OTP can refer a patient to a buprenorphine prescriber but this divided system presents obstacles and delays to a smooth transition especially when it is urgent to begin treatment, which is almost always the case. Therefore, the reality is that the current delivery system for many patients delivers a choice of medication based on which door the patient walks through.
Some programs have been developed across the country including Project Respect in Boston and the Milagro program in Albuquerque that offer hospital admission, education, counseling, prenatal care initiation, assessment, appropriate medication selection, and induction as inpatients. There are obvious advantages to this type of treatment but it has limited availability and some disadvantages as well. Some women may not be willing to spend several days in a hospital due to child-care responsibilities, work, transportation, or other issues. This type of treatment generally needs to be offered on an obstetrical unit for women with pregnancies approaching viability. To expand such programs, there is a need for more obstetricians and family medicine physicians offering maternity care to be trained and knowledgeable in MAT.
As until recently methadone was considered the “gold standard” for MAT in pregnancy, most large hospitals will have guidelines to initiate methadone for pregnant women presenting in acute withdrawal. Not all hospitals will be prepared for how to transition or refer the patient to an outpatient setting upon hospital discharge. It is critical to avoid gaps in dosing when transitioning the patient from inpatient to outpatient. It should be noted that physicians do not require special licensure to prescribe methadone or buprenorphine for hospital inpatients for the treatment of acute opioid withdrawal if they are hospitalized for another reason (e.g. pregnancy).
Patients selected for buprenorphine treatment instead of methadone treatment need to be able to self-administer the drug safely, assure safe storage, and maintain adherence with their treatment regimen. Compared with methadone clinics, the less stringent structure of buprenorphine treatment may make it inappropriate for some patients who require more intensive structure and supervision [33].
Unique Buprenorphine Considerations
Buprenorphine has been developed as an outpatient office-based alternative to methadone, which can be used in primary care settings. For pregnant women living far from federally certified opiate treatment programs, buprenorphine can provide access to MAT through a local buprenorphine-trained provider or by traveling periodically. If a pregnant woman is to be started on buprenorphine for MAT, then it is necessary that the hospital at which she will deliver has maternity care and newborn care providers, nurses, anesthesia, pharmacy and social work that are familiar with the use of buprenorphine.
The initiation of buprenorphine treatment requires that an opioid-dependent woman go through moderate withdrawal prior to receiving her initial dose of buprenorphine. The timing can be based in part on when the patient last used heroin, fentanyl, or other opioids; however, it is important to distinguish between use of short acting agents (e.g. heroin, oxycodone, hydrocodone, fentanyl,) and long acting agents (e.g. methadone, MS Contin, OxyContin). A COWS score (Figure 11.1) of 10–12 indicates moderate withdrawal and this is appropriate timing to administer the first dose of buprenorphine which may be 2 or 4 mg sublingual. COWS scoring can vary from one institution to another so each institution should determine what score in their institution correlates with at least moderate withdrawal. Waiting for the signs and symptoms of moderate withdrawal will decrease the likelihood of precipitating withdrawal in comparison to solely using a set time since the last opiate use. It can be helpful to wait for observable pupillary dilation, which is a relatively late symptom of withdrawal and thus, if present, less likely for precipitated withdrawal to occur.
