CHAPTER 4 PREGNANCY AND NEONATAL WITHDRAWAL Authors: McCarthy, J. J.; Stephenson, D. 4.1. Introduction efficacy [95]. Methadone and buprenorphine significantly improve perinatal outcomes, reducing maternal and neonatal complications. 4.1.1. Pregnant Patients Need treatment There are many treatment issues unique to pregnancy and the postpartum period that will be discussed, but the most important issue when treating a pregnant patient on MAT Few areas of addiction medicine are as challenging and is understanding adequate and appropriate medication rewarding as helping a pregnant women recover from use during pregnancy. Two overriding issues influence all opioid use disorder (OUD) through medication assisted treatment interventions: treatment (MAT) and having them deliver healthy, drug- free babies. Many physicians have received little to no 1. The fact of fetal dependence with the risk for Neonatal training in the management of pregnancy complicated Abstinence Syndrome (NAS); by OUD, which makes them understandably reticent to 2. The profound maternal pharmacokinetic changes treat this population; they may feel uncertain about the that occur throughout pregnancy and the perinatal physiologic needs of the fetus and the fetal response to period, which complicate medication use, especially methadone or buprenorphine. Is the fetus dependent? Are methadone use [96]. medications needed or not? Are the medications beneficial or harmful? Is one medication better than the other? MAT These guidelines provide information specific to the medical is often misunderstood, and potentially viewed as THE management of OUD during pregnancy and the postpartum cause of Neonatal Abstinence Syndrome (NAS). However, period, focusing on the use of methadone or buprenorphine most women are already physically dependent on an to optimize treatment of maternal/fetal dependence given opioid before MAT is started, so the fetus was already at the altered physiology and pharmacokinetics associated risk of opioid-related NAS. The exception is women who with the perinatal period. Optimized treatment increases conceive on methadone or buprenorphine. In this situation, the likelihood of term delivery of a drug-free baby and the question becomes, “Given that a woman is opioid decreases the risk of NAS. dependent when she learns she is pregnant, does MAT raise or lower the risk of NAS or other adverse outcomes?” 4.1.2. Pharmacokinetic Changes during Decades of research support the safety and efficacy Pregnancy of methadone use in pregnancy in facilitating maternal recovery; maternal recovery rates of over 90% have been [94] It is not uncommon for mothers maintained on methadone reported . Buprenorphine has been implemented for to experience opioid withdrawal between doses soon a much shorter time, but the research supports similar after conception. For most women, this process of www.csam-asam.org 47 increased methadone clearance and metabolically-induced 4.1.3. Medication selection withdrawal continues throughout the pregnancy, with Considerations: Methadone vs. significant individual differences in intensity[96] . Increased clearance of buprenorphine is less likely to occur and less Buprenorphine pronounced when it does. The most important point about the treatment of pregnant Pharmacokinetic science has documented major alterations women with OUD is that withdrawal puts the woman, the in drug metabolism secondary to induction of the pregnancy and the baby at risk for adverse outcomes. Cytochrome P450 (CYP) enzyme system by the hormones In view of this risk, methadone maintenance is often the of pregnancy. Methadone and buprenorphine are both treatment of choice. Methadone induction does not require CYP450 substrates whose metabolism is accelerated by a woman to be in withdrawal at the time of the first dose pregnancy. However and poses no risk of precipitated withdrawal. Treatment Methadone is quickly converted to an inactive retention rates are higher with methadone maintenance, metabolite; whereas and treatment retention correlates strongly with abstinence. The longer a woman remains in treatment, the more likely Buprenorphine is a pro-drug, which is converted to three she is to become and remain drug-free, increasing the active metabolites. likelihood of term delivery of a healthy, drug-free baby that Pregnancy specifically induces CYP enzymes 34A[97] , 2D6 remains in the patient’s custody. [98], and 2B6 [99]. Methadone is primarily metabolized by CYP There are some cases where buprenorphine may be a 34A, 2B6, and by lesser and variable contributions from better choice: 2D6, 2C19, and 1A2. The parent molecule is demethylated into inactive EDDP (2-ethylidene-1,5dimethyl-3,3- Women who meet DSM-5 criteria for OUD, are seeking dyiphenylpyrrolidine) [100, 101]. Changes in pregnancy can treatment because they are fearful of relapse, but are shorten the effective half-life of methadone from its usual not physically dependent at the time of presentation for 24-hour range to 12 hours, and at times to as short as 4-6 treatment. [94] hours . There is a 17-fold variation in methadone serum present for treatment in moderate to [102] Women who concentration for a given dosage in large part due to severe withdrawal, because of the time elapsed since CYP genetic polymorphism. the most recent opioid use. Alteration in the half-life means that methadone is rarely a When buprenorphine is used in pregnancy, the mono- once a day medication in pregnancy. Pregnancy changes product, Subutex, is the recommended formulation. methadone from a long-acting drug, which can be given Buprenorphine has several advantages: stabilization on a once a day, to a short-acting drug that must be given in therapeutic dose may be accomplished in two or three days multiple (divided) doses to maintain stability of maternal/ vs. the weeks or months it takes with methadone. There are fetal opioid activity and avoid withdrawal. The significant no regulatory constraints limiting divided doses. The rate of variability in the rate of metabolism during pregnancy metabolism of buprenorphine over the course of a pregnancy creates significant challenges to safe and effective perinatal and post-partum is less variable, so that fewer dose management. Using divided doses to compensate for the adjustments are required to maintain a therapeutic dose. reduced half-life has been associated with a reduced rate of NAS requiring treatment (29% compared to the published Women should be provided with information about both [94] rates of 60-80%) . On rare occasions, rapid clearance of medications and asked which medication they would prefer. methadone may cause the urine drug screen to become Their preference should be honored to the extent possible. negative for methadone or methadone metabolite. The They should be informed that the goal of MAT is stabilization physician must review the situation to determine whether on a therapeutic dose to ensure complete suppression the most likely explanation is a low methadone blood level of opioid withdrawal. they should be advised that it is or diversion of the PM dose. easy to transition from buprenorphine to methadone at any point, but that transition from methadone to Despite buprenorphine’s accelerated metabolism during buprenorphine is significantly more difficult and should pregnancy, once per day dosing is feasible because it is not be attempted in pregnancy. converted to active metabolites, but there is evidence that [103] twice per day may be preferable . A critical question is whether there are differences between methadone and buprenorphine on outcomes, especially Clearly, dose amount and scheduled regimen must be NAS severity. A study was done by NIDA (the MOTHER individualized regardless of whether a pregnant woman is Study) to try to answer this question. prescribed methadone or buprenorphine. Basing the dosing regimen on pharmacokinetics maximizes the desired the MotHEr study (Maternal opioid pharmacodynamic effect, which is stability of mu receptor treatment: Human Experimental research) occupancy by the medication in the maternal and fetal brain. The stability of the opioid system during pregnancy is The MOTHER Study is the most comprehensive presumed to be very important for promoting normal fetal research effort to date on the use of methadone verses brain development. buprenorphine for the treatment of OUD in pregnancy. This study examines the safety and efficacy of methadone verses buprenorphine for mothers and babies. The study is well known and widely quoted, so it is important for 48 Guidelines for Physicians Working in California Opioid Treatment Programs Ch. 4: Pregnancy and Neonatal Withdrawal physicians treating pregnant women with OUD to be aware vulnerable to increased NAS severity, but methadone- of it. The data from this study continues to be analyzed, exposed neonates that are not separated are not. new questions explored and new articles written to share the findings. There are many important findings from this The drop-out rate due to medication dissatisfaction was study. Unfortunately, it did not resolve the question about significantly greater for buprenorphine than for methadone, whether methadone or buprenorphine is more likely to indicating that a mixed partial agonist/antagonist cause NAS. medication is not optimal for many pregnant women. Perhaps the most important finding is that buprenorphine Methadone vs. Buprenorphine – other is a safe and effective alternative to methadone for treating Considerations OUD in pregnancy. The rates