Use of buprenorphine in pregnancy: patient management and effects on the neonate

Abstract

It is estimated that 55–94% of infants born to opioid-dependent mothers in US will show signs of opioid withdrawal. Buprenorphine has been reported to produce little or no autonomic signs or symptoms of opioid withdrawal following abrupt termination in adults. To date, there have been 21 published reports representing approximately 15 evaluable cohorts of infants exposed to buprenorphine in utero. Of approximately 309 infants exposed, a neonatal abstinence syndrome (NAS) has been reported in 62% infants with 48% requiring treatment; apparently greater than 40% of these cases are confounded by illicit drug use. The NAS associated with buprenorphine generally appears within 12–48 h, peaks at approximately 72–96 h, and lasts for 120–168 h. These results appear similar to or less than that observed following in utero exposure to methadone. From a review of the literature, buprenorphine appears to be safe and effective in both mother and infant with an NAS that may differ from methadone both qualitatively and quantitatively.

Introduction

In both the United States and Europe, one-third of the population entering treatment for opioid abuse and dependence are women in their childbearing years. As the availability of buprenorphine increases, the number of women who become pregnant while being treated with buprenorphine will increase. The treating physician will have three options: dose taper, opioid maintenance on a recommended pharmacotherapy, or continued buprenorphine administration. Dose taper is not recommended (FDA/NIDA Guidance, 1992, Finnegan, 1991a, Finnegan and Wapner, 1988) since it has been reported in one subject to induce fetal stress (Zuspan et al., 1975), and currently the only recommended maintenance therapy in the United States and Europe for opioid-dependent pregnant women is methadone.

Data from a 1992 survey reported that an estimated 7000 heroin- and methadone-exposed infants are born (National Pregnancy and Health Survey, 1996) annually in US and approximately 55–94% of these infants will show signs of an opioid withdrawal syndrome (American Academy of Pediatrics Committee on Drugs, 1998). The neonatal abstinence syndrome (NAS) is a generalized disorder characterized by signs and symptoms indicating dysfunction of the autonomic nervous system, gastrointestinal tract, and respiratory system (e.g., Kaltenbach and Finnegan, 1990, Connaughton et al., 1975, Blinick et al., 1969). In general, neonates of heroin-dependent and methadone-maintained mothers exhibit an opioid withdrawal syndrome following birth (e.g., Zelson et al., 1971, Glass, 1975, Harper et al., 1977), which requires intensive and extended treatment. Infants born to methadone-maintained mothers tend to be in a neurologically distressed condition; they cry incessantly, are more labile, tremulous, irritable, excited, hypertonic, aroused, respond poorly to visual stimuli, and have less motor maturity (e.g., Kaltenbach and Finnegan, 1990). One study has suggested that the duration of tremulousness and irritability is longer in babies born to methadone-maintained mothers when compared with mothers using heroin (Rajeqowda et al., 1972). Of the neonates born to methadone-maintained mothers, 60–87% require treatment for an opioid NAS (Rosen and Johnson, 1982, Wilson et al., 1981, Connaughton et al., 1975, Stimmel et al., 1982–1983, Finnegan, 1988, Finnegan and Ehrlich, 1990) and 10–30% of these are admitted to the Neonatal Intensive Care Unit (NICU; Svikis et al., 1997, Kissin et al., 1997). The NAS and prematurity are the primary reasons for extended hospitalization in these infants. In one study, mean duration of hospitalization varied in infants between 17 (methadone-treated plus prenatal care) and 20 days (heroin-exposed with no prenatal care) (Connaughton et al., 1977), while in another study (Fischer et al., 1999) the mean duration of treatment for the NAS after exposure to oral methadone and slow-release oral morphine was 18 days.

It has been shown that there is a significant improvement in maternal and birth outcomes when pregnant opioid-dependent women are maintained on methadone and provided comprehensive prenatal care (Kandall et al., 1976, Connaughton et al., 1977, Finnegan, 1991b, Svikis et al., 1997). Whether this improvement is due directly to the pharmacologic effects of methadone (i.e., consistent opioid blood levels, decreased withdrawal symptomatology, etc.) or due primarily to better prenatal care (i.e., improved nutrition, medical care, etc.) is not clear. Although outcomes are improved when opioid-dependent women are maintained on methadone and receive prenatal care, the NAS in infants born to mothers maintained on methadone is not trivial. This fact has caused much debate over the appropriate use of methadone (i.e., dose taper or maintenance, dose reduction or increase or split dose, etc.) in pregnant opioid-dependent women. There are those who advocate dose taper to limit fetal exposure to exogenous opioids, and there are situations where women may need to be withdrawn (Jarvis and Schnoll, 1994). Most addiction specialists advocate maintenance therapy with a dose sufficient to eliminate and prevent withdrawal symptoms and craving. This dose generally ranges for 50–150 mg per day (Substance Abuse and Mental Health Services Administration, 1995). Appropriate treatment of the opioid dependence will assist in retaining women in treatment and help ensure continuous prenatal care. Overall, the cost:benefit ratio seems to be greater when the mother is maintained on opioid substitution therapy and she receives prenatal care than when her dose is tapered to zero or receives no drug abuse treatment (Svikis et al., 1997).

The availability of new medications for the treatment of opioid dependence may provide valuable alternatives to improve both maternal and infant outcomes (i.e., less NAS). One new pharmacotherapy that holds promise is buprenorphine, a partial mu-opioid agonist. Studies of buprenorphine in adults (that did not include pregnant subjects) generally report little or no autonomic signs or symptoms of opioid withdrawal following the abrupt termination of buprenorphine (Jasinski et al., 1978, Mello and Mendelson, 1980, Mello et al., 1982, Reisinger, 1985, Seow et al., 1986, Fudala et al., 1990); this is in contrast to reports for methadone and heroin. From these and other data, it has been concluded that the abstinence syndrome associated with buprenorphine is quantitatively different from full mu-opioid agonists such as morphine or methadone. Using these data, it has been hypothesized that the neonate born to buprenorphine-maintained mothers will experience a shorter and milder withdrawal syndrome than that observed with methadone or heroin.

One concern with the use of any new medication during pregnancy is the possibility of toxic or teratogenic effects. Buprenorphine has been reported to lack physical teratogenic effects in rodents (Mori et al., 1982a). No teratogenic effects were observed in the rat and rabbit, respectively, after oral doses (most comparative to sublingual route) 150 and 50 times greater than the daily recommended dose (16 mg/m²) for the treatment of opioid dependence. Although significant increases in skeletal abnormalities have been observed in rats after subcutaneous administration of 1 mg/kg per day and greater, these effects were not observed after oral doses 95 times greater than the daily recommended dose for human (personal communication, Reckitt Benckiser Pharmaceuticals, Inc., 2002). Fertility and peri- and post-natal animal toxicity studies with buprenorphine have reported difficult parturition and high neonatal mortality, particularly at high oral dose levels (i.e., 50 times the daily recommended dose) but there was no evidence that buprenorphine had adverse effects on pregnancy rates or fertility. It is possible that the difficulty in parturition and the high neonatal mortality may be due to the sedative effects of buprenorphine or buprenorphine's effect on maternal endocrine function. A slight decrease in growth rate occurred in offspring whose mothers were treated with buprenorphine during lactation and there was a slightly higher mean post-implantation loss at oral doses 6 and 50 times the recommended daily dose for treating opioid dependence in the rat and rabbit, respectively (personal communication, Reckitt Benckiser Pharmaceuticals, Inc., 2002).

Teratology studies in rodents and rabbits have shown either no difference or mixed effects on maternal water intake, maternal weight gain, external defects, internal anomalies, skeletal defects, intra-uterine deaths, litter and mean fetal weights, litter size, crown-rump length, survival, weight gain, or early post-natal behavior of buprenorphine-exposed offspring compared with non-exposed controls (Hutchings et al., 1995, Evans et al., 1989, Mori et al., 1982b, Robinson and Wallace, 2001). Overall, it appears that buprenorphine is associated with pre-implantation loss in the rodent and rabbit. The doses of buprenorphine associated with this loss have ranged from 1.25 to 50, and 12.5 times the daily recommended dose for the treatment of opioid dependence for the rabbit and rodent, respectively.

Unlike methadone, prenatal exposure with buprenorphine does not appear to affect activity, cycles of rest-activity, or developmental milestones (Enters et al., 1991, Zagon and McLaughlin, 1984, Zagon et al., 1979, Hutchings et al., 1979, Hutchings et al., 1996). However, at relatively high doses, buprenorphine, like other opioids, has been reported to alter sexually dimorphic non-reproductive (spontaneous parental behavior and saccharin consumption) behaviors (Barron and Chung, 1997). Buprenorphine has been shown to reduce both striatal nerve growth factor (Robinson, 2000, Wu et al., 2001), and transiently affect acetylcholine content (Robinson, 2002) and to produce toxic effects (Mori et al., 1982b) similar to methadone. Specific to acetylcholine content, buprenorphine effects varied across a wide dose range which could be explained by it being a partial agonist at the mu-opioid receptor. Additionally, it has been reported that, unlike methadone, prenatal exposure to buprenorphine does not reduce encephaline levels in the rat brain (Tiong and Olley, 1988). The exact implication of this difference between methadone and buprenorphine on post-natal development is not currently known.

Overall, any deleterious effect observed with buprenorphine during pregnancy do not appear greater or to differ significantly from methadone and other opioids. Although the evidence is limited comparing buprenorphine and methadone, the effects of buprenorphine during pregnancy do not seem to be significantly different from methadone and other opioids based on their pharmacologic, teratogenic, fertility, reproductive, and safety profile. Thus, the general consensus is that exposure of pregnant women to buprenorphine will not expose them or their fetus to greater risk than expected for methadone or other opioids.

The purpose of this paper is to review the current literature describing the use of buprenorphine (Subutex®) in pregnant opioid-dependent women as it relates to patient management and effects on the neonate. Although a combination tablet of buprenorphine plus naloxone 4:1 (Suboxone®) has recently been approved by the Food and Drug Administration in the United States for the treatment of opioid dependence, there have been no reports of Suboxone® being administered to opioid-dependent women during pregnancy. Therefore, the combination of buprenorphine plus naloxone 4:1 will not be discussed in this review.