毒理性
◉ 哺乳期使用总结：由于母乳中丁丙诺啡含量低，婴儿口服生物利用度低，母乳喂养婴儿的血清和尿液中药物浓度低，哺乳期母亲可以接受使用。监测婴儿是否嗜睡、呼吸抑制、体重是否适当增加以及发育里程碑，尤其是年幼的纯母乳喂养婴儿。虽然可能性不大，但如果婴儿出现嗜睡（比平时更多）、母乳喂养困难、呼吸困难或无力的迹象，应立即联系医生。如果突然停止母乳喂养，观察婴儿是否有戒断症状。
应鼓励在怀孕期间因阿片类药物滥用而接受丁丙诺啡治疗且病情稳定的妇女在产后母乳喂养婴儿，除非有其他禁忌症，如使用街头毒品。在母体丁丙诺啡治疗阿片类药物滥用期间母乳喂养婴儿的长期结果尚未得到很好的研究。因阿片类药物依赖而服用丁丙诺啡的母亲的母乳喂养率可能低于其他母亲；然而，在将丁丙诺啡作为禁欲计划一部分的女性中，哺乳期母亲的保留率可能比非哺乳期母亲更好。
◉ 对母乳喂养婴儿的影响：据报道，许多婴儿在接受丁丙诺啡麻醉戒断治疗期间进行母乳喂养，没有不良反应，其中一名婴儿持续6个月。牛奶中丁丙诺啡的含量可能不足以防止新生儿戒断，可能需要对婴儿进行治疗。
尽管母乳喂养和婴儿血清药物水平相对较高，但一名母亲在怀孕和产后因海洛因依赖而每天服用4毫克丁丙诺啡（未指定途径），其新生儿出现轻度丁丙诺吗啡戒断反应。这表明牛奶中出现的剂量不足以防止新生儿禁欲。
10名接受过足月新生儿剖宫产的妇女接受了200 mcg硬膜外丁丙诺啡治疗，随后每小时服用8.4 mcg，并在产后3天内使用麻醉剂治疗术后疼痛。另一组10名女性仅接受硬膜外麻醉，不使用丁丙诺啡。产后11天内，丁丙诺啡组母亲的新生儿的牛奶摄入量和体重增加比非丁丙诺吗啡组低得多。作者认为硬膜外丁丙诺啡抑制了婴儿母乳喂养。未进行婴儿神经行为评估。
六名母亲在怀孕和产后服用丁丙诺啡的婴儿接受了母乳喂养。其中四名婴儿有阿片类药物戒断的迹象，表明母乳中丁丙诺啡的含量不足以防止戒断。出院后1个月，所有婴儿发育正常，体重增加。
七名平均年龄为1.12个月（范围0.58至1.85个月）的婴儿在怀孕和哺乳期间由服用丁丙诺啡作为阿片类药物替代品的母亲进行母乳喂养。尿液筛查显示，4名母亲也在使用大麻，1名母亲在使用未经处方的苯二氮卓类药物，1名女性同时使用大麻和苯二氮唑类药物。其中4名婴儿完全由母乳喂养，3名婴儿主要由母乳喂养。婴儿没有明显的药物相关不良反应，发育进展令人满意。
一位母亲在怀孕期间使用丁丙诺啡（剂量和适应症未说明）。她的婴儿出生时没有表现出新生儿禁欲的迹象。婴儿一直母乳喂养（程度未说明），直到4个月大时母亲停止母乳喂养。两天后，婴儿出现戒断症状，包括频繁打哈欠、打喷嚏、瞳孔扩张、躁动、出汗、莫罗反射亢进、肌阵挛、震颤和失眠。婴儿服用美沙酮后，戒断症状立即得到改善。婴儿的戒断症状可能是由于突然停止母乳喂养引起的。
在一项对7名服用丁丙诺啡的女性进行的研究中，她们的中位剂量为每天7毫克（每天2.4至24毫克），对母乳喂养的婴儿在3周和4周大时进行了随访。4名婴儿完全母乳喂养，3名婴儿部分母乳喂养。在随访中，对婴儿的体重增加、睡眠模式、肤色以及排泄和水合模式进行了评估。随访时，所有婴儿的这些参数值均在正常范围内。
在挪威的一项研究中，对124名在怀孕期间接触过阿片类药物维持治疗的婴儿进行了产后随访。服用丁丙诺啡的母亲生下了46名婴儿。总体而言，母乳喂养的婴儿新生儿戒断症状发生率较低，新生儿戒断治疗持续时间较短。然而，对于母亲服用丁丙诺啡的婴儿子集，差异没有统计学意义。
对在维也纳一家诊所接受丁丙诺啡治疗阿片类药物依赖的孕妇及其新生儿进行了研究。母乳喂养（n=31）和非母乳喂养婴儿（n=41）在新生儿戒断的平均测量值、吗啡的剂量要求、新生儿戒断的治疗时间或住院时间方面没有差异。
一项全州范围的回顾性数据库研究发现，被诊断为NAS的婴儿如果接受母乳喂养，住院时间平均比未接受母乳喂养的婴儿少2天。
对两项多中心队列研究的结果进行了比较。最初的研究有86名新生儿禁欲，第二项研究有113名婴儿。所有婴儿在子宫内都接触过美沙酮或丁丙诺啡。与非母乳喂养的婴儿相比，母乳喂养婴儿的住院时间缩短了4.5至7.5天。与接触美沙酮的婴儿相比，接触丁丙诺啡的婴儿住院时间缩短了4至5天。
一项对89名孕妇进行丁丙诺啡治疗以维持阿片类药物戒断的研究。与非纯母乳喂养的婴儿相比，纯母乳喂养婴儿中需要吗啡治疗新生儿戒断症状的婴儿更少。与非纯母乳喂养的婴儿相比，纯母乳喂养婴儿出现禁欲症状的时间更早，住院天数更少。
一名2周大的婴儿因嗜睡和喂养不良被送往急诊室。他昏昏欲睡，入院时瞳孔缩小，格拉斯哥昏迷评分为5分，血糖为79 mg/dL。两剂0.15 mg纳洛酮导致婴儿哭闹并改善了音调。婴儿的母亲因阿片类药物使用障碍，连续几个月每天两次服用8毫克丁丙诺啡。她完全母乳喂养，否认使用非法药物。入院后，婴儿多次出现低血糖症状，需要再次服用纳洛酮治疗心动过缓、嗜睡和瞳孔缩小，症状有所改善。停止母乳喂养，婴儿出现轻度戒断症状，不需要治疗。婴儿的症状可能是由丁丙诺啡引起的，但母乳喂养的贡献无法与产前暴露区分开来。
◉ 对哺乳和母乳的影响：丁丙诺啡可以增加血清催乳素。然而，已建立哺乳期的母亲的催乳素水平可能不会影响她的母乳喂养能力。
在一项针对246名因阿片类药物依赖而接受美沙酮或丁丙诺啡治疗的孕妇的多中心前瞻性研究中，153名孕妇接受了高剂量丁丙诺芬治疗。22%接受丁丙诺啡治疗的女性用母乳喂养婴儿，这一比例与接受美沙酮治疗的女性相同。
一项对276名在爱婴医院分娩的阿片类药物依赖母亲的回顾性图表审查发现，服用丁丙诺啡或美沙酮治疗阿片类依赖的母亲不太可能母乳喂养婴儿。在20名服用丁丙诺啡的母亲中，只有45%开始母乳喂养。在研究中的所有女性中，60%在出院前停止了母乳喂养。
一项回顾性病例系列报告了2007年12月至2012年8月期间，85名阿片类药物依赖妇女在怀孕和产后继续服用丁丙诺啡。在这些女性中，有65人出院时正在哺乳，其中66%的人在6至8周的随访时正在哺乳（未说明哺乳程度）。
澳大利亚的一项回顾性队列研究比较了服用丁丙诺啡、其他阿片类或非阿片类药物（如苯二氮卓类、苯丙胺、可卡因、酒精、吸入剂、大麻素、精神药物）的吸毒母亲出院时的母乳喂养率。出院时的母乳喂养率如下：丁丙诺啡27%，其他阿片类31%，非阿片类51%。
一项小型回顾性研究发现，接受丁丙诺啡联合纳洛酮治疗阿片类药物依赖的10名孕妇中，只有3名在出院时正在母乳喂养婴儿。
一项对150名参加药物滥用治疗项目的女性进行的回顾性队列研究发现，服用美沙酮的女性母乳喂养率高于服用丁丙诺啡和纳洛酮的女性。然而，这种差异似乎与美沙酮组在分娩前更倾向于母乳喂养有关。
对母乳喂养对母亲在怀孕和产后服用美沙酮的婴儿结局影响的研究进行了系统综述，得出的结论是，在母乳中接触丁丙诺啡的新生儿中，新生儿喂养方法与新生儿戒断综合征之间的关联尚不清楚。
一项对64名因阿片类药物使用障碍而在产后服用丁丙诺啡的母亲的回顾性图表审查发现，母乳喂养婴儿的母亲更有可能在产后10至14周内接受随访。
一项针对19名阿片类药物使用障碍母亲的小型回顾性研究发现，服用丁丙诺啡的母亲比服用美沙酮的母亲更有可能母乳喂养婴儿（70%对29%）。
◉ Summary of Use during Lactation:Because of the low levels of buprenorphine in breastmilk, its poor oral bioavailability in infants, and the low drug concentrations found in the serum and urine of breastfed infants, its use is acceptable in nursing mothers. Monitor the infant for drowsiness, respiratory depression, adequate weight gain, and developmental milestones, especially in younger, exclusively breastfed infants. Although unlikely, if the baby shows signs of increased sleepiness (more than usual), difficulty breastfeeding, breathing difficulties, or limpness, a physician should be contacted immediately. Observe infants for withdrawal signs if breastfeeding is stopped abruptly.
Women who received buprenorphine for opiate abuse during pregnancy and are stable should be encouraged to breastfeed their infants postpartum, unless there is another contraindication, such as use of street drugs. The long-term outcome of infants breastfed during maternal buprenorphine therapy for opiate abuse has not been well studied. The breastfeeding rate among mothers taking buprenorphine for opiate dependency may be lower than in other mothers; however, among women taking buprenorphine as part of an abstinence program, the retention rate may be better in nursing mothers than in non-breastfeeding mothers.
◉ Effects in Breastfed Infants:Numerous infants have been reported to breastfeed during maternal narcotic abstinence therapy with buprenorphine with no adverse effects, one for 6 months. The amounts of buprenorphine in milk may not be sufficient to prevent neonatal withdrawal, and treatment of infant may be required.
Despite breastfeeding and relatively high infant serum drug levels, mild buprenorphine withdrawal occurred in the neonate of a mother taking buprenorphine 4 mg daily (route not specified) during pregnancy and postpartum for heroin dependency. This indicates that an insufficient dosage appeared in milk to prevent neonatal abstinence.
Ten women who had undergone cesarean section delivery of term newborns were given extradural buprenorphine 200 mcg followed by 8.4 mcg/hour with an anesthetic for postoperative pain for 3 days postpartum. A control group of 10 other women were given extradural anesthetic only without buprenorphine. Over 11 days postpartum, newborns of mothers in the buprenorphine group had much lower milk intake and lower weight gain than those in the non-buprenorphine group. The authors suggested that extradural buprenorphine suppressed infant breastfeeding. Infant neurobehavioral assessments were not performed.
Six infants whose mothers were taking buprenorphine during pregnancy and postpartum were breastfed. Four of the infants had signs of opioid abstinence, indicating that the amounts of buprenorphine in breastmilk were inadequate to prevent withdrawal. At 1 month after discharge from the hospital, all infants had normal development and weight gain.
Seven infants who averaged 1.12 months of age (range 0.58 to 1.85 months) were being breastfed by mothers taking buprenorphine for opiate substitution during pregnancy and lactation. Urine screening indicated that 4 mothers had also been using cannabis, 1 was using unprescribed benzodiazepines, and 1 mother was using both cannabis and benzodiazepines. Four of the infants were exclusively breastfed and 3 were mostly breastfed. Infants had no apparent drug-related adverse effects and showed satisfactory developmental progress.
A mother used buprenorphine (dose and indication not stated) during pregnancy. Her infant displayed no signs of neonatal abstinence at birth. The infant was breastfed (extent not stated) until 4 months of age when the mother stopped breastfeeding. Two days later the infant had withdrawal symptoms including frequent yawning, sneezing, pupillary dilation, agitation, sweating, hyperactive Moro reflex, myoclonic jerks, tremors, and insomnia. The infant was given methadone with immediate improvement of her withdrawal symptoms. The infant’s withdrawal symptoms were probably caused by abrupt withdrawal of breastfeeding.
In a study of 7 women taking buprenorphine in a median dose of 7 mg daily (range 2.4 to 24 mg daily) , breastfed infants were followed-up at 3 and 4 weeks of age. Four infants were exclusively breastfed and 3 were partially breastfed. At the follow-up visits, infants were assessed for weight gain, sleeping patterns, skin color, and elimination and hydration patterns. All infants had values within normal limits for these parameters at follow-up.
A cohort of 124 infants exposed during pregnancy to maternal medication for opioid maintenance therapy were followed postpartum in a Norwegian study. Forty-six infants were born to mothers taking buprenorphine. Overall, infants who were breastfed had a lower rate of neonatal abstinence symptoms and a shorter duration of therapy for neonatal abstinence. However, the differences were not statistically significant for the subset of infants whose mothers took buprenorphine.
A study of pregnant women being treated for opiate dependency with buprenorphine at a clinic in Vienna were followed as were their newborn infants. No difference was found between breastfed (n = 31) and nonbreastfed infant (n = 41) in average measures of neonatal abstinence, dosage requirements of morphine, durations of treatment for neonatal abstinence or durations of hospital stays.
A statewide retrospective database study found that infants diagnosed with NAS spent a median of 2 days less in the hospital if they were breastfed than those who were not breastfed.
The results of two multicenter cohort studies were compared. The original study had 86 newborns with neonatal abstinence and the second had 113 infants. All infants had been exposed to methadone or buprenorphine in utero. Infants who were breastfed had a shorter hospitalization by 4.5 to 7.5 days than infants who were not breastfed. Infants who were exposed to buprenorphine had a shorter hospitalization by 4 to 5 days than those exposed to methadone.
A study of 89 pregnant women were treated with buprenorphine for maintenance of opioid abstinence. Fewer of their infants who were exclusively breastfed required morphine for neonatal abstinence symptoms than those who were not exclusively breastfed. Exclusively breastfed infants had an earlier time to peak abstinence symptoms and fewer days in the hospital than the nonexclusively breastfed infants.
A 2-week-old infant was brought to the emergency department for drowsiness and poor feeding. He was lethargic and had pinpoint pupils upon admission, with a Glasgow coma score of 5 and blood glucose of 79 mg/dL. Two doses of naloxone 0.15 mg resulted in infant crying and improved tone. The infant’s mother had been taking buprenorphine 8 mg twice daily for several months for opioid use disorder. She was exclusively breastfeeding and denied illicit drug use. After admission to the hospital, the infant has several episodes of hypoglycemia and required another dose of naloxone for bradycardia, lethargy and pinpoint pupils with some improvement. Breastfeeding was stopped and the infant developed mild withdrawal symptoms that did not require treatment. The infant’s symptoms were probably caused by buprenorphine, but the contribution by breastfeeding cannot be differentiated from prenatal exposure.
◉ Effects on Lactation and Breastmilk:Buprenorphine can increase serum prolactin. However, the prolactin level in a mother with established lactation may not affect her ability to breastfeed.
In a multicenter prospective study of 246 pregnant women receiving either methadone or buprenorphine for opiate dependency, 153 women were receiving high-dose buprenorphine. Twenty-two percent of women receiving buprenorphine breastfed their infants, which was the same percentage as those receiving methadone.
A retrospective chart review of 276 opiate-dependent mothers who delivered in a Baby Friendly Hospital found that mothers taking buprenorphine or methadone for opiate dependency were unlikely to breastfeed their infants. Only 45% of the 20 mothers on buprenorphine maintenance initiated breastfeeding. Of all women in the study, 60% discontinued breastfeeding before discharge from the hospital.
A retrospective case series reported on 85 opioid-dependent women maintained on buprenorphine during pregnancy and postpartum during the period of December 2007 to August 2012. Of these women, 65 were breastfeeding on discharge from the hospital and 66% of these were breastfeeding at their 6- to 8-week follow-up appointment (extent of nursing not stated).
A retrospective cohort study in Australia compared breastfeeding rates on discharge of drug-using mothers who were taking either buprenorphine, other opiates or nonopioids (e.g., benzodiazepines, amphetamines, cocaine, alcohol, inhalants, cannabinoids, psychotropics). Breastfeeding rates at discharge from the hospital were as follows: buprenorphine 27%, other opiates 31%, and nonopioids 51%.
A small retrospective study found that only 3 of 10 pregnant women treated with buprenorphine plus naloxone for opioid dependence were breastfeeding their infants at the time of hospital discharge.
A retrospective cohort study of 150 women enrolled in a substance abuse treatment program found that women taking methadone had a higher prevalence of breastfeeding than women taking buprenorphine plus naloxone. However, this difference appeared to be related to the greater intention to breastfeed before delivery in the methadone group.
A retrospective cohort study of 228 women enrolled in a perinatal substance abuse treatment program found that women taking buprenorphine had a higher prevalence of breastfeeding than women taking methadone. The intention to breastfeed before delivery was similar in both groups.
A systematic review of studies on the effect of breastfeeding on the outcomes of infants whose mothers were taking methadone during pregnancy and postpartum concluded that the association between newborn feeding method and neonatal abstinence syndrome among newborns exposed to buprenorphine in breastmilk was unclear.
A retrospective chart review of 64 mothers given buprenorphine postpartum for opioid use disorder found that mothers who breastfed their infants were more likely to attend a follow-up appointment within 10 to 14 weeks postpartum.
A small retrospective study of 19 mothers with for opiate use disorder found that mothers who were taking buprenorphine were more likely to breastfeed their infants than mothers taking methadone (70% vs 29%).
来源:Drugs and Lactation Database (LactMed)
