毒理性
哺乳期间的使用总结：大多数婴儿接受的剂量估计为母亲体重调整剂量的1%至3%，少数为5%至6%，低于用于治疗新生儿戒断症状的剂量。产后开始使用美沙酮或增加母亲的剂量超过每天100毫克，无论是治疗性还是滥用，同时哺乳都存在使婴儿昏睡和呼吸抑制的风险，特别是如果婴儿在子宫内未接触过美沙酮。如果婴儿表现出过度嗜睡（比平时更甚）、呼吸困难或软弱无力，应立即联系医生。在哺乳期间，首选其他药物而不是美沙酮进行疼痛控制。
哺乳期间对婴儿的影响：一个中心报告了10位在美沙酮维持治疗期间哺乳的母亲，他们的婴儿没有观察到不良反应。但有一名5周大的婴儿，出生时早产1周，母亲曾滥用海洛因，婴儿死亡可能与母乳中的美沙酮有关。该婴儿出生后一直哺乳，母亲每天口服美沙酮维持治疗，剂量不详。法医诊断为大剂量美沙酮中毒。婴儿尸检时血清中美沙酮含量很高；然而，高水平可能是产后重新分布所致（可能增加2至10倍）。婴儿也被发现有“明显营养不良”。尸检发现大脑、肝脏和其他器官异常，似乎婴儿曾被忽视。
三例足月婴儿，母亲在孕期和哺乳期间口服美沙酮维持治疗，剂量为每天45至70毫克，没有报告不良反应。他们出生后得到良好照顾，并于出生后2至3天与母亲一同健康出院。在3周至6个月的随访中，这些婴儿在哺乳期间没有出现镇静或美沙酮戒断症状。一名在3周大时停止哺乳的婴儿出现了过度兴奋和失眠的戒断症状。另外两名婴儿在4至6个月内逐渐断奶，停止哺乳后没有出现戒断症状。作者警告说，在美沙酮维持治疗期间，突然停止哺乳可能会导致婴儿戒断症状的出现。
在一项来自澳大利亚的回顾性研究中，对190名药物依赖母亲的医疗记录进行了研究。其中62位母亲在哺乳期间服用美沙酮（平均剂量为每天68.5毫克；最高剂量为每天150毫克）哺育了他们的婴儿，而87位母亲服用美沙酮（平均剂量为每天79.6毫克）选择配方奶粉喂养。与配方奶粉喂养的婴儿相比，哺乳的婴儿出现戒断症状的时间更长（10天对3天）。哺乳的婴儿不太可能需要药物治疗，并且用于治疗戒断的吗啡剂量较低。哺乳婴儿的治疗持续时间也较短（85天对108天）。
对哺乳和母乳的影响：美沙酮可以增加血清催乳素。然而，对于已经建立哺乳的母亲来说，催乳素水平可能不会影响她哺乳的能力。
在一项针对法国246名怀孕妇女的多中心前瞻性研究中，其中93名妇女接受美沙酮治疗。接受美沙酮治疗的妇女中有24%选择哺乳，这与接受丁丙诺啡治疗的妇女没有差异。
在新西兰，有报道称15名婴儿的母亲因疼痛而服用美沙酮，18名婴儿的母亲因维持戒毒而服用美沙酮，都成功地进行了哺乳。这两组母亲服用的剂量范围很广，平均每天剂量分别为40毫克和60毫克。另有8名婴儿选择瓶喂，2名婴儿的喂养方式未知。
在一项对276名阿片类药物依赖母亲分娩的回顾性图表审查中，发现接受美沙酮或丁丙诺啡治疗的母亲不太可能哺乳她们的婴儿。在美沙酮维持治疗的132名母亲中，只有27%开始哺乳。在所有研究对象中，有60%在出院前停止了哺乳。
在一项对150名参加药物滥用治疗项目的妇女进行的回顾性队列研究中，发现服用美沙酮的妇女哺乳的比例高于服用丁丙诺啡加纳洛酮的妇女。然而，这种差异似乎与美沙酮组在分娩前有更强的哺乳意愿有关。
在一项对228名参加围产期药物滥用治疗项目的妇女进行的回顾性队列研究中，发现服用丁丙诺啡的妇女哺乳的比例高于服用美沙酮的妇女。两组在分娩前有相似的哺乳意愿。前催产素和儿茶酚-O-甲基转移酶基因的变异也会影响对新生儿戒断症状治疗药物的需求。
在一项针对19名阿片类药物滥用母亲的小型回顾性研究中，发现服用美沙酮的母亲比服用丁丙诺啡的母亲更不可能哺乳她们的婴儿（29%对70%）。
◉ Summary of Use during Lactation:Most infants receive an estimated dose of methadone ranging from 1 to 3% of the mother's weight-adjusted methadone dosage with a few receiving 5 to 6%, which is less than the dosage used for treating neonatal abstinence. Initiation of methadone postpartum or increasing the maternal dosage to greater than 100 mg daily therapeutically or by abuse while breastfeeding poses a risk of sedation and respiratory depression in the breastfed infant, especially if the infant was not exposed to methadone in utero. If the baby shows signs of increased sleepiness (more than usual), breathing difficulties, or limpness, a physician should be contacted immediately. Other agents are preferred over methadone for pain control during breastfeeding.
Women who received methadone maintenance during pregnancy and are stable should be encouraged to breastfeed their infants postpartum, unless there is another contraindication, such as use of street drugs. Breastfeeding may decrease, but not eliminate, neonatal withdrawal symptoms in infants who were exposed in utero. Some studies have found shorter hospital stays, durations of neonatal abstinence therapy and shorter durations of therapy among breastfed infants, although the dosage of opiates used for neonatal abstinence may not be reduced. The long-term outcome of infants breastfed during maternal methadone therapy for opiate abuse has not been well studied. Abrupt weaning of breastfed infants of women on methadone maintenance might result in precipitation of or an increase in infant withdrawal symptoms, and gradual weaning is advised. The breastfeeding rate among mothers taking methadone for opiate dependency has been lower than in mothers not using methadone in some studies, but this finding appears to vary by institution, indicating that other factors may be important.
◉ Effects in Breastfed Infants:One center reported 10 women who breastfed during methadone maintenance with no observed adverse effects in their infants.
The death of a 5-week-old infant who was born 1 week prematurely to a former heroin-abusing mother was possibly related to methadone in breastmilk. The infant had been breastfeeding since birth and the mother was taking an unreported daily dose of oral methadone maintenance. The medical examiner's diagnosis was methadone intoxication. A high level of methadone was found in the infant's serum at autopsy; however, the high level might have been caused by postpartum redistribution (which can be 2- to 10-fold). The infant was also noted to be "obviously malnourished." Abnormal brain, liver and other organs on autopsy were also found and it appeared that the infant had been neglected.
Three breastfed term infants of mothers taking oral methadone maintenance 45 to 70 mg daily during pregnancy and lactation had no reported adverse effects. They were cared for in a well-baby nursery after birth and discharged in good health home with their mothers at 2 to 3 days of age. At follow up over 3 weeks to 6 months of age, the infants had no symptoms of sedation or methadone withdrawal while breastfeeding. One infant who had breastfeeding discontinued at 3 weeks of age developed withdrawal symptoms of hyperirritability and sleeplessness. The other 2 infants were slowly weaned over 4 to 6 months and did not experience withdrawal upon breastfeeding discontinuation. The authors cautioned against abrupt breastfeeding discontinuation during methadone maintenance.
A partially breastfed 3.5-month-old infant of a mother taking oral methadone maintenance 73 mg once daily died of sudden infant death syndrome. The mother was reportedly mostly bottle feeding the infant due to diminished milk supply. There was no methadone detected in the infant's blood at autopsy (lower limit of the assay not reported).
Twelve fullterm breastfed (extent not stated) newborns of mothers taking oral methadone maintenance (range 20 to 80 mg daily) during pregnancy and lactation were observed during their first week of age. Seven of these infants developed methadone withdrawal and 6 required treatment. The authors considered maternal methadone maintenance to be compatible with breastfeeding in the first week of a newborn's life but cautioned that newborn methadone withdrawal may occur despite breastfeeding.
The hospital course of 88 breastfed newborns were compared to 32 non-breastfed newborns. All had mothers who were taking oral methadone maintenance at an average dose of 40 mg daily (range 5 to 175 mg daily). Although the breastfed newborns developed neonatal abstinence syndrome and required rehospitalization after discharge at the same rate as bottle-fed infants, they did have a shorter hospital stay than bottle-fed newborns.
Two fully breastfed term infants of mothers taking oral methadone maintenance 70 and 130 mg daily during pregnancy and lactation had no adverse effects and required no treatment for methadone withdrawal prior to postpartum hospital discharge at 8 and 6 days of age, respectively. Both infants were rehospitalized and treated for methadone withdrawal symptoms at 6 weeks and 17 days of age, respectively, shortly after their mothers abruptly discontinued breastfeeding. The authors surmised that the appearance of symptoms were probably due to withdrawal from methadone in breastmilk.
A Swiss descriptive report found that among the newborns of 84 mothers on methadone maintenance, the neonatal abstinence syndrome was less frequent in breastfed infants than in non-breastfed infants, 26% and 78%, respectively. Twenty-seven infants were breastfed and 54 were formula-fed. "Breastfed" was defined by the authors as more than 50% of feeding from breastmilk while in the hospital.
A 5-week-old breastfed infant became cyanotic and required mouth-to-mouth resuscitation and intubation. The infant's urine was positive for opioids and the infant responded positively to naloxone; the level of consciousness improved over 2 days and extubation was accomplished. The infant's mother admitted to taking methadone and a hydrocodone-acetaminophen combination product that had been prescribed for migraine headache before she was breastfeeding.
A retrospective review from Australia was conducted on the medical records of 190 drug-dependent mothers and their infants. One hundred forty-nine of the mothers were taking methadone at delivery; 62 mothers taking methadone (average dose 68.5 mg daily; maximum dose 150 mg daily) breastfed their infants and 87 mothers taking methadone (average dose 79.6 mg daily) formula-fed their infants. Breastfed infants had a longer median time to withdrawal symptoms (10 days) than formula-fed infants (3 days). Breastfed infants were less likely to require pharmacologic treatment and doses of morphine required to treat withdrawal were lower in breastfed infants. Treatment duration was also shorter in breastfed infants (85 vs. 108 days).
A hospital in England reported outcomes among infants whose mothers were taking methadone maintenance during pregnancy over 2 time periods. Several changes were made in the management of mothers taking methadone between the 2 time periods. In the first time period (1991-1994), only 10% breastfed their infants (4% exclusive); in the second time period (1997-2001), 30% breastfed their infants (20% exclusive). During the second time period, the frequency of jaundice, and convulsions were less frequent in all infants, even though the average maternal methadone dose was twice as high as in the earlier period. Pharmacologic treatment of the infants for withdrawal, days of hospitalization, days in intensive care, and percentage of infants admitted to intensive care were all lower during the second time period.
Eight breastfed and 8 formula-fed newborn infants whose mothers were receiving methadone maintenance in a median dose of 70 mg daily (range 50 to 105 mg daily). No differences were noted between infants in the 2 groups on days 3, 14 or 30 in 9 neurobehavioral measures or on the percentage requiting pharmacologic management of withdrawal. Four of these breastfed infants were followed for 6 months. No health concerns arose during this time. Another infant who was partially breastfed for 1 year had no important health or developmental problems during this time.
A retrospective review of the charts of 68 newborn infants exposed to methadone in utero found that infants who were breastfed had a trend towards requiring shorter durations of treatment for neonatal abstinence syndrome, although the trend was not statistically significant.
A retrospective cohort study reviewed the records of 437 newborn infants whose mothers were taking methadone maintenance therapy. Infants who were breastfed for 72 or more hours had a 45% reduced risk of experiencing neonatal abstinence syndrome compared to those who were not. Neonatal abstinence syndrome was more likely in mothers who were also receiving a benzodiazepine.
A 13-month-old infant was being primarily breastfed by a mother who was taking hydrocodone and acetaminophen for pain. On 2 occasions 4 hours apart, she substituted a dose of 40 mg of methadone for the acetaminophen-hydrocodone combination. The child nursed 2 and 6 hours after the second dose for 45 minutes each time, then fell asleep for 45 minutes. Forty-five minutes later, the infant's mother noted that the infant was drowsy and not responsive. Emergency responders confirmed that the baby had cyanosis, myosis, and decreased breathing. Upon arrival at the emergency room, the child was unarousable, but had normal vital signs. The baby awoke after naloxone 0.2 mg was given intravenously. The infant's urine drug screen was positive for opiates, including methadone metabolites. Eighteen hours after the mother's first dose, the infant remained intermittently drowsy with oxygen saturation dropping as low as 91%. During this 18-hour time period, the infant received 4 doses of naloxone intravenously. Eventually, the baby returned to normal state of good health.
A retrospective study in the United States of 128 infants exposed during pregnancy and breastfeeding to methadone found an inverse relationship between the amount of breastfeeding and duration of hospitalization for neonatal abstinence syndrome. Five of the breastfed infants were readmitted for withdrawal symptoms after discontinuing or markedly reducing breastmilk intake after discharge.
A retrospective review of the charts of the infants of mothers taking methadone during pregnancy and postpartum at 2 hospitals in Maine was made. Infants who breastfed (n = 8) had lower neonatal abstinence scores than infants who were formula-fed (n = 9) or had mixed feeding (n = 11).
A retrospective review of the charts of the infants of mothers taking methadone during pregnancy and postpartum at an Ontario Canada hospital was made. Infants who were breastfed (n = 14) had statistically significantly shorter hospital stays than those who were given formula or mixed feeding (n = 118).
A retrospective cohort study of the infants of 354 mothers receiving methadone maintenance in Glasgow, Scotland compared the weight loss of infants who were breastfed to those who were given formula. Infants in the entire breastfed (including partial) group lost a maximum of 10.2% of body weight after birth compared with a weight loss of 8.5% in the formula-fed group and 9.3% in the exclusively breastfed subgroup. Weight loss was less in infants who were small for gestational age compared to infants with normal birth weights. Median maximal weight loss occurred on day 5 postpartum, except for exclusively breastfed infants in whom it occurred on day 4. Neither methadone dose nor polydrug abuse correlated with weight loss. These weight loss values were greater than local values for infants who were not exposed to drugs.
A tertiary care hospital in British Columbia analyzed the charts of 295 women receiving methadone maintenance who delivered an infant over a 39-month period. Infants who were breastfed had a 79% reduced chance of requiring morphine to treat withdrawal symptoms than nonbreastfed infants. All infants were rooming-in, which may have assisted by increasing on-demand feeding and skin-to-skin contact.
A cohort of 124 infants exposed during pregnancy to maternal medication for opioid maintenance therapy were followed postpartum in a Norwegian study. Seventy-eight infants were born to mothers taking methadone. Overall, infants who were breastfed had a lower rate of neonatal abstinence symptoms and a shorter duration of therapy for neonatal abstinence. Among infants exposed to methadone, 53% of breastfed infants and 80% of nonbreastfed infants required treatment. Breastfed infants required treatment for an average of 31 days compared with an average of 49 days among nonbreastfed.
Two infants whose mothers were on methadone maintenance therapy died. Both infants were heterozygous for the lower activity form of the P-glycoprotein transporter, and one had a pharmacogenetic variant for CYP2B6 thought to reduce methadone metabolism. Both also had other factors that could have contributed to their deaths. The authors state that it would inappropriate to assume that methadone from breastmilk was the sole cause of death in thee infants.
A study of pregnant being treated for opiate dependency with methadone at a clinic in Vienna were followed as were their newborn infants. Compared to infants who were not breastfed (n = 118), breastfed infants (n = 48) had lower average measures of neonatal abstinence, lower dosage requirements of morphine (4.35 mg vs 12.65 mg), shorter durations of treatment for neonatal abstinence (8.1 vs 17 days) and shorter hospital stays (17.2 vs 29.4 days).
A retrospective chart review of 194 new mothers who were on methadone maintenance and their infants found that predominant breastfeeding during the first 2 days postpartum delayed the onset on neonatal abstinence syndrome (NAS) in the infants compared to formula feeding. However, breastfeeding did not decrease the need for treatment of the infant for NAS.
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 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 breastfeeding was associated with decreased frequency and duration of pharmacologic treatment, shorter hospital length of stay, and decreased severity of NAS.
A search was performed of the shared database of all U.S. poison control centers for the time period of 2001 to 2017 for calls regarding medications and breastfeeding. Of 2319 calls in which an infant was exposed to a substance via breastmilk, 7 were classified as resulting in a major adverse effect, and three of these involved methadone. A one-month-old infant was admitted to the intensive care unit and described as being agitated and irritable and having tremor, respiratory arrest, diarrhea, drowsiness and lethargy. A 13-month-old infant was admitted to the intensive care unit with respiratory depression. A 6-month-old exposed to methadone and benzodiazepines was admitted to the intensive care unit with drowsiness, lethargy, seizure, and tremor. The dosages and extent of breastfeeding were not reported and all of the infants survived.
An infant was born to a mother with opioid use disorder who was taking up to 2 grams of intravenous fentanyl daily. In the hospital she was transitioned to intravenous hydromorphone 120 mg three times daily, oral hydromorphone 32 mg every hour as needed, and methadone 70 mg daily by mouth. After 9 days of tapering the oral morphine dosage, the infant was given 72 mL of the mother’s expressed milk. On day 10, the infant received two doses of 0.1 mg of oral morphine and then breastfed for 30 minutes 3 hours after a maternal dose of 110 mg of intravenous hydromorphone. The infant was alert and active, feeding and sleeping well, and the infant’s morphine was discontinued. There were no clinically relevant episodes of apnea, bradycardia, desaturation, signs of respiratory depression, or excessive sedation. The infant continued to receive formula plus either breastfeeding or expressed milk with no clinically important adverse effects. The mother’s hydromorphone dose was tapered over 47 days while oral methadone and oral slow-release morphine were increased to 190 mg and 1200 mg daily, respectively, and she was discharged on day 58 postpartum. The extent of breastfeeding after hospital discharge was not reported. At 4 months of age, the infant scored above average on all developmental domains.
◉ Effects on Lactation and Breastmilk:Methadone can increase serum prolactin. However, the prolactin level in a mother with established lactation may not affect her ability to breastfeed.
In a French multicenter prospective study of 246 pregnant women in receiving either methadone or buprenorphine for opiate dependency, 93 women were receiving methadone. Twenty-four percent of women receiving methadone breastfed their infants, which was not different from those receiving buprenorphine.
Successful breastfeeding was reported in New Zealand in 15 infants whose mothers were taking methadone for pain and 18 infants whose mothers were taking methadone for maintenance of narcotic abstinence. Both groups of mothers were taking a wide range of doses with median daily dosages of 40 and 60 mg, respectively. An additional 8 infants were bottle-fed and the feeding method was unknown in 2.
A woman who was not breastfeeding, but who had 2 children (breastfeeding history not stated), was prescribed methadone 30 mg daily for heroin dependency. When the dose was increased to 40 mg daily, she developed galactorrhea. Her serum prolactin levels were elevated on 3 occasions over the next year, but all other examinations were normal. Galactorrhea and amenorrhea persisted for at least 2 years with continuous methadone use. The authors of the article stated that 3 cases of hyperprolactinemia had been reported to the United Kingdom's drug regulatory agency. Causality was not proven in any of these cases.
A retrospective chart review of 276 opiate-dependent mothers who delivered in a Baby Friendly Hospital found that mothers taking methadone or buprenorphine for opiate dependency were unlikely to breastfeed their infants. Only 27% of the 132 mothers on methadone maintenance initiated breastfeeding. Of all women in the study, 60% discontinued breastfeeding before discharge from the hospital.
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. Variations in the prepronociceptin and catechol-O-methyltransferase genes also affected the needed for infant drug treatment for neonatal abstinence.
A small retrospective study of 19 mothers with for opiate use disorder found that mothers who were taking methadone were less likely to breastfeed their infants than mothers taking buprenorphine (29% vs 70%).
来源:Drugs and Lactation Database (LactMed)
