1. Are opioids effective in the fetus?
2. How well do maternally administered opioids cross to the fetus?
3. What are potential fetal side effects of opioid use?
1.阿片剂在胎儿是否有效？
2.给母体使用阿片剂，是否对胎儿有作用？
3.使用阿片剂的对胎儿的潜在副作用有哪些？
1.阿片剂在胎儿是否有效？
有大量药物可用于预防疼痛、降低应激反应，阿片剂成为用于各种情况的药物选择之一，并用于不同年龄患者[1]。胎儿代表了药物最有效作用的另一类群体。因为伤害性生理变化随年龄而发生显著变化，因此很难研究阿片剂在胎儿和新生儿早期的作用。而且因为在监测药理效果和胎儿经受的疼痛量化上的困难，这样的研究很难进行[2]。机械通气情况下，对早产儿和足月新生儿进行行为和生理功能的评估的研究，在一定程度上可帮助我们理解。关于这方面研究的文章也并不一致，有综述表明，阿片剂可成功调节与疼痛相关的行为学和生理学体征[2]。此外，研究发现，血浆吗啡浓度和镇痛效果在早产组和成熟组间无显著性差异。如果据此往前推理至出生前，可提示阿片剂可能在预防胎儿疼痛方面有效果[2]。
2.给母体使用阿片剂，是否对胎儿有作用？
高脂溶性阿片剂如芬太尼，以及水溶性阿片剂，可迅速转移并进入胎儿体内。Cooper等[3]对38名8～14周妊娠的女性进行研究发现，其接受终止妊娠手术过程中芬太尼可转移通过早期的胎盘内。麻醉诱导给与芬太尼2μg/kg单次注射，采集母体血（n=38）、胎盘（n=38）、羊水（n=38）和胎儿大脑组织（n=7）样本，通过放射免疾分析法测定芬太尼。在所有的胎盘和胎儿脑组织中都可检测到芬太尼，但羊水中未检测到。静脉注射后产妇血清芬太尼浓度快速下降，而胎盘浓度知道30min后才开始下降。不同胎龄间胎盘药物浓度检测无差异。作者因此得出结论，在早期妊娠芬太尼可迅速进入胎儿体内；在给与母体最初剂量的药物后，胎儿组织中的药物可保持一定时间。
DeVane等[4]对孕鼠单次或持续输注水溶性阿片剂吗啡后检测腹膜腔内吗啡浓度。通过高压液相色谱测定血浆和组织中的吗啡含量。作者发现，胎儿药物分布迅速，胎儿和胎盘的吗啡浓度比母体血浆浓度高2.6到27.6倍。浓度-时间曲线（AUC）下面积个组织的情况为：胎盘≥胎肝＞胎脑＞胎儿全身＞母体脑。胎脑与母体脑吗啡AUC比率为9.5，表明两者之间的血脑屏障通透性存在较大差别。这些结果表明，母体给与吗啡后，可迅速分布到胎儿，并形成胎儿组织吗啡的高浓度。
3.使用阿片剂的对胎儿的潜在副作用有哪些？
在一定程度上，母体/胎盘和胎儿循环保护胎儿免受阿片剂副作用的影响。比如，胎儿血供通过胎盘氧和，因此，新生儿自主呼吸抑制不必惊慌[5]。但是，阿片剂的血流动力学反应应该引起注意，因为岂可潜在影响胎儿血液循环。近期有关于给与阿片剂后胎儿表现一定的副作用（心动过缓或低血压）。Holsey等[6]研究了DALDA（酪氨酸-D-精氨酸-苯丙氨酸-赖氨酸-NH2，一种选择性μ阿片受体激动剂）在接受长期器械植入术的羊的胎儿中的效果，观察心率和血压变化。分别进行三个独立的实验，单次注射DALDA，同时给与阿片拮抗剂纳洛酮或其类似物naloxone methiodide，和β受体阻滞剂心得安（2mg/h）。作者发现，所有组DALDA增加心率，而不改变血压。此外，该作用可被纳洛酮（P <.001）和naloxone methiodide（P =.003）以及心得安（P <.001）所阻断。因此作者得出结论认为，DALDA通过μ阿片受体和中枢交感神经激活增加胎儿心率而不改变血压。DALDA的这些作用与成人不同（心动过缓和低血压），表明作用位点和机制存在差异。
值得注意的是阿片剂对胎儿免疫功能的作用。研究表明δ和κ阿片受体（内源性神经受体）具有免疫调控特性。近期研究表明，κ阿片受体可抑制人类小胶质细胞和脑定居巨噬细胞的免疫缺陷病毒1（HIV-1）的表达。为验证μ阿片受体变体1和2是否影响HIV-1复制，Peterson等[7]将其加入脑细胞进行观察。结果发现，在混合神经胶质/神经细胞和单纯的小胶质细胞，μ阿片受体变体1可能影响病毒表达。需要注意的是，μ阿片受体变体1的放大效应可通过脑细胞的预处理而被阻断。对临床有意义的是，作者也证实传统的μ受体激动剂和DAMGO对病毒表达或变体1的放大效应没有作用。
Are opioids effective in the fetus?
Although a number of agents have been utilized for the provision of analgesia and the reduction of stress responses, opioids have become agents of choice for many situations and in many different aged populations (1). Fetuses represent another population where these agents are most likely effective. As nociceptive physiology changes markedly with age, it is difficult to study the effects of opioids on the fetus and early neonatal period. Moreover, due to the difficulties in measuring both the pharmacologic effects and the amount of pain being experienced in this fetal population, studies are difficult to conduct (2). To some extent, evidence derived from premature and term neonates undergoing behavioral and physiologic evaluations while on mechanical ventilation may assist in our understanding. While not uniformly demonstrated, a review of a number of these studies indicates that opioids successfully modulate behavioral and physical signs associated with pain (2). In addition, no significant differences between plasma morphine and analgesic effects between premature and mature groups has been observed; if extrapolated to late prenatal life, this may suggest that opioids could be beneficial for the prevention of fetal sentience (2).
How well do maternally administered opioids cross to the fetus?
Especially with opioids of high lipid solubility such as fentanyl, but also with water soluble opioids, rapid transfer and an extended fetal presence has been noted. Cooper et al. (3) investigated the transfer of fentanyl across the early human placenta in 38 women (8-14 weeks' gestation) undergoing termination of pregnancy. Following administration of a bolus dose of fentanyl 2 micrograms kg-1 at induction of anesthesia, maternal blood (n = 38), placenta (n = 38), amniotic fluid (n = 38) and fetal brain (n = 7) samples were collected and assayed for fentanyl by radioimmunoassay. Fentanyl was detected in all placental and fetal brain samples but not in amniotic fluid. There was a rapid decrease in fentanyl concentrations in maternal serum after the bolus but placental concentrations did not start to decline until 30 min later. No difference in placental drug concentrations at different gestational ages was detected. The authors concluded that there is rapid transfer of fentanyl to the fetus in early pregnancy and that the drug remains in fetal tissue for some time after the initial dose is given to the mother.
In terms of water soluble opioids like morphine, DeVane et al. (4) examined the disposition of intraperitoneal dosing of a single dose or continuous infusion of morphine in pregnant rats. Plasma and tissue levels were evaluated via a high-pressure liquid chromatography assay for morphine. Following morphine administration, the authors noted that fetal distribution was rapid and concentrations in fetal and placental tissues were from 2.6 (whole fetus) to 27.6 (placenta) times higher than maternal plasma concentrations. The rank order of the area under the concentration vs. time curve (AUC) of morphine in tissues was: placenta > = fetal liver > fetal brain > whole fetus > maternal brain. The fetal brain to maternal brain AUC ratio for morphine was 9.5, suggesting large differences in their blood-brain barrier permeability. These results suggest that fetal distribution of morphine following maternal administration occurs rapidly with high tissue levels being obtained.
What are potential fetal side effects of opioid use?
To some extent, the physiology of the maternal/placental unit and the fetal circulation protects the fetus from the full impact of common opioid side effects. For instance, as the fetal blood supply is oxygenated via the placenta, the respiratory depression witnessed in neonates ventilating spontaneously is not of concern (5). However, the hemodynamic responses to opioids merits some attention, as this can potentially affect fetal blood circulation. A recent evaluation of fetal opioid administration suggests limited cardiovascular effects (bradycardia or hypotension). Holsey et al. investigated the effects of DALDA (tyrosine-D-arginine-phenylalanine-lysine-NH2), a mu-selective opioid peptide, on heart rate and blood pressure in fetal sheep with long-term instrument implantation. In three separate experiments, DALDA was given alone as an intravenous bolus, with the opioid antagonist naloxone or its quaternary analog naloxone methiodide, and with the beta-adrenergic antagonist propranolol (2 mg/h). The authors found that DALDA actually increased fetal heart rates at all doses and did not change blood pressure. In addition, this response was abolished by naloxone (P <.001), naloxone methiodide (P =.003), and propranolol (P <.001). The authors concluded that DALDA increases fetal heart rate without any change in blood pressure by way of the mu receptor and through central sympathetic activation. These effects of DALDA are different from those seen in the adult (bradycardia and hypotension), suggesting different sites and mechanisms of action.
One novel effect that deserves additional attention is the effect of opioids on fetal immunoreactivity. Endogneous delta and kappa opioid peptides have been noted to possess a variety of immunomodulatory properties, and kappa-opioid receptor ligands recently were shown to suppress the expression of human immunodeficiency virus type 1 (HIV-1) in microglial cells, the resident macrophages of the brain. To determine whether the newly discovered endogenous mu-opioid receptor ligands endomorphin-1 and -2 would affect HIV-1 replication, Peterson et al. (7) added these peptides to acutely infected brain cell cultures. The authors discovered that endomorphin-1 potentiated viral expression in a bell-shaped dose-response manner in both mixed glial/neuronal cell and purified microglial cell cultures. Of note, endomorphin-1's amplifying effect was blocked by pretreatment of brain cells with either the mu-opioid receptor selective antagonist beta-funaltrexamine or the G protein inhibitor pertussis toxin. Of great interest to clinical practice, the authors also demonstrated that the classical mu receptor agonists morphine and DAMGO (Tyr-d-Ala-Gly-N-Me-Phe-Gly-ol) had no effect on viral expression or on endomorphin-1's amplifying effect. However, taken together, these findings suggest that in this in vitro model of HIV-1 brain infection, endomorphin-1 potentiates viral expression via activation of an atypical mu-selective opioid receptor and provides evidence, for the first time, that an endogenous mu-opioid peptide has neuroimmunomodulatory activity.
Authors note: For related readings in the postnatal population, an excellent review on newborn opioid pharmacology is provided by Marsh, Hatch and Fitzgerald (3).
References:
1. Duncan HP, Cloote A, Weir PM et al. Reducing stress responses in the pre-bypass phase of open heart surgery in infants and young children: a comparison of different fentanyl doses. Br J Anaesth 2000 May;84(5):556-64.
2. Marsh DF, Hatch DJ, Fitzgerald M. Opioid systems and the newborn. Br J Anaesth 1997;79:787-95.
3. Cooper J, Jauniaux E, Gulbis B, et al. Placental transfer of fentanyl in early human pregnancy and its detection in fetal brain. Br J Anaesth 1999;82:929-31.
4. DeVane CL, Simpkins JW, Boulton DW, et al. Disposition of morphine in tissues of the pregnant rat and fetus following single and continuous intraperitoneal administration to the mother. J Pharm Pharmacol 1999;51(11):1283-7.
5. Fahnenstich H, Steffan J, Kau N, Bartmann P. Fentanyl-induced chest wall rigidity and laryngospasm in preterm and term infants. Crit Care Med. 2000 Mar;28(3):836-9.
6. Holsey YS, Wu D, Soong Y et al. Cardiovascular effects of a mu-selective opioid agonist (tyrosine-D-arginine-phenylalanine-lysine-NH2) in fetal sheep: sites and mechanisms of action. Am J Obstet Gynecol 1999 May;180(5):1127-30.
7. Peterson PK, Gekker G, Hu S et al. Endomorphin-1 potentiates HIV-1 expression in human brain cell cultures: implication of an atypical mu-opioid receptor. Neuropharmacology 1999;38(2):273-8.
编辑：西门吹血
