Anesth Analg 2002;94:184-187
© 2002 International Anesthesia Research Society
OBSTETRIC ANESTHESIA
Colostrum Morphine Concentrations During Postcesarean Intravenous Patient-Controlled Analgesia
Nour-Eddine Baka, MD*,
Françoise Bayoumeu, MD*,
Marie-Jeanne Boutroy, MD PhD
, and
Marie-Claire Laxenaire, MD PhD*
*Department of Anesthesiology, and Clinical Pharmacology and Neonatal Intensive Care Unit, Maternité Régionale Universitaire, Nancy, France
Address correspondence and reprint requests to Nour-Eddine Baka, MD, Department of Anesthesiology, Maternité Régionale, 10 rue du Dr Heydenreich, BP 4213, 54042 Nancy cedex, France. Address e-mail to ne.baka{at}maternite.chu-nancy.fr
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Abstract
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Patient-controlled analgesia (PCA) with morphine is a convenient method for providing postoperative analgesia. Despite the fact that it is used after cesarean delivery, data on transfer of morphine and of its active metabolite morphine-6 glucuronide (M6G) into maternal milk are scarce. It is not known whether breast-feeding during PCA with morphine has neonatal implications. We sought to measure morphine and M6G concentrations in colostrum during postpartum IV PCA and evaluate the potential for drug intake by neonates being breast-fed by these mothers. Seven informed and consenting mothers, given IV PCA with morphine, were investigated. Plasma and milk samples were obtained at titration, and at 12, 24, 36, and 48 h. Morphine and M6G were measured by high-performance liquid chromatography. In plasma, morphine concentrations ranged from <1 to 274 ng/mL, M6G ranged from <5 to 974 ng/mL. In milk, opioids were found in only 3 patients in whom morphine concentrations ranged from <1 to 48 ng/mL and M6G from <5 to 1084 ng/mL. The milk-to-plasma ratio was always <1 for morphine. In conclusion, we observed very small morphine and M6G concentrations in colostrum during PCA with morphine. Under these conditions, the amounts of drug likely to be transferred to the breast-fed neonate are negligible.
IMPLICATIONS: Colostrum concentrations of morphine and its active metabolite morphine-6 glucuronide were measured in mothers receiving patient-controlled analgesia with morphine after cesarean delivery. The concentrations were found to be very small, thus supporting the safety of breast-feeding in mothers receiving IV patient-controlled analgesia with morphine.
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Introduction
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Patient-controlled analgesia (PCA) with IV opioids is increasingly used for postoperative pain relief after cesarean delivery (1–3). Many opiates have been evaluated for this use, with equivalent efficacy being reported (1–4). Morphine is widely used for PCA after cesarean delivery at our institutions (5,6), despite the potential deleterious influence of this opiate on neonatal behavior. Some authors suggest that breast-feeding is contraindicated in the mother receiving IV morphine via PCA, whereas others approve breast-feeding because preservation of neonatal alertness in babies breast-fed by treated mothers has been reported (7,8).
Before elimination, morphine is conjugated in the liver into an inactive form, morphine-3 glucuronide, and in an active form, morphine-6 glucuronide (M6G) in a ratio of 9:1 (9). Although M6G represents only 10% of the metabolites, because it has analgesic and sedative properties, it may have implications to the neonate.
Morphine transfer into the maternal milk has been described as increased (10) or weak (8). Our aim was to evaluate the transfer of morphine and its active metabolite M6G into breast milk, by measuring morphine and M6G concentrations in plasma and colostrum of breast-feeding mothers receiving morphine via PCA after cesarean delivery.
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Methods
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This study was initiated after approval of the IRB. Written, informed consent was obtained from seven ASA physical status I or II parturients scheduled for cesarean delivery. Patients were excluded if they did not plan to breast-feed, if they were given epidural analgesia for postoperative pain, and if the ASA status was III or more. The cesarean delivery was scheduled for maternal and/or fetal indications: premature rupture of membranes with hyperthermia in three patients, mild preeclampsia with severe intrauterine growth retardation in one patient, cardiotocogram abnormalities and growth retardation in two patients, and uterine hypoplasia in one patient.
All patients but one (who received intrathecal anesthesia) received general anesthesia with endotracheal intubation. In the recovery room, before the procedure was begun, the patients completed a baseline assessment using a 10-cm visual analog scale (VAS) for pain, 0 representing no pain and 10 cm the worst pain. Postoperative analgesia titration was started IV with a standardized schedule, independent of the body weight. The initial dosing was 4 mg IV morphine, followed by 1 mg every 10 min until obtaining VAS < 3. IV PCA morphine sulfate (1 mg/mL) was administered via a Graseby pump 3300 (Graseby Medical France, Montreuil, France) in a 1-mg incremental dose with a 10-min lockout and a 20-mg maximal cumulative load per 4 h. IV propacetamol (2 g) was administered every 6 h.
The vital signs (respiratory rate, sedation level, heart rate, blood pressure) were assessed every 2 h for the first 24 h and then every 4 h during the next 24 h.
Blood (5 mL) and milk (
2 mL) samples were obtained at initial titration and at 12, 24, 36, and 48 h. Plasma was isolated after centrifugation. All samples were stored at -20°C until analyzed. Morphine and M6G measurements were performed by high-performance liquid chromatography with coulometric detection, using nalorphine as an internal standard (11). The intra-assay coefficients of variation in plasma were 5.3% and 11% for morphine and M6G, respectively. The inter-assay coefficients of variation were 3.6%–1.8% and 7.3%–3.8% for morphine and M6G, respectively.
IV PCA was discontinued at the end of the second postoperative day. Infants were not nursed during the study time because of neonatal factors unrelated to this study. The drug amounts potentially transferred to the infant, breast-fed with 100 mL of milk per day, were calculated with the largest concentration values observed for morphine and M6G. Results were expressed as mean ± SEM except for the opioid concentrations, expressed as median ± interquartile because of the wide scattering of the values.
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Results
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Seven patients were enrolled in the study, aged 30.2 ± 1.6 yr, and weighing 67.5 ± 2.6 kg. The mean gestational age at time of cesarean delivery was 31.1 ± 0.9 wk. The titration was obtained for morphine doses from 0.10 to 0.15 mg/kg. All of the patients used their pumps. The cumulative dose necessary to achieve patient satisfaction was 0.58 ± 0.07 mg/kg during the first 24-h period (range 0.33–0.92 mg/kg) and 0.17 ± 0.06 mg/kg during the following 24-h period (range 0.01–0.48 mg/kg). VAS scores remained 
4 in all patients except 1 (VAS 5).
Changes in plasma morphine and M6G are shown in Table 1. Morphine concentrations ranged from <1 to 170 ng/mL in the first 24-h period and from <1 to 274 ng/mL in the second 24-h period. M6G concentrations ranged from <5 to 559 ng/mL in the first period and from <5 to 974 ng/mL in the second period. In three patients, M6G concentration was always below the detection limit.
In colostrum (Table 2), morphine and M6G were identified in only three subjects. Morphine concentrations ranged from <1 to 37 ng/mL in the first period and from <1 to 48 ng/mL in the second period. M6G concentrations ranged from <5 to 1084 ng/mL in the first 24-h period and from <5 to 816 ng/mL in the second period. Morphine Cmax was observed at titration in Patient 2 (31 ng/mL), at 12 h in Patient 3 (25 ng/mL), and at 48 h in Patient 4 (48 ng/mL). In three patients, the concentrations were below the detection limit for both morphine and M6G, and in one patient, no milk was secreted.
Morphine concentrations were always smaller in the milk than in the plasma, as compared with the M6G concentrations, which were always larger. The milk-to-plasma concentration ratios are shown in Table 3. They were 0.32 ± 0.09 for morphine and 1.33 ± 0.25 for M6G. Both ratios were at their peak at 12 h. The M6G-to-morphine ratio was 6.73 ± 1.32 in the plasma and 38.76 ± 13.90 in the colostrum.
According to the largest concentration values observed among all patients, the drug amounts likely to be transferred to the infant if breast-fed were 0.0048 mg/100 mL milk for morphine and 0.1 mg/100 mL milk for M6G.
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Discussion
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Data relating to the transfer of morphine into the colostrum or breast milk are scarce. In this study, we have shown that this transfer does occur during IV morphine analgesia by PCA after cesarean delivery, but the amounts found in colostrum are clinically insignificant.
Only one previous study has evaluated this transfer in similar clinical conditions, and the results are very close to ours. Wittels et al. (7) found the same large interindividual variation between the morphine concentrations in colostrum. In that study, the maximal mean concentration of morphine in colostrum was 60 ng/mL over a 24-hour period in 5 women undergoing IV PCA. However, the opioid plasma concentrations were not known.
It is important to emphasize that the conditions of postoperative analgesia and the constitution of milk are similar in that study and ours. By contrast, the conditions reported by Feilberg et al. (12) and Robieux et al. (10) are different and therefore not comparable to the analgesia achieved by IV PCA. In the patients reported by Robieux et al., morphine was given orally for the last 4 months of pregnancy and the first week after delivery (200 mg/day), then given again in decreasing doses because the mother experienced withdrawal symptoms 5 days after stopping the treatment. The day of the study, the mother received 2 doses of 5 mg. In the study by Feilberg et al., 5 breast-feeding mothers received IM postoperative analgesia with morphine (4–15 mg) 1 month after giving birth.
The transfer into milk of conjugated morphine metabolites has been adequately studied for morphine-3-glucuronide, but not for M6G. This is because M6G only represents 10% of metabolites (9). Nevertheless, we studied it because it has a similar profile to morphine and can thus lead to potentially harmful effects (13). We identified M6G in the plasma and in the colostrum, at concentrations always larger than those of morphine (6-fold larger in plasma and 38-fold larger in milk). Indeed, the majority of morphine present in the colostrum exists in the form of conjugate metabolite. Although active, the quantities of M6G remain so small that they appear inconsequential. Moreover, oral bioavailability is only 20% to 30%, which further lessens the neonatal risks. This is supported by studies performed by Wittels et al. (7,8), showing that the neurologic behavior of children born by cesarean delivery and breast-fed by mothers treated with morphine PCA is comparable to that of children who have undergone a vaginal delivery. Despite the safety profile suggested by our data, we should emphasize that, although the milk/plasma ratio of morphine and the opioid concentrations are small in the current study, that may not be the case when morphine is administered in doses and durations different from those of our study.
In summary, morphine and M6G concentrations found in breast milk are very small in nursing mothers receiving IV morphine via PCA after cesarean delivery. Furthermore, neonatal uptake does not seem to be significant. Therefore, in our opinion, mothers receiving routine doses of morphine via PCA after cesarean delivery should be allowed to breast-feed.
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Acknowledgments
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This work was supported by grants from A.D.A.M.A.T (Association des anesthésistes de la maternité) and Maternité Régionale Universitaire of Nancy, France.
The authors gratefully acknowledge the technical assistance of M. Barberi-Heyob and thank the anesthesia and intensive care staffs for their valuable assistance.
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References
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Accepted for publication August 31, 2001.
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Abstract
Introduction
