Narcotic Agonist Analgesic
PREGNANCY RECOMMENDATION: Human Data Suggest Risk in 3rd Trimester
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
PREGNANCY SUMMARY
Remifentanil was not teratogenic or toxic in animals, but the absence of reports in early gestation prevents an assessment of its risk to the human fetus. However, narcotic analgesics are not considered to be human teratogens. Neonatal respiratory depression and sedation immediately after birth are potential complications of all narcotics when administered to a woman during labor. The short duration of remifentanil and its apparent rapid metabolism by the fetus may lessen these potential effects, but additional studies are needed to demonstrate this benefit. If remifentanil is used in pregnancy, health care professionals are encouraged to call the toll free number 800-670-6126 for information about patient enrollment in the Motherisk study.
FETAL RISK SUMMARY
Remifentanil is a rapid-onset, short-acting, synthetic mu-opioid agonist analgesic that is administered IV, in combination with other agents, for the induction and maintenance of general anesthesia. The elimination half-life is approximately 3–10 minutes. Because remifentanil is extensively metabolized by nonspecific esterases, not plasma cholinesterase (pseudocholinesterase), a normal duration of action is expected in patients with atypical cholinesterase. Further, remifentanil is not appreciably metabolized by the liver or lung (1), as are other opioid analgesics.
Fertility studies in male and female rats were conducted with IV doses 40 and 80 times, respectively, the maximum recommended human dose based on BSA (MRHD) (1). Reduced fertility was observed in male rats when the dose was administered daily for more than 70 days. In contrast, no effect was observed on the fertility of female rats dosed daily for at least 15 days before mating. Reproduction studies conducted in pregnant rats and rabbits at doses up to 400 and 125 times, respectively, the MRHD revealed no evidence of teratogenicity (1). The timing of the exposures was not specified. When remifentanil was given to rats throughout late gestation and lactation at a dose about 400 times the MRHD, no significant effect on the survival, development, or reproductive performance was observed in the exposed offspring. The drug crosses the placenta in pregnant rats and rabbits (1).
Consistent with its molecular weight (about 413) and high lipid solubility, remifentanil crosses the human placenta (1–3). The manufacturer reported that in human clinical trials, the average maternal concentration was approximately twice the levels observed in the fetus (1). However, in some cases, the maternal:fetal ratios were similar. The umbilical artery:umbilical vein (UA:UV) ratio, however, was approximately 0.30 suggesting metabolism of the drug in the fetus (1).
In an abstract (2) and a full report (3), information was presented on the placental transfer of remifentanil in 16 healthy women who were delivered by nonemergent cesarean section. Anesthesia appropriate for cesarean section was established with a lidocaine/epinephrine epidural before starting an IV infusion of remifentanil (0.1 mcg/kg/minute) that was continued until skin closure. The mean umbilical vein:maternal artery (UV:MA) and UA:UV ratios for remifentanil were 0.88 and 0.29, respectively (3). For remifentanil acid, the inactive primary metabolite, the mean UV:MA and UA:UV ratios were 0.56 and 1.23, respectively (3). These results suggested to the investigators that the narcotic rapidly crossed the placenta and was metabolized and redistributed in the fetus. The mean Apgar scores (ranges in parentheses) at 1, 5, 10, and 20 minutes were 8 (4–9), 9 (8–9), 9 (9–10), and 9 (9–10), respectively. Neurobehavioral and Adaptive Capacity Scores noted at 30 and 60 minutes were 37 (range 35–39) and 35 (range 34–39), respectively, all within normal limits. Although there were no adverse effects in the newborns, sedative and respiratory depressant effects were noted in the mothers (3).
A 1998 report described the case of a woman at term with mixed mitral valve disease, marked obesity, asthma, and preeclampsia (4). After receiving a bupivacaine/fentanyl epidural, she was delivered by an emergency cesarean section under general anesthesia. Rapid-sequence induction was conducted with remifentanil (2 mcg/kg), etomidate (20 mg), and succinylcholine (100 mg). A male infant (birth weight not given) was delivered 3 minutes after induction of anesthesia. The Apgar scores were 6, 8, and 8 at 1, 5, and 10 minutes, respectively. No signs of respiratory depression were observed (4).
A 30-year-old woman was delivered by cesarean section at 36 weeks’ because of the need for surgical resection of a right acoustic neuroma (5). Remifentanil (0.1–0.2 mcg/kg/minute) was infused for induction of general anesthesia followed by propofol and succinylcholine. A healthy 2970-g female infant was delivered 7 minutes after the start of remifentanil. Apgar scores were 7 and 8 at 1 and 5 minutes, respectively. Although there were no clinical signs of respiratory distress, her initial room air oxygen saturation was 85%–91% and she was placed in a 40% oxygen tent for 1 hour. She was discharged home at 3 days of age (5).
A 23-year-old woman at 37 weeks’ gestation whose condition was complicated by a recurrent aortic coarctation with 50% narrowing of the aortic arch was delivered by an elective cesarean section (6). Remifentanil infusion up to 0.2 mcg/kg/minute was combined with etomidate, succinylcholine, and isoflurane. Delivery took place 7 minutes after induction of anesthesia. The newborn (sex and weight not specified) had Apgar scores of 6 and 9 at 1 and 5 minutes, respectively. The infant did well after birth with no need for naloxone or evidence of respiratory distress (6).
Three studies have been located that describe the use of remifentanil for labor pain (7–9). In one study, four laboring women with singleton term pregnancies were treated with remifentanil either from a patient-controlled analgesia (PCA) pump (0.25 mcg/kg, 5-minute lockout duration) or with IV bolus doses (0.25–0.50 mcg/kg every 2 minutes as needed) (7). Failure of the pain to respond to increased doses and adverse effects (sedation, oxygen desaturation episodes, respiratory depression, nausea and vomiting, and pruritus) resulted in removal of the patients from the study. Healthy newborns (sex and weight not specified) were delivered 4–6 hours after discontinuance of remifentanil. All had Apgar scores of 9 or 10 (7). A study published in 2000 described two women in labor who were treated with remifentanil administered by a PCA pump (8). The on-demand dose was 20 mcg with a 3-minute lockout duration (no basal infusion). The total doses administered during labor were 740 and 940 mcg. No adverse effects attributable to the analgesic were observed in the newborns. The effects of remifentanil PCA on 42 laboring women were described in a 2001 abstract (9). The technique used was thought to be safe for the mother and newborn (9).
A 1999 study concluded that remifentanil-based general anesthesia (combined with propofol or isoflurane but without nitrous oxide) was a suitable alternative to sedation (induced by midazolam, diazepam, or propofol) for oocyte retrieval in an in vitro fertilization program (10). In a comparison between the general anesthesia and sedation groups, no significant differences were observed in the number of fertilized oocytes, or in the cleavage and pregnancy rates. However, the number of collected oocytes was significantly higher in the general anesthesia group (10).
BREASTFEEDING SUMMARY
No reports describing the use of remifentanil in a lactating woman have been located. The molecular weight (about 413) and high lipid solubility suggest that it will be excreted into breast milk. Other narcotic agents (e.g., codeine, fentanyl, and morphine) are excreted into breast milk but are classified as compatible with breastfeeding by the American Academy of Pediatrics (see specific agents). The very short elimination time suggests that use of remifentanil during cesarean section or other surgery would not represent a significant risk to a newborn that started or continued breastfeeding a few hours later.
References
1.Product information. Ultiva. Abbott Laboratories, 2001.
2.Hughes SC, Kan RE, Rosen MA, Kessin C, Preston PG, Lobo EP, Johnson LR, Johnson JL. Remifentanil: ultra-short acting opioid for obstetric anesthesia (abstract). Anesthesiology 1996;85:A894.
3.Kan RE, Hughes SC, Rosen MA, Kessin C, Preston PG, Lobo EP. Intravenous remifentanil. Placental transfer, maternal and neonatal effects. Anesthesiology 1998;88:1467–74.
4.Scott H, Bateman C, Price M. The use of remifentanil in general anaesthesia for caesarean section in a patient with mitral value disease. Anaesthesia 1998;53:691–701.
5.Bedard JM, Richardson MG, Wissler RN. General anesthesia with remifentanil for cesarean section in a parturient with an acoustic neuroma. Can J Anesth 1999;46:576–80.
6.Manullang TR, Chun K, Egan TD. The use of remifentanil for cesarean section in a parturient with recurrent aortic coarctation. Can J Anesth 2000;47:454–9.
7.Olufolabi AJ, Booth JV, Wakeling HG, Glass PS, Penning DH, Reynolds JD. A preliminary investigation of remifentanil as a labor analgesic. Anesth Analg 2000;91:606–8.
8.Thurlow JA, Waterhouse P. Patient-controlled analgesia in labour using remifentanil in two parturients with platelet abnormalities. Br J Anaesth 2000;84:411–3.
9.Evron S, Sadan O, Ezri T, Boaz M, Glezerman M. Remifentanil: a new systemic analgesic for labor pain and an alternative to dolestine (abstract). Am J Obstet Gynecol 2001;185:S210.
10.Hammadeh ME, Wilhelm W, Huppert A, Rosenbaum P, Schmidt W. Effects of general anaesthesia vs. sedation on fertilization, cleavage and pregnancy rates in an IVF program. Arch Gynecol Obstet 1999;263:56–9.