Narcotic Agonist Analgesic
PREGNANCY RECOMMENDATION: Human Data Suggest Risk
BREASTFEEDING RECOMMENDATION: Limited Human Data—Potential Toxicity
The National Birth Defects Prevention Study discussed below found evidence that opioid use during organogenesis is associated with a low absolute risk of congenital birth defects. Use for prolonged periods or in high doses at term has the potential to cause withdrawal or respiratory depression in the newborn.
FETAL RISK SUMMARY
Oxycodone is a narcotic analgesic available as a single agent or in combination with nonnarcotic analgesics, such as acetaminophen or aspirin. The drug is rapidly metabolized in the liver to noroxycodone (weakly active), oxymorphone (active), and their glucuronides. Plasma protein binding is about 45%. The elimination half-lives of the extended-release and immediate-release formulations are 4.5 and 3.2 hours, respectively (1).
Reproduction studies in rats and rabbits at doses up to 3 and 46 times the human dose of 160 mg/day based on BSA, respectively, found no evidence of fetal harm (1).
The Collaborative Perinatal Project monitored 50,282 mother–child pairs, 8 of whom had 1st trimester exposure to oxycodone (2). No evidence was found to suggest a relationship to large categories of major or minor malformations or to individual defects.
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 281 newborns had been exposed to oxycodone during the 1st trimester (F. Rosa, personal communication, FDA, 1993). A total of 13 (4.6%) major birth defects were observed (12 expected), including (observed/expected) 3/3 cardiovascular defects and 1/1 hypospadias. No anomalies were observed in four other defect categories (oral clefts, spina bifida, polydactyly, and limb reduction defects) for which specific data were available. These data do not support an association between the drug and congenital defects.
At a 1996 meeting, data were presented on 118 women using oxycodone (N = 78) or hydrocodone (N = 40) during the 1st trimester for postoperative pain, general pain, or upper respiratory infection who were matched with a similar group using codeine for these purposes (3). Six (5.1%) of the infants exposed to oxycodone or hydrocodone had malformations, an odds ratio of 2.61 (95% confidence interval 0.6–11.5, p = 0.13). There was no pattern evident among the six malformations (3).
A 26-year-old woman with chronic pain and depression took oxycodone 60 mg/day, quetiapine 400 mg/day, and fluoxetine 40 mg/day throughout pregnancy (4). She gave birth at 37 weeks’ gestation to an apparently normal 3.4-kg (50th percentile) male infant, and then continued these drugs during breastfeeding. The infant’s weight at 3 months of age was 5.6 kg (25th percentile), but the Denver development assessment was consistent with his chronological age (4).
Neonatal withdrawal associated with maternal use of oxycodone has been reported (5,6). A 37-year-old woman underwent a cesarean section to give birth to a normal 3685-g female infant with Apgar scores of 8 and 9 (5). The infant was excessively irritable during the first 48 hours but did not require any therapeutic intervention. When the mother suffered an acute abstinence syndrome after delivery, it was discovered that she had taken Percodan (oxycodone + aspirin) daily throughout pregnancy (5). The second case involved a 24-year-old woman who had used IV oxycodone (120–500 mg/day) and oral methadone during pregnancy (6). At 39 weeks’, she gave birth to a 2864-g (>25th percentile) male infant, Apgar scores 7 and 10, without structural anomalies. The infant’s length (47 cm, <5th percentile) and head circumference (33 cm, <5th percentile) were restricted. The infant had a shrill cry at birth and developed severe neonatal abstinence syndrome. The infant’s urine was positive for oxymorphone (a metabolite of oxycodone) but not for methadone. The infant was discharged to foster care on day 16 of life (6).
Results of a National Birth Defects Prevention Study (1997–2005) were published in 2011 (7). This population-based case–control study examined the association between maternal use of opioid analgesics and >30 types of major structural birth defects. In 17,449 case mothers, therapeutic opioid use was reported by 454 (2.6%) compared with 134 (2.0%) of 6701 control mothers. Indications for use of opioid analgesics were surgical procedures (41%), infections (34%), chronic diseases (20%), and injuries (18%). Dose, duration, and frequency were not evaluated. The exposure period evaluated was from 1 month before to 3 months after conception. Limiting the exposure period to the first 2 months after conception produced similar results. Infants with >1 defect were included in multiple birth defect categories. The following opioids were included (number of cases for each agent not specified): codeine, hydrocodone, hydromorphone, fentanyl, meperidine, methadone, morphine, oxycodone, pentazocine, propoxyphene, and tramadol. The birth defect, total number, number exposed, and the adjusted odds ratio (aOR) with 95% confidence interval (CI) were as follows:
The authors speculated that the activity of opioids and their receptors as growth regulators during development of the embryo might be a mechanism to explain the above findings. The exposure data were obtained by retrospective maternal self-report; the authors acknowledged that recall bias and misclassification might have affected their results. They concluded that the absolute risk was a modest absolute increase above the baseline risk for birth defects (7).
Oxycodone is excreted into breast milk. Six healthy postpartum women received a combination product of oxycodone and acetaminophen, one or two capsules every 4–7 hours, while breastfeeding their newborn infants (8). Maternal plasma levels were in the expected range of 14–35 ng/mL and milk concentrations ranged from <5 to 226 ng/mL. Peak milk concentrations occurred 1.5–2.0 hours after the first dose, and then at variable times after multiple doses. Although a large degree of variability was present, the mean milk:plasma ratio was 3.4:1. No mention was made of any effects observed in the nursing infants (8).
In a 2012 report, neonatal central nervous system (CNS) depression was assessed in three cohorts of breastfeeding mother–infant pairs exposed to oxycodone (N = 139), codeine (N = 210), or acetaminophen only (N = 184) (9). More infants had CNS depression with oxycodone (20.1%) compared with 0.5% in the acetaminophen cohort (20.1%; OR 46.16, 95% CI 6.2–344.2; p <0.0001) and 16.7% in the codeine cohort (16.7%; OR 0.79, 95% CI 0.46-1.38; p >0.05). In the oxycodone and codeine cohorts, mothers of infants with symptoms took significantly higher doses compared with mother of infants with no symptoms in the same cohorts: oxycodone—median 0.4 mg/kg/day (range 0.03–4.06 mg/kg/day) vs. median 0.15 mg/kg/day (range 0.02–2.25 mg/kg/day); p = 0.005; codeine—median 1.4 mg/kg/day (range 0.7–10.5 mg/kg/day) vs. median 0.9 mg/kg/day (range 0.18–5.8 mg/kg/day); p ≤0.001. In addition, significantly more mothers in the oxycodone cohort had sedation compared with the codeine cohort. Based on these results, the authors concluded that oxycodone was not a safer alternative to codeine in breastfed infants (9).
If a mother is receiving oxycodone, her nursing infant should be monitored for sedation and other adverse effects, such as gastrointestinal effects and changes in feeding patterns.
1.Product information. Oxycontin. Endo Pharmaceuticals, 2004.
2.Heinonen OP, Slone D, Shapiro S. Birth Defects and Drugs in Pregnancy. Littleton, MA: Publishing Sciences Group, 1977:287.
3.Schick B, Hom M, Tolosa J, Librizzi R, Donnfeld A. Preliminary Analysis of First Trimester Exposure to Oxycodone and Hydrocodone (abstract). Presented at the Ninth International Conference of the Organization of Teratology Information Services, Salt Lake City, Utah, May 2–4, 1996. Reprod Toxicol 1996;10:162.
4.Rampono J, Kristensen JH, Ilett KF, Hackett LP, Kohan R. Quetiapine and breast feeding. Ann Pharmacother 2007;41:711–4.
5.Weintraub SJ, Naulty JS. Acute abstinence syndrome after epidural injection of butorphanol. Anesth Analg 1985;64:452–3.
6.Rao R, Desai NS. OxyContin and neonatal abstinence syndrome. J Perinatol 2002;22:324–5.
7.Broussard CS, Rasmussen SA, Reefhuis J, Friedman JM, Jann MW, Riehle-Colarusso T, Honein MA, for the National Birth Defects Prevention Study. Maternal treatment with opioid analgesics and risk for birth defects. Am J Obstet Gynecol 2011;204:314–7.
8.Marx CM, Pucino F, Carlson JD, Driscoll JW, Ruddock V. Oxycodone excretion in human milk in the puerperium (abstract). Drug Intell Clin Pharm 1986;20:474.
9.Lam J, Kelly L, Ciszkowski C, Landsmeer MLA, Nauta M, Carleton BC, Hayden MR, Madadi P, Koren G. Central nervous system depression of neonates breastfed by mothers receiving oxycodone for postpartum analgesia. J Pediatr 2012;160:33–7.