Hydromorphone Transfer Into Breast Milk After Intranasal Administration

Jeffrey E. Edwards, B.S., Anita C. Rudy, Ph.D., Daniel P. Wermeling, Pharm.D., Nirmala Desai, M.D., Patrick J. McNamara, Ph.D.


Pharmacotherapy. 2003;23(2) 

In This Article

Abstract and Introduction

Study Objectives: To determine the distribution of hydromorphone into breast milk and the potential exposure of the suckling infant, and whether the distribution of hydromorphone into milk can be predicted accurately by a passive diffusion model.
Design: Single-dose, pharmacokinetic study.
Setting: University clinical research unit.
Patients: Eight lactating, nonsmoking, healthy women aged 24-32 years.
Intervention: Hydromorphone HCl 2 mg was given intranasally to the women to characterize its pharmacokinetics and extent of its transfer into breast milk.
Measurements and Main Results: Plasma and milk samples were analyzed using liquid chromatography with tandem mass spectrometry detection. The milk:plasma ratio (M:P) was calculated as the total area under the concentration-time curve (AUC) of the milk divided by the total AUC of the plasma. Predicted in vitro M:P ratios were calculated using a diffusion model. Protein binding in milk and plasma, partitioning into milk fat (whole milk:skim milk ratios), as well as pH partitioning between plasma and milk were incorporated in the model. Protein binding was determined by equilibrium dialysis. Protein binding was minimal in both milk and plasma, with unbound fractions of 1 and 0.84, respectively. There was little partitioning into milk fat, as demonstrated by the whole milk:skim milk ratio of 0.98. The observed and predicted M:P ratios ± SD for hydromorphone were 2.57 ± 0.47 and 1.11 ± 0.28, respectively. The 95% confidence interval for the observed M:P ratio overlapped the confidence interval of the predicted M:P ratio, a finding that supports a role for both passive diffusion and active transport as mechanisms of hydromorphone transfer into milk.
Conclusion: Hydromorphone distributes rapidly from plasma into breast milk; however, the drug does not partition into fat. The suckling infant would receive approximately 0.67% of the maternal dose of hydromorphone (adjusted for body weight). As this is a limited exposure, further studies are needed to determine any potential impact to an infant who is fed breast milk from a mother treated with hydromorphone.

Breastfeeding during drug therapy is a major concern for mothers and health care professionals. The benefits of breastfeeding versus the risk of exposure of an infant to a drug must be weighed. There is little information concerning the distribution of most drugs into breast milk. Even less is known about the mechanisms (i.e., passive diffusion, active transport) by which a drug can gain access to milk from plasma.

Lipophilicity, protein binding in milk and plasma, fat partitioning, and ionization have been used to predict the extent of drug accumulation in milk.[1,2,3,4,5,6] One model assumes that drugs passively diffuse into breast milk.[1] This model successfully predicted the extent of passage of a number of drugs (e.g., alprazolam, caffeine, diazepam, phenytoin, propranolol) into breast milk.[1,7,8] However, a few drugs (e.g., cimetidine, nitrofurantoin) have been shown to be actively transported into milk.[9,10] It is important to understand not only the extent of drug distribution into milk but also the mechanism by which drugs gain access to milk.

Opioid analgesics are used to treat pain during pregnancy and lactation.[11] Studies have shown that the levels of morphine in nursing mothers are slightly higher in milk than in plasma.[12] One report describes clinically significant concentrations of morphine in a nursing neonate who received morphine through breast milk.[13]

Hydromorphone is an opioid approved by the Food and Drug Administration for treatment of pain during and after pregnancy.[11] The distribution of hydromorphone into breast milk has not been ascertained. Hydromorphone is marketed in intravenous, suppository, and tablet formulations. An intranasal formulation is under evaluation; our study was conducted as part of that evaluation process. The goals of the study were to determine the distribution of hydromorphone into breast milk and the potential exposure to a suckling infant. We also sought to determine whether the distribution of hydromorphone into milk can be predicted accurately by a passive diffusion model.


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