Combined spinal epidural anesthesia has become increasingly popular as a method of providing rapid onset of analgesia or surgical block with access for further administration of analgesics or anesthetics. No in vivo studies have evaluated the relationship between dural puncture and drug transfer from the epidural space to the cerebrospinal fluid (CSF). To determine whether morphine administered in the epidural space adjacent to a dural puncture results in increased CSF concentrations at the cisterna magna (CM), 12 adult ewes were studied. Each animal was assigned to one of three groups. Animals in Group 1 served as a control and received no dural puncture. Animals in Group 2 received a dural puncture with a 25-gauge (G) Whitacre needle, while Group 3 animals received a dural puncture with an 18-G Tuohy needle. One hour after dural puncture, each animal was given epidural morphine, 0.2 mg/kg. Six hours after the administration of epidural morphine, CSF from the CM was sampled and analyzed by gas chromatography-mass spectrometry for morphine concentration. The mean morphine concentration at the CM for Group 1 (control) was 22 +/- 12 ng/mL, whereas animals with 25-G and 18-G dural punctures had concentrations of 154 +/- 32 ng/mL and 405 +/- 53 ng/mL, respectively (P = 0.0005). These data demonstrate that a significant increase in CSF morphine concentration at the brainstem will occur when lumbar epidural morphine is administered adjacent to a dural puncture. Furthermore, the increase in CSF morphine concentration is positively correlated with the size of the needle producing the dural puncture. These findings highlight the potential for delayed respiratory depression when epidural opiate administration follows a dural puncture.