Sustained-release morphine for epidural analgesia in rats

Background: Epidural opioid analgesia often requires either continuous infusion or repeated injections, which are inconvenient for patients, increase risk of infection, and consume expensive physician and nursing time. In addition, potential respiratory depression is a major safety concern. The authors studied whether a single dose of epidurally administered, sustained-release morphine could prolong analgesia and reduce toxic effects in rats. Methods: Sustained-release morphine (DTC401) was prepared by encapsulating morphine sulfate in DepoFoam (Dep. Tech, San Diego, CA), a lipid-based, sustained-release drug delivery system. A standard hot-plate test for analgesia, pulse oximetry for hemoglobin oxygen saturation, corneal-reflex loss, and incidence of catalepsy were used to assess efficacy and toxicities. Cerebrospinal fluid and serum pharmacokinetic studies were performed after a single epidural dose, using a commercially available radioimmunoassay kit. Results: Single epidural doses of DTC401 resulted in equivalent onset time to peak analgesia but significantly prolonged analgesia compared with morphine sulfate. Hemoglobin oxygen saturation was decreased minimally, and the incidences of catalepsy and corneal-reflex loss were minimal, even at large doses of DTC401. In contrast, the larger doses of morphine sulfate significantly decreased hemoglobin oxygen saturation, and caused catalepsy and loss of the corneal-reflex. The C-max for DTC401 was 32% in cerebrospinal fluid and 6% in serum, relative to morphine sulfate. The terminal half-life for DTC401 was increased 32 fold in the cerebrospinal fluid compared with morphine sulfate. Conclusions: A single epidural dose of DTC401, compared with morphine sulfate, prolonged duration of analgesia, with minimal supraspinal toxic effects, in rats.