Investigation of Pharmacokinetics and Pharmacodynamics of Epidural Methadone in Healthy Volunteers

Acute postoperative pain control remains a major challenge in healthcare, with a need to balance analgesic effectiveness, patient safety, and cost. Excellent analgesia is a universal clinical imperative, but our current approaches are often inadequate. Epidural opioids can be useful tools, but each carries its own strengths and limitations. Bolus morphine is long lasting but exhibits rostral spread in the cerebrospinal fluid, which raises risks of adverse effects, particularly late-onset respiratory depression. Lipophilic opioids such as fentanyl and sufentanil exhibit selective segmental analgesia but are of short duration due to systemic absorption. As such, they require continuous epidural administration via an indwelling epidural catheter and a pump (patient-controlled or continuous infusion), which has implications for nursing, pain management services, and hospital cost. Methadone's physico-chemical properties suggest that epidural methadone administration would be ideal in providing long-duration analgesia with fewer of the adverse effects seen with medications like morphine.

The aim of this study is to compare the effects of two medications given epidurally: morphine and methadone. We will do so using a randomized, double-blinded, crossover design study. During each of two study visits, participants will receive a single epidural bolus of either morphine or methadone. We will examine the ability of the medication to blunt pain from heat or pressure using quantitative sensory testing at both the dermatome of injection (leg) and a distant dermatome (face); in doing so, we will demonstrate relative segmental versus supraspinal or systemic opioid activity. Additionally, we will assess signs and symptoms of supraspinal opioid activity, which may predispose to adverse effects, and blood concentrations of each medication. Each of the aforementioned measurements will be conducted at multiple points over a 24 hour period. Following a washout period, patients will return for a second visit, at which time the protocol will be repeated using the other medication.