The metabolite morphine-6-glucuronide contributes to the analgesia produced by morphine infusion in patients with pain and normal renal function

Abstract

Morphine-6-glucuronide is a metabolite of morphine that binds to the opioid receptor and is analgesic in animals and humans. Although accumulation of morphine-6-glucuronide in patients with renal insufficiency has been implicated in morphine toxicity, the contribution of the metabolite to morphine analgesia in patients with normal renal function has not been established. To evaluate this contribution, we repeatedly sampled blood and assessed effects during and after a loading infusion with morphine (mean duration, 168 minutes) in 14 patients with chronic pain, all of whom had normal serum creatinine levels. Plasma concentrations of morphine and morphine-6-glucuronide were assayed by use of high performance liquid chromatography with electrochemical detection. Patients were divided into three groups on the basis of the molar concentration ratio of morphine-6-glucuronide:morphine from the start of the infusion until 240 minutes later: Group 1 (n = 5) had a mean ratio greater than or equal to 0.7:1; group 2 (n = 4) had a mean ratio less than 0.7:1 but greater than or equal to 0.4:1; and group 3 (n = 5) had a mean ratio less than 0.4:1. Time-effect plots revealed that average and peak relief were greater in group 1 than group 2 and greater in group 2 than group 3. For all patients, mean morphine-6-glucuronide:morphine ratio throughout the study was significantly correlated with mean pain relief (r = 0.611, p less than 0.02). These data suggest that morphine-6-glucuronide contributes to morphine analgesia in patients with normal renal function. The role of the metabolite should be considered when morphine is used clinically.