Epidural methadone and morphine pharmacokinetics and clinical effects in healthy volunteers: A randomized, crossover-design trial

Abstract

Aims: Epidural opioids can provide effective analgesia for acute postoperative pain. Due to its unique physicochemical properties and long systemic elimination half-life, epidural methadone may provide lasting analgesia with minimal adverse effects; however, human studies are lacking. The aim of the study was to test the hypothesis that epidural methadone would exhibit greater segmental analgesia (analgesia at the dermatome of injection vs. distant dermatomes) than epidural morphine.

Methods: In a prospective, randomized, double-blinded, crossover study, thirteen healthy volunteers received a 4-mg epidural bolus of methadone or morphine at L3-L4 and underwent repeated assessment of dermatomal heat pain tolerance and pressure pain threshold at lumbar (L3) and trigeminal (V2) dermatomes, pupil diameter, respiratory parameters and venous opioid concentration for 24 h. The primary outcome was selective (lumbar vs. trigeminal) segmental analgesia for heat pain, as a marker of a spinal analgesic mechanism.

Results: The degree of segmental analgesia to heat pain tolerance was not different between morphine and methadone (P = .09), although morphine (P = .0009) but not methadone (P = .81) produced significant analgesia to heat pain at the lumbar vs. trigeminal dermatome over 0-12 h. Morphine overall provided longer lasting analgesia to heat pain vs. methadone (24 vs. 2 h, respectively). Morphine elicited greater systemic effects, including miosis (P = .009) and opioid-related adverse effects (P = .002).

Conclusions: These results suggest that, with equal epidural doses, both methadone and morphine produced analgesia and methadone did not produce greater segmental effects than morphine. Epidural methadone provided a more favourable adverse effect profile.

Keywords: opioids; pain; pharmacodynamics; pharmacokinetics.

Figure 1 –

CONSORT diagram of participant flow through the study.

Figure 2 –

Change from baseline in HPT (in °C) over time after administration of morphine (blue) and methadone (red). Figure 2A shows each dermatome tested; lumbar dermatomes are dark shades and trigeminal dermatomes are light shades. Figure 2B shows preferential change in HPT at lumbar versus trigeminal dermatomes, as measured by (HPT_Lumbar – HPT_{Lumbar-baseline}) - (HPT_Trigeminal – HPT_{Trigeminal-baseline}). A positive value represents greater increase in HPT (more analgesia) at the lumbar dermatome; a negative value represents greater increase in HPT (more analgesia) at the trigeminal dermatome. Error bars represent 95% confidence intervals.

Figure 3 –

Change from baseline in HPT (in kg) over time after administration of morphine (blue) and methadone (red). Figure 3A shows each dermatome tested; lumbar dermatomes are dark shades and trigeminal dermatomes are light shades. Figure 3B shows preferential change in HPT at lumbar versus trigeminal dermatomes, as measured by (PPT_Lumbar – PPT_{Lumbar-baseline}) - (PPT_Trigeminal – PPT_{Trigeminal-baseline}). A positive value represents greater increase in PPT (more analgesia) at the lumbar dermatome; a negative value represents greater increase in PPT (more analgesia) at the trigeminal dermatome. Error bars represent 95% confidence intervals.

Figure 4 –

Change from baseline in pupil diameter (mm) over time after administration of morphine (blue) and methadone (red). A negative number represents pupillary miosis. Error bars represent 95% confidence intervals.

Figure 5 –

change from baseline in ventilatory status for morphine (blue) and methadone (red). Figure 5A shows changes in breaths per minute. Figure 5B shows changes in end-expiratory CO₂ (mm Hg). Error bars represent 95% confidence intervals.

Figure 6 -

Plasma concentrations (nmol/L) of study medications and their metabolites over time (hours). Figure 6A shows concentrations of morphine (MOR) and its metabolites morphine-3-glucuronide (M3G), and morphine-3-glucuronide (M6G) over time after a single 4mg bolus of epidural morphine. To convert morphine, M3G, and M6G from nmol/L to ng/ml, multiply by 0.28534, 0.461462, and 0.461462, respectively. Figure 6A shows concentrations of methadone (MTD) and its metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) over time (hours) after a single 4mg bolus of epidural methadone. Error bars represent 95% confidence intervals. To convert methadone and EDDP from nmol/L to ng/ml, multiply by 0.309445 and 0.2774, respectively. Error bars represent 95% confidence intervals.