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

Author:

Hincker Alexander12ORCID,Reschke Matthew3,Ginosar Yehuda4,Kagan Leonid5,Kharasch Evan D.6ORCID,Siemiątkowska Anna57,Park Celine5,Bakos Kristopher8,Ben‐Abdallah Arbi1,Haroutounian Simon19ORCID

Affiliation:

1. Department of Anesthesiology Washington University School of Medicine Saint Louis MO USA

2. Division of Obstetric Anesthesiology Mercy Hospital Saint Louis Saint Louis MO USA

3. Department of Anesthesiology Banner University Medical Center Phoenix AZ USA

4. Department of Anesthesiology, Critical Care and Pain Medicine, Hadassah Ein Karem Medical Center, Faculty of Medicine Hebrew University of Jerusalem Israel

5. Department of Pharmaceutics and Center of Excellence for Pharmaceutical Translational Research and Education, Ernest Mario School of Pharmacy, Rutgers The State University of New Jersey Piscataway NJ USA

6. Department of Anesthesiology Duke University School of Medicine; Bermaride LLC Durham NC USA

7. Department of Physical Pharmacy and Pharmacokinetics Poznan University of Medical Sciences Collegium Pharmaceuticum, 3 Rokietnicka Street Poznan 60‐806 Poland

8. Investigational Drug Service, Department of Pharmacy Barnes‐Jewish Hospital Saint Louis MO USA

9. Washington University Pain Center Washington University School of Medicine St Louis MO USA

Abstract

AimsEpidural 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.MethodsIn 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.ResultsThe 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).ConclusionsThese 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.

Funder

Society for Obstetric Anesthesia and Perinatology

National Institute of General Medical Sciences

National Institutes of Health

Publisher

Wiley

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