Pain Medicine  |   December 2019
Analgesic and Respiratory Depressant Effects of R-dihydroetorphine: A Pharmacokinetic–Pharmacodynamic Analysis in Healthy Male Volunteers
Author Notes
  • From the Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands (E.O., M.B., E.S., M.vV., A.D., M.N.); Mundipharma Research Limited, Cambridge, United Kingdom (P.B., K.J.S., A.O.); and Rudolf-Buchheim-Institut für Pharmakologie (Rudolph-Buchheim Institute for Pharmacology), University of Giessen, Giessen, Germany (A.O.). Current affiliations: Sosei Heptares, Cambridge, United Kingdom (P.B.).
  • This article is featured in “This Month in Anesthesiology,” page 1A.
    This article is featured in “This Month in Anesthesiology,” page 1A.×
  • Submitted for publication February 27, 2019. Accepted for publication August 19, 2019.
    Submitted for publication February 27, 2019. Accepted for publication August 19, 2019.×
  • Address correspondence to Dr. Dahan: Department of Anesthesiology, Leiden University Medical Center, H5-22, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. a.dahan@lumc.nl. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Pain Medicine / Clinical Science / Pain Medicine / Pharmacology / Respiratory System
Pain Medicine   |   December 2019
Analgesic and Respiratory Depressant Effects of R-dihydroetorphine: A Pharmacokinetic–Pharmacodynamic Analysis in Healthy Male Volunteers
Anesthesiology 12 2019, Vol.131, 1327-1339. doi:https://doi.org/10.1097/ALN.0000000000002991
Anesthesiology 12 2019, Vol.131, 1327-1339. doi:https://doi.org/10.1097/ALN.0000000000002991
Abstract

Editor’s Perspective:

What We Already Know about This Topic:

  • Opioid agonists acting at the nociception/orphanin FQ, δ-opioid, and κ-opioid receptors may counteract respiratory depression induced by activation of the µ-opioid receptor

  • R-dihydroetorphine is an opioid with full agonism and high affinity for the µ-opioid, κ-opioid, and δ-opioid receptors and low affinity for the nociception/orphanin FQ receptor

What This Article Tells Us That Is New:

  • The effects of four R-dihydroetorphine doses (12.5, 75, 125, and 150 ng/kg) on isohypercapnic ventilation and antinociception were studied in 40 healthy male volunteers

  • Over the dose range tested, an apparent maximum in respiratory depression to 33% of baseline ventilation was identified, but a maximum in antinociception was not reached

  • At an R-dihydroetorphine effect-site concentration of 20 pg/ml, the probability of analgesia was 60%, while the probability of analgesia without respiratory depression was 45%

  • The probability of analgesia increased to 95% at 100 pg/ml, but the probability of analgesia without respiratory depression was reduced to 20%

Background: There is an ongoing need for potent opioids with less adverse effects than commonly used opioids. R-dihydroetorphine is a full opioid receptor agonist with relatively high affinity at the μ-, δ- and κ-opioid receptors and low affinity at the nociception/orphanin FQ receptor. The authors quantified its antinociceptive and respiratory effects in healthy volunteers. The authors hypothesized that given its receptor profile, R-dihydroetorphine will exhibit an apparent plateau in respiratory depression, but not in antinociception.

Methods: The authors performed a population pharmacokinetic–pharmacodynamic study (Eudract registration No. 2009-010880-17). Four intravenous R-dihydroetorphine doses were studied: 12.5, 75, 125, and 150 ng/kg (infused more than 10 min) in 4 of 4, 6 of 6, 6 of 6, and 4 of 4 male subjects in pain and respiratory studies, respectively. The authors measured isohypercapnic ventilation, pain threshold, and tolerance responses to electrical noxious stimulation and arterial blood samples for pharmacokinetic analysis.

Results: R-dihydroetorphine displayed a dose-dependent increase in peak plasma concentrations at the end of the infusion. Concentration-effect relationships differed significantly between endpoints. R-dihydroetorphine produced respiratory depression best described by a sigmoid EMAX-model. A 50% reduction in ventilation in between baseline and minimum ventilation was observed at an R-dihydroetorphine concentration of 17 ± 4 pg/ml (median ± standard error of the estimate). The maximum reduction in ventilation observed was at 33% of baseline. In contrast, over the dose range studied, R-dihydroetorphine produced dose-dependent analgesia best described by a linear model. A 50% increase in stimulus intensity was observed at 34 ± 11 pg/ml.

Conclusions: Over the dose range studied, R-dihydroetorphine exhibited a plateau in respiratory depression, but not in analgesia. Whether these experimental advantages extrapolate to the clinical setting and whether analgesia has no plateau at higher concentrations than investigated requires further studies.