Title:Non-Analgesic Effects of Opioids: Opioid-induced Respiratory Depression
VOLUME: 18 ISSUE: 37
Author(s):Merel Boom, Marieke Niesters, Elise Sarton, Leon Aarts, Terry W. Smith and Albert Dahan
Affiliation:Department of Anesthesiology, Leiden University Medical Center, P5-Q, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
Keywords:Ventilatory control, opioid receptor, opioid receptor agonist, opioid receptor antagonist, morphine, fentanyl, buprenorphine, naloxoxe, glia, half-life.
Abstract:Opioids induce respiratory depression via activation of μ-opioid receptors at specific sites in the central nervous system including
the pre-Bötzinger complex, a respiratory rhythm generating area in the pons. Full opioid agonists like morphine and fentanyl affect
breathing with onset and offset profiles that are primarily determined by opioid transfer to the receptor site, while the effects of partial
opioid agonists such as buprenorphine are governed by transfer to the receptor site together with receptor kinetics, in particular dissociation
kinetics. Opioid-induced respiratory depression is potentially fatal but may be reversed by the opioid receptor antagonist naloxone,
an agent with a short elimination half-life (30 min). The rate-limiting factor in naloxone-reversal of opioid effect is the receptor kinetics
of the opioid agonists that requires reversal. Agents with slow dissociation kinetics (buprenorphine) require a continuous naloxone infusion
while agents with rapid kinetics (fentanyl) will show complete reversal upon a single naloxone dose. Since naloxone is non-selective
and will reverse analgesia as well, efforts are focused on the development of compounds that reverse opioid-induced respiratory depression
without affecting analgesic efficacy. Such agents include ampakines and serotonin agonists which are aimed at selectively enhancing
central respiratory drive. A novel approach is aimed at the reduction of respiratory depression from opioid-activation of (micro-)glia cells
in the pons and brainstem using micro-glia cell stabilizers. Since this approach simultaneously enhances opioid analgesic efficacy it
seems an attractive alternative to the classical reversal strategies with naloxone.
