Non-analgesic effects of opioids: opioid-induced respiratory depression.

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.