Opioid-induced respiratory depression in humans: a review of pharmacokinetic–pharmacodynamic modelling of reversal

Abstract

Background: Opioids are potent painkillers but come with serious adverse effects ranging from addiction to potentially lethal respiratory depression. A variety of drugs with separate mechanisms of action are available to prevent or reverse opioid-induced respiratory depression (OIRD). Methods: The authors reviewed human studies on reversal of OIRD using models that describe and predict the time course of pharmacokinetics (PK) and pharmacodynamics (PD) of opioids and reversal agents and link PK to PD. Results: The PKPD models differ in their basic structure to capture the specific pharmacological mechanisms by which reversal agents interact with opioid effects on breathing. The effect of naloxone, a competitive opioid receptor antagonist, is described by the combined effect-compartment receptor-binding model to quantify rate limitation at the level of drug distribution and receptor kinetics. The effects of reversal agents that act through non-opioidergic pathways, such as ketamine and the experimental drug GAL021, are described by physiological models, in which stimulants act at CO 2 chemosensitivity, CO 2 -independent ventilation, or both. The PKPD analyses show that although all reversal strategies may be effective under certain circumstances, there are conditions at which reversal is less efficacious and sometimes even impossible. Conclusions: Model-based drug development is needed to design an 'ideal' reversal agentdthat is, one that is not influenced by opioid receptor kinetics, does not interfere with opioid analgesia, has a rapid onset of action with longlasting effects, and is devoid of adverse effects.

High Efficacy by GAL-021: A Known Intravenous Peripheral Chemoreceptor Modulator that Suppresses BKCa-Channel Activity and Inhibits IK(M) or Ih

“…GAL-021 treatment is noted to have a short duration of action after a bolus injection [1,52]. The major effect of GAL-021 on ionic currents (e.g., I K(Ca) or I K(M) ) shown here also had a rapid onset of action.…”

Biased versus Partial Agonism in the Search for Safer Opioid Analgesics

“…In addition, the rewarding properties of morphine (but not of cocaine), assessed using the conditioned place preference test, were larger in βarr2(−/−) than βarr2(+/+) mice [ 20 ]. The logical next step of the investigation of morphine responses in βarr2(−/−) mice was to study the most common acute side effects of opioid drugs; constipation [ 21 ] and respiratory depression [ 22 , 23 ]. As far as opioid-induced constipation is concerned the effects of morphine were investigated in βarr2(−/−) and βarr2(+/+) mice by measuring accumulated fecal boli and bead expulsion time.…”

Characterisation and monitoring of postoperative respiratory depression: current approaches and future considerations

“…This is because naloxone, being highly lipid soluble, has both a rapid uptake and a rapid elimination across the bloodebrain barrier. 157,158 A naloxone infusion may best prevent the recurrence of OIRD. 159…”