Averting Opioid-induced Respiratory Depression without Affecting Analgesia

Abstract

The ventilatory control system is highly vulnerable to exogenous administered opioid analgesics. Particularly respiratory depression is a potentially lethal complication that may occur when opioids are overdosed or consumed in combination with other depressants such as sleep medication or alcohol. Fatalities occur in acute and chronic pain patients on opioid therapy and individuals that abuse prescription or illicit opioids for their hedonistic pleasure. One important strategy to mitigate opioid-induced respiratory depression is cotreatment with nonopioid respiratory stimulants. Effective stimulants prevent respiratory depression without affecting the analgesic opioid response. Several pharmaceutical classes of nonopioid respiratory stimulants are currently under investigation. The majority acts at sites within the brainstem respiratory network including drugs that act at α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (ampakines), 5-hydroxytryptamine receptor agonists, phospodiesterase-4 inhibitors, D1-dopamine receptor agonists, the endogenous peptide glycyl-glutamine, and thyrotropin-releasing hormone. Others act peripherally at potassium channels expressed on oxygen-sensing cells of the carotid bodies, such as doxapram and GAL021 (Galleon Pharmaceuticals Corp., USA). In this review we critically appraise the efficacy of these agents. We conclude that none of the experimental drugs are adequate for therapeutic use in opioid-induced respiratory depression and all need further study of efficacy and toxicity. All discussed drugs, however, do highlight potential mechanisms of action and possible templates for further study and development.

Respiratory depression and analgesia by opioid drugs in freely-behaving larval zebrafish

“…To determine whether respiratory stimulants can reverse respiratory depression by opioids in larval zebrafish, we tested two types of agonists targeting excitatory receptors: ampakines which comprise drugs acting on AMPA receptors (Ren, Poon, Tang, Funk, & Greer, 2006) and serotoninergic agents (Manzke et al, 2003). CX-614, an ampakine allosteric modulator of AMPA receptors, did not reverse respiratory depression in our larval zebrafish models, which is not consistent with its effects in rodents (Ren et al, 2006) or humans (Dahan et al, 2018). This lack of ampakine effects may be due to the low concentration used in this study because higher doses of CX-614 were inducing severe seizures in larval zebrafish (data not shown).…”

“…Such approach has the potential to validate many drug candidates without making any assumptions on their mechanisms of action or targets. Our drug discovery approach proposes to test whether drugs or combinations of drugs can be used as analgesics without the side-effects of respiratory depression and such strategy is of considerable interest (Dahan et al, 2018; (Montandon & Slutsky, 2019). We combined several assays to test the respiratory depressant effects of pain killers and their analgesics properties.…”

Pharmacokinetic and pharmacodynamic considerations for NMDA-receptor antagonist ketamine in the treatment of chronic neuropathic pain: an update of the most recent literature

“…The second question has recently been addressed by Jonkman et al [64]. They showed that ketamine effectively counteracts opioid-induced respiratory depression, possibly through its (indirect) actions at the AMPA receptor [65]. This is an important observation that is relevant in perioperative care as well in NP patients treated with (high dose) opioids.…”

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

“…GAL-021 has recently been developed as a novel breathing control modulator thought to preserve respiratory drive and to protect patients from the respiratory impairment resulting from opioids and other modalities; moreover, it notably did not influence analgesia [1][2][3][4][5][6][7]. The studies have also reported that this agent is an experimental drug demonstrated to inhibit Ca 2+ -activated K + channels with big conductance functionally expressed on type 1 cells of the carotid bodies [1,8,9].…”