Abstract
Strong opioid analgesics are the mainstay of therapy for the relief of moderate to severe acute nociceptive pain that may occur post-operatively or following major trauma, as well as for the management of chronic cancer-related pain. Opioid-related adverse effects include nausea and vomiting, sedation, respiratory depression, constipation, tolerance, and addiction/abuse liability. Of these, respiratory depression is of the most concern to clinicians owing to the potential for fatal consequences. In the broader community, opioid overdose due to either prescription or illicit opioids or co-administration with central nervous system depressants may evoke respiratory depression. To address this problem, there is ongoing interest in the identification of non-opioid respiratory stimulants to reverse opioid-induced respiratory depression but without reversing opioid analgesia. Promising compound classes evaluated to date include those that act on a diverse array of receptors including 5-hydroxytryptamine, D 1-dopamine, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), N-methyl-D-aspartate (NMDA) receptor antagonists, and nicotinic acetylcholine as well as phosphodiesterase inhibitors and molecules that act on potassium channels on oxygen-sensing cells in the carotid body. The aim of this article is to review recent advances in the development potential of these compounds for countering opioid-induced respiratory depression.
Highlights
Introduction the incidence of opioid-induced respiratory depression in the post-operative setting is low, it is of major concern to clinicians because of the potential for fatal consequences when clinical monitoring is inadequate
Of additional concern is the large increase in opioid-related deaths over the past decade due to respiratory depression, in overdose and in individuals consuming other central nervous system depressants such as sedatives and alcohol[1]
Apart from strategies aimed at risk mitigation by reducing clinical opioid administration, drug discovery programs have been aimed at discovering a new generation of opioids that retain potent analgesic activity but with less respiratory depression[4,5,6]
Summary
The incidence of opioid-induced respiratory depression in the post-operative setting is low, it is of major concern to clinicians because of the potential for fatal consequences when clinical monitoring is inadequate. 5-HT, 5-hydroxytryptamine; α4β2, alpha-4 beta-2 nicotinic receptor; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; D1, dopamine receptor D1; GIRK, G-protein-gated inwardly rectifying potassium; i.c.v., intracerebroventricular; i.m., intramuscular; i.p., intraperitoneal; i.t., intrathecal; i.v., intravenous; KM, Kun Ming; NMDA, N-methyl-D-aspartate; PaCO2, partial pressure of carbon dioxide; PaO2, partial pressure of oxygen; PDE4, phosphodiesterase 4; PKA, protein kinase A; SaO2, oxygen saturation; s.c., subcutaneous; SD, Sprague Dawley; WH, Wistar Han. Other pharmacological classes assessed for their ability to blunt opioid-induced respiratory depression include PKA inhibitors, GIRK inhibitors, and thyrotropin-releasing hormone (TRH) analogs. In a proof-of-concept clinical study in healthy human subjects, i.v. infusion of the NMDA receptor antagonist esketamine at a subanesthetic dose dose-dependently reversed respiratory depression induced by i.v. remifentanil[35] This was underpinned by a stimulatory effect on ventilatory CO chemosensitivity that was otherwise reduced by remifentanil alone[35]. Of concern is that two of 14 subjects withdrew from the study owing to the psychotomimetic side-effects of esketamine[35]
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