Countering opioid-induced respiratory depression by non-opioids that are respiratory stimulants

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, D1-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.

Dual mechanisms of opioid-induced respiratory depression in the inspiratory rhythm-generating network

“…However, a role of β-arrestin2 in mediating the respiratory side effects of opioids has not been reproducible among laboratories (Kliewer et al, 2020, Kliewer et al, 2019, Bachmutsky et al, 2021, casting doubt on the potential for biased agonists to mitigate OIRD. A second approach involves the use of respiratory stimulants in combination with opioid medication as a compensatory strategy to protect against OIRD (Algera et al, 2019, Manzke et al, 2003, Imam et al, 2020. Such strategies have shown promise in animal models (Mosca et al, 2014, Kimura et al, 2015, Guenther et al, 2010, Sun et al, 2019, Haw et al, 2016, Dai et al, 2017 and in some human trials (Oertel et al, 2010, Persson et al, 1999 but not others (Lötsch et al, 2005, Oertel et al, 2007.…”

Oxytocin Receptor Activation Rescues Opioid-Induced Respiratory Depression by Systemic Fentanyl in the Rat

“…Clinically, reversal of OIRD is achieved by antagonizing opioid receptors (Handal et al, 1983), but loss of analgesia and painful withdrawal effects limit the utility of this approach (Dahan et al, 2010). Respiratory stimulants are an alternative approach that might preserve opioid analgesia (Imam et al, 2020). Here, we provide evidence that peptide (Fig.…”

Opioid-Induced In-Hospital Deaths: A 10-Year Review of Australian Coroners’ Cases Exploring Similarities and Lessons Learnt

“…In future, novel opioid development could target the provision of potent analgesia whilst minimalising respiratory depression, utilising co-administration of respiratory stimulants potentially reducing OIVI events [21].…”