Advances in Reversal Strategies of Opioid-induced Respiratory Toxicity

Rutger van der Schrier, M.D.; Jack D. C. Dahan, B.Sc.; Martijn Boon, M.D., Ph.D.; Elise Sarton, M.D., Ph.D.; Monique van Velzen, Ph.D.; Marieke Niesters, M.D., Ph.D.; Albert Dahan, M.D., Ph.D.


Anesthesiology. 2022;136(4):618-632. 

In This Article

Drugs Acting at the Carotid Bodies

The carotid bodies, located in between the internal and external carotid arteries, just above the bifurcation, contain the peripheral chemoreceptors. These receptors respond to acidosis and low oxygen concentrations in blood with the release of neurotransmitters that activate the sinus nerve, a branch of the glossopharyngeal nerve, which results in a brisk hyperventilatory response. A variety of neuromodulators and receptors within the carotid body involved in the transduction of low oxygen partial pressure into a ventilatory response may be a possible target for reversal or prevention of opioid induced respiratory depression. For example, while dopamine blunts ventilatory responses originating at the carotid bodies, dopamine antagonists enhance carotid body output, albeit more pronounced at low oxygen levels.[56,57] More viable targets are the so-called background potassium channels of the K2P potassium channel family, i.e., hypoxia and acid-stimulated TASK-1, TASK-3, and heterodimer TASK-1/TASK-3 channels, which provide hypoxia-sensitive background potassium conductance in the carotid body type 1 cell.[58–60] In response to hypoxia, these channels mediate the depolarization of the type 1 carotid body cell.[61] Exogenous blockers of these potassium channels, i.e., drugs that mimic hypoxia within the carotid body, produce respiratory stimulation and may be used to overcome centrally mediated opioid-induced respiratory depression.[6,62] Research development into the efficacy of potassium channel blockers in reversing opioid toxicity has been slow in the last 5 yr with just two published investigations, one on the analeptic drug doxapram and another on the experimental drug PK-THHP, both of which inhibit TASK-1 and TASK-3 channels and stimulate breathing.[26,38] In etorphine-immobilized goats, doxapram effectively reversed respiratory depression but with adverse effects such as excitation and arousal.[38] These findings agree with human data showing that doxapram, at doses causing respiratory stimulation, induces adverse events including hypertension, dyspnea, headache, dizziness, flushing, sweating nausea/vomiting, muscle spasms, and sometimes severe anxiety.[61] The enhanced pressor response is probably related to an enhanced afferent input from the doxapram-activated carotid bodies to pressure centers in the brainstem.[61]

Interestingly, another carotid body stimulant, ENA001, previously known as GAL021, and an analog of the respiratory stimulant almitrine, acts at large-conductance calcium voltage–activated potassium channels, BKCa channels, formerly known as maxi-K channels, stimulates breathing, and partly counters opioid-induced respiratory depression in humans, without causing significant adverse effects.[63,64] It remains unknown why these two stimulants, doxapram and ENA001, acting via the same target organ but at different receptor subtypes, have such different side effect profiles. Finally, PK-THPP, yet another TASK-1 and TASK-3 channel inhibitor, did not enhance breathing or improve arterial blood gas values in rats treated with sufentanil.[26] These data indicate that selectivity in carotid body channel targets is important in countering opioid-induced respiratory depression. It remains unknown whether drugs like ENA001 are able to overcome opioid-induced apnea.[65] Modeling studies based on human data suggest a ceiling in the ability of ENA001 to reverse alfentanil-induced respiratory depression.[64] Possibly combining ENA001 with naloxone may enhance its ability to effectively treat overdose with potent opioids, where ENA001 initially is ineffective.