Opioid-induced respiratory depression: reversal by non-opioid drugs

Abstract

The human body is critically dependent on the ventilatory control system for adequate uptake of oxygen and removal of carbon dioxide (CO2). Potent opioid analgesics, through their actions on μ-opioid receptor (MOR) expressed on respiratory neurons in the brainstem, depress ventilation. Opioid-induced respiratory depression (OIRD) is potentially life threatening and the cause of substantial morbidity and mortality. One possible way of prevention of OIRD is by adding a respiratory stimulant to the opioid treatment, which through activation of non-opioidergic pathways will excite breathing and consequently will offset OIRD and should not affect analgesia. Various new respiratory stimulants are currently under investigation including (a) potassium channel blockers acting at the carotid bodies, and (b) ampakines and (c) serotonin receptor agonists acting within the brainstem. (a) GAL-021 targets BKCa-channels. Initial animal and human experimental evidence indicates that this potassium channel blocker is a potent respiratory stimulant that reverses OIRD without affecting antinociception. GAL021 is safe and better tolerated than the older K+-channel blocker doxapram and more efficacious in its effect on respiration. (b) Ampakines modulate glutamatergic respiratory neurons in brainstem respiratory centers. Various ampakines have been studied showing their ability to increase respiratory drive during OIRD by increasing respiratory rate. Currently, CX717 is the most promising ampakine for use in humans as it is safe and does not affect opioid analgesia. (c) While animal studies show that serotonin receptor agonists increase respiratory drive via activation of serotonin receptors in brainstem respiratory centers, human studies are without success. Further clinical studies are required to improve our care of patients that are treated with potent opioid analgesics. The use of non-opioid adjuvants may reduce the probability of OIRD but does never relieve us of our duty to continuously monitor these patients, irrespective whether they are treated in-house or in an ambulatory setting.

Side effects of pain and analgesia in animal experimentation

“…Opioid-induced respiratory depression and other opioid-related respiratory responses are well-known side effects of opioid treatment and are caused by the activation of opioid receptors expressed in the respiratory centers of the brain stem 47 . These effects might lead to complications during anesthesia and the post-anesthetic recovery period.…”

Ampakine CX1942 attenuates opioid-induced respiratory depression and corrects the hypoxaemic effects of etorphine in immobilized goats (Capra hircus)

“…Doxapram, which is primarily a potassium channel antagonist (Van der Schier et al. ), is a respiratory stimulant commonly used by wildlife veterinarians in opioid‐immobilized animals (Burroughs et al. ).…”

“…) as a result of the doxapram‐induced increase in the cardiac workload associated with hypertension and increased cardiac output (Van der Schier et al. ), probably as a result of catecholamine release (Yost ). The use of doxapram for the improvement of oxygenation is therefore considered with caution nowadays in human medicine (Yost ).…”

Blockade of phosphodiesterase 4 reverses morphine-induced ventilatory disturbance without loss of analgesia

“…On the other hand, agents such as doxapram, GAL-021 and almitrine that block potassium channels in the carotid bodies are also useful approaches for offsetting opioid-induced respiratory depression without loss of analgesia [10,45]. Since the reversal of opioid-induced respiratory depression by caffeine and rolipram occurred in in vitro preparations [33], the present study focused on their central effects.…”