Opioids may produce life-threatening
respiratory depression and death from their actions at the
opioid receptors within the brainstem respiratory neuronal network. Since there is an increasing number of conditions where the administration of the
opioid receptor antagonist naloxone is inadequate or undesired, there is an increased interest in the development of novel reversal and prevention strategies aimed at providing efficacy close to that of the
opioid receptor antagonist naloxone but with fewer of its drawbacks such as its short duration of action and lesser ability to reverse high-affinity
opioids, such as
carfentanil, or
drug combinations. To give an overview of this highly relevant topic, the authors systematically discuss predominantly experimental
pharmacotherapies, published in the last 5 yr, aimed at reversal of
opioid-induced
respiratory depression as alternatives to
naloxone. The
respiratory stimulants are discussed based on their characteristics and mechanism of action: nonopioid
controlled substances (e.g.,
amphetamine,
cannabinoids,
ketamine),
hormones (
thyrotropin releasing hormone,
oxytocin),
nicotinic acetylcholine receptor agonists, ampakines,
serotonin receptor agonists,
antioxidants, miscellaneous
peptides,
potassium channel blockers acting at the carotid bodies (
doxapram, ENA001), sequestration techniques (scrubber molecules, immunopharmacotherapy), and
opioids (partial agonists/antagonists). The authors argue that none of these often still
experimental therapies are sufficiently tested with respect to efficacy and safety, and many of the agents presented have a lesser efficacy at deeper levels of
respiratory depression, i.e., inability to overcome
apnea, or have ample side effects. The authors suggest development of reversal strategies that combine
respiratory stimulants with
naloxone. Furthermore, they encourage collaborations between research groups to expedite development of viable reversal strategies of potent synthetic
opioid-induced
respiratory depression.