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

Controlled Substances: Nonopioids


In the early 1940s, the respiratory stimulatory effect of amphetamine was already recognized. For example, in 1945, Handley and Ensberg compared the effect of amphetamine to other respiratory stimulants including caffeine and ephedrine to reverse morphine-induced respiratory depression.[10] In 14 human subjects, they observed that amphetamine sulfate (benzedrine) produces a brisk reversal of morphine-induced respiratory depression exceeding the effects of all other tested stimulants. In 2020, the ability of D-amphetamine was examined to accelerate recovery from high-dose fentanyl in rats.[11] It was shown that D-amphetamine shortened recovery from unconsciousness and enhanced respiratory drive in terms of improvement of hypercapnia and hypoxia within 5 min of D-amphetamine administration. Amphetamine inhibits synaptic reuptake of monoamine including dopamine, serotonin, and norepinephrine. It is hypothesized that enhancement of dopaminergic neurotransmission and activation of D1-dopamine receptors cause arousal and respiratory stimulation. Activated D1-dopamine receptors increase cyclic adenosine monophosphate (cAMP) in respiratory neurons and consequently increased breathing activity. Earlier studies showed that D1-dopamine receptor agonists are able to overcome fentanyl- and enkephalin-induced respiratory depression without affecting analgesia.[12,13] Additionally, increased levels of serotonin within the pre-Bötzinger complex may be involved as well in D-amphetamine–induced respiratory stimulation.[11] It is important to realize, however, that D-amphetamine has other effects within the central nervous system, and it is doubtful whether D-amphetamine, currently available for the treatment of attention deficit hyperactivity disorder, is sufficiently selective to be useful as medical countermeasure to rescue or prevent opioid-induced respiratory depression.

Cannabinoid 2 Receptor Agonists

The endocannabinoid system consists of cannabinoid type 1 and type 2 receptors, their endogenous ligands, so-called endocannabinoids, and enzymes that control formation and degradation of these ligands.[14,15] Endocannabinoids play a modulatory role in various physiologic systems including the ventilatory control system. Recent studies indicate the presence of cannabinoid receptors in respiratory centers in the brainstem, including the pre-Bötzinger complex.[15] Activation of cannabinoid type 1 receptors by Δ9-tetrahydrocannabinol produces respiratory depression, while cannabinoid type 2 receptors activated by endocannabinoids have a tonic excitatory respiratory effect.[15,16] Given this, it seems attractive to determine whether activation of cannabinoid type 2 receptors reverses opioid-induced respiratory depression. Two studies addressed this issue. Zavala et al.[14] tested the ability of the G-protein biased cannabinoid type 2 agonist LY2828360, which does not recruit the β-arrestin signaling pathway, to attenuate fentanyl-induced respiratory depression in wild-type and cannabinoid type 2 knockout mice. While LY2828360 fully reversed fentanyl respiratory depression in wild-type animals, no effects were observed in cannabinoid type 2 knockout mice. In an independent study, Wiese et al.[15] demonstrated that cannabinoid type 1 and cannabinoid type 2 agonist Δ9-tetrahydrocannabinol produces respiratory depression and that the selective cannabinoid type 2 receptor agonist AM2301 reversed morphine respiratory depression. However, the effect was observed only when 10 mg/kg morphine was reversed by 10 mg/kg AM2301; at higher morphine doses, AM2301 was insensitive, even after increasing the AM2301 dose to 100 mg/kg, suggestive of a saturation in effect of AM2301.


Cocaine is a psychostimulant that induces sympathetic activation by enhancing monoamine neurotransmission. When administered to rodents, cocaine increases oxygen entry into brain tissue by 10 to 15%.[17] Thomas et al.[18] studied whether cocaine is able to reverse the decrease in brain oxygen levels that occurs after heroin administration. To determine the oxygen levels, oxygen sensors were placed in the nucleus accumbens, as a measure of the functional output of breathing activity. While modest cocaine effects were observed after low-dose heroin administration, no cocaine effect was observed in an attempt to reverse the 50% drop in oxygen content from a heroin overdose. These data indicate no protective effect when cocaine is abused simultaneously with potent opioids such as heroin. In fact, the high prevalence of cocaine found in blood of heroin overdose deaths suggests that cocaine increases the likelihood of opioid-induced respiratory depression. The cerebral vasodilation and blood redistribution toward the brain induced by cocaine is unable to offset the neuronal depression and consequent oxygen dynamics induced by an opioid overdose.


In 1998, Mildh et al.[19] showed in healthy volunteers that a single subanesthetic bolus dose of racemic ketamine attenuated mild fentanyl-induced respiratory depression, but did not prevent a decrease in blood oxygenation. Jonkman et al.[20] tested the effect of escalating doses (4, 8, 12, and 16 mg, each dose given during 15 min) of esketamine, the S(+)-isomer of ketamine, and observed dose-dependent, albeit partial, reversal of remifentanil-induced respiratory depression in healthy volunteers. Ketamine reduced the depression in ventilation to about 50% of baseline. No effect on breathing was observed when esketamine was administered without opioid. Since esketamine is a potent analgesic, these data suggest that esketamine may be used to stabilize respiration, for example in the postoperative period, and simultaneously reduce opioid consumption, further improving respiratory activity. Several mechanisms may be involved in the stimulatory effects of ketamine including enhancement of monoaminergic neurotransmission, or agonist activity of ketamine and its metabolites at the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor.[20] Blockade of glutamatergic neurotransmission has been proposed as well,[20] but there are data showing that loss of glutamate drive to the Bötzinger complex reduces inspiratory and expiratory duration as well as peak phrenic amplitude, and the subsequent reduced glutamatergic drive to the pre-Bötzinger complex causes the complete loss of the respiratory pattern.[21] Interestingly, Jonkman et al.[20] showed that esketamine only stimulates carbon dioxide–dependent ventilation, very similar to the ampakines, suggestive of a common mechanistic pathway. Finally, at a high dose, ketamine produces respiratory depression that is naloxone-sensitive, indicative of an effect at the opioid receptor system.[22]

In summary, the majority of the nonopioid scheduled substances discussed here show a respiratory stimulatory effect, and further studies are needed to determine their use in opioid overdose toxicity. We need to realize that all of them come with unwanted side effects ranging from a high risk of abuse and addiction to schizotypical experiences that may be frightful to the patient. In this context, low-dose ketamine may offer the best clinical utility of all of these agents, where enhancement of respiratory activity and a reduction of opioid consumption in the perioperative setting outbalances its side effects.