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

Sequestration of Opioid Molecules in the Circulation

The techniques mentioned thus far all produce respiratory stimulation via activation or inhibition of systems that do not interfere with the opioid load at the opioid receptors. A radically different method is to sequester the exogenous opioids in blood in such a way that few opioid molecules cross the blood–brain barrier into the brain compartment or cause the rapid redistribution of the opioids back into the blood compartment due to the drop in nonbound opioid concentration in blood. Sequestration may be done by administration of container or scrubber molecules, or by immunopharmacotherapy, in which the opioids are bound to and consequently "neutralized" by antibodies. In both cases, the opioid is unavailable to interact with the central opioid receptor system as the complex cannot cross the blood–brain barrier due to its size and polarity. Similar to the administration of naloxone, the reduction in activated opioid receptors will uncover underlying symptoms such as pain and opioid craving and may cause withdrawal and agitation. This is different from the aforementioned therapies that leave the opioid-receptor interaction intact. However, in contrast to naloxone therapy, opioids that are not the target of the sequestration may be used to treat these secondary symptoms. Opioid sequestration may be used at the end of surgery to counteract the residual effect of potent opioids or treat an inadvertent opioid overdose, prevent renarcotization after naloxone treatment, or treat opioid toxicity in case of accidental or intended exposure, for example in case of a mass chemical attack with opioids as occurred in the 2002 Moscow theater hostage rescue attack.[66] Additionally, immunopharmacotherapy may be used to prevent a fatal opioid overdose in individuals with an opioid use disorder after a drug-free period—for example, due to incarceration or stay in a drug rehabilitation center or as part of their treatment.

Container Molecules

The container molecule calabadion 1 is an acyclic cucurbit[n]uril that selectively encapsulates ammonium cations, such as the phenylammonium ion moiety of fentanyl.[67] In awake and isoflurane-anesthetized rats, calabadion 1 is able to dose-dependently reverse fentanyl-induced respiratory depression and muscle rigidity with correction of impaired blood gasses.[67] The calabadion–fentanyl complexes are rapidly eliminated via renal clearance, avoiding the risk of renarcotization. Calabadion 1 binds fentanyl with high affinity but is less effective in binding other opioids such as morphine, hydromorphone, or pethidine. It is able to encapsulate these bigger molecules, but due to a conformational change of the molecule, the binding capacity is reduced. This may be advantageous in perioperative care when high-dose potent opioids such as fentanyl are replaced by morphine or hydromorphone for postoperative pain management. A similar container molecule, calabadion 2, is able to encapsulate the anesthetics ketamine and etomidate, but binds fentanyl at lower affinity than calabadion 1.[68] Also, other container molecules are being developed to bind fentanyl and fentanyl analogs, such as β-cyclodextrin, which binds the amide phenyl ring of the vast majority of fentanyl analogs.[69]


Immunopharmacotherapy is the use of specific antibodies that target and bind specific drugs, e.g., opioid molecules such as fentanyl, heroin, or oxycodone, in the bloodstream.[70–73] The antibodies may be obtained after active immunization with a conjugate vaccine or by passive immunization through administration of monoclonal antibodies. While the former requires some time before sufficient antibodies have been created by immune cells, the latter leads to immediate sequestration of the targeted opioids. Since the opioid molecules are small, the immune system is "blind" to them, and the vaccine must contain an opioid analog (a hapten) that is linked to an immunogenic carrier (e.g., adenoviruses). After immunization, the opioid–antibody complex is too large to cross the blood–brain barrier. While many studies describe the development of opioid vaccines, few of them test their ability to overcome the respiratory effects of potent opioids. Results of these studies are predominantly positive. For example, Raleigh et al.[74] show that a conjugate fentanyl vaccine is effective in the prevention of overt respiratory depression in the rat after fentanyl administration as measured by the decrease in oxygen saturation. Brain fentanyl concentrations were 73% lower in vaccinated rats compared to control animals after fentanyl injection. Similarly, a conjugate fentanyl vaccine tested in mice showed a reduction in fentanyl lethality compared to control mice with no fatalities in vaccinated mice versus 18 to 55% in control mice after fentanyl administration.[75] In an independent study, immunization against fentanyl reduced respiratory depression, and showed cross-reactivity with sufentanil, albeit only for its analgesic effects, but not with alfentanil or remifentanil.[76] In this same study, immunization did not interfere with propofol, dexmedetomidine, or isoflurane anesthesia. In contrast, a rat vaccine to treat oxycodone use disorder that produced high and sustained antibody titers failed to reduced oxycodone-induced respiratory depression but prevented antinociception and reduced the self-reinforcing effects of intravenous oxycodone.[77] Finally, Raleigh et al. combined a vaccine against oxycodone with extended-release naltrexone and observed greater efficacy than just the vaccine regarding antinociception and respiratory depression.[78]

A different method is passive immunization by administration of monoclonal antibodies, generated in mouse hybridomas after vaccination of the mice with a conjugate opioid vaccine.[70,79,80] Smith et al.[79] showed that passive immunization is effective in increasing fentanyl survival after administration of high-dose fentanyl (above the 50% lethal dose). In fact, the specific antibody tested was as effective as naloxone in the reversal of fentanyl and carfentanil antinociception but with a much longer half-life of 6 days. Importantly, these authors performed a pharmacokinetic–pharmacodynamic simulation study to extrapolate their data to fentanyl-induced respiratory depression in a human. The simulations revealed that a 60-kg individual who received a lethal dose of 3,000 μg intravenous fentanyl as a bolus will show a sharp reduction in ventilation toward apnea followed by a slow restoration of ventilation with return to 40% of baseline ventilation after 20 min. It is reasonable to assume that this individual would have died in the meantime. After treatment with a 500-mg dose of fentanyl antibodies, 24 h before the fentanyl dose, fentanyl caused a similar initial drop in ventilation, which, however, was rapidly followed by a return to 50% of baseline ventilation after about 3 min and 80% after 5 min. The authors calculated that the antibody needs to have a binding association rate constant of at least 1 nM−1 · s−1 and a dissociation constant of 0.7 h−1 or less to be effective in rapidly reversing fentanyl toxicity.[79]

These findings are promising and may result in effective treatment and prevention options in a variety of conditions that might induce opioid-induced respiratory depression. The advantages of targeted and specific opioid sequestration, i.e., long duration of action, ability to effectively treat pain and withdrawal with nontargeted opioids, are evident. Still, some challenges remain such as less efficacy in immune-compromised patients, possibly loss of effective treatment over time and with higher opioid doses, and need for multiple vaccines in case of polydrug abuse/overdose.[65]

Finally, we would like to mention another sequestration technique, i.e., the development of a nano-sponge holding purified human opioid receptors that will buffer opioids in the circulation (NarcoBond; CellCure, USA).[7,81] The nano-sponge consists of a nanoparticle coated with lipid bilayer cell membrane containing μ-opioid receptors. After intravenous injection, the nano-sponge binds and traps opioid molecules and effectively lowers the unbound opioid concentration at the receptor site. No studies have been published on its ability to rescue animals after an overdose from respiratory depression.