Emergency Room Use of Opioid Antagonists in Drug Intoxication and Overdose

Clarke, Simon; Török, Rob; Dargan, Paul I.; Jones, Alison L

doi:10.1007/978-1-59745-197-0_27

Cited by 3 publications

(4 citation statements)

References 120 publications

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“…Thus, renarcotization and respiratory depression can re‐occur, with an increased risk of death. 7 , 8 , 9 Even if a long‐acting formulation of naloxone were to be developed, there is still a risk for re‐overdose if a higher dose of agonist were to be taken. An antagonist, like MCAM, that binds essentially irreversibly would not have these limitations of naloxone.…”

Section: Discussionmentioning

confidence: 99%

“…However, because naloxone is a competitive antagonist with a relatively short half‐life in vivo, its antagonism can be surmounted if a revived overdose victim re‐ingests a higher dose of agonist or if blood levels of the administered naloxone fall before that of the ingested agonist. Thus, renarcotization and respiratory depression can re‐occur, with an increased risk of death 7‐9 . Even if a long‐acting formulation of naloxone were to be developed, there is still a risk for re‐overdose if a higher dose of agonist were to be taken.…”

Section: Discussionmentioning

confidence: 99%

“…fentanyl ). 7 , 8 , 9 Importantly, since NLX is now frequently administered out of a medical setting, renarcotization may not be recognized leading to increased risk of re‐overdose and death when antagonism by administered NLX wanes. 10 To counter renarcotization, larger, more frequent, or continuous (intravenous drip) administration of naloxone is required.…”

Section: Introductionmentioning

confidence: 99%

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Long‐term antagonism and allosteric regulation of mu opioid receptors by the novel ligand, methocinnamox

Zamora

Smith

Jennings

et al. 2021

Pharmacology Res & Perspec

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Opioid overdose is a leading cause of death in the United States. The only treatment available currently is the competitive antagonist, naloxone (Narcan®). Although naloxone is very effective and has saved many lives, as a competitive antagonist it has limitations. Due to the short half‐life of naloxone, renarcotization can occur if the ingested opioid agonist remains in the body longer. Moreover, because antagonism by naloxone is surmountable, renarcotization can also occur in the presence of naloxone if a relatively larger dose of opioid agonist is taken. In such circumstances, a long‐lasting, non‐surmountable antagonist would offer an improvement in overdose treatment. Methocinnamox (MCAM) has been reported to have a long duration of antagonist action at mu opioid receptors in vivo. In HEK cells expressing the human mu opioid receptor, MCAM antagonism of mu agonist‐inhibition of cAMP production was time‐dependent, non‐surmountable and non‐reversible, consistent with (pseudo)‐irreversible binding. In vivo, MCAM injected locally into the rat hindpaw antagonized mu agonist‐mediated inhibition of thermal allodynia for up to 96 h. By contrast, antagonism by MCAM of delta or kappa agonists in HEK cells and in vivo was consistent with simple competitive antagonism. Surprisingly, MCAM also shifted the concentration‐response curves of mu agonists in HEK cells in the absence of receptor reserve in a ligand‐dependent manner. The shift in the [D‐Ala2,N‐MePhe4,Gly‐ol5]‐enkephalin (DAMGO) concentration‐response curve by MCAM was insensitive to naloxone, suggesting that in addition to (pseudo)‐irreversible orthosteric antagonism, MCAM acts allosterically to alter the affinity and/or intrinsic efficacy of mu agonists.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Long‐term antagonism and allosteric regulation of mu opioid receptors by the novel ligand, methocinnamox

Zamora

Smith

Jennings

et al. 2021

Pharmacology Res & Perspec

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“…Concerns with withdrawal symptoms have been noted with higher doses, and in contrast, the emergence of withdrawal symptoms or aggression were rarely reported in a study using intramuscular doses of 0.4 mg [5]. Clarke et al [6] recommend using a dose just sufficient to reverse opioid toxicity to reduce the precipitation of acute withdrawal symptoms, supporting a dosetitration approach; however, they also note that there is insufficient research to understand the relationship between dose and acute withdrawal symptoms [6]. The dose required will depend upon the amount and type of opioid consumed so a universal dose is unlikely to exist, and multiple doses will probably remain the standard of care.…”

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confidence: 99%

Commentary on McDonald et al. (2018): Intranasal naloxone—from the laboratory to the real world

2018

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Commentary on McDonald et al. (2018): Intranasal naloxone-from the laboratory to the real world It is timely that research and technology combine to develop products addressing barriers to naloxone administration in community and prison settings. Addressing potential implementation barriers and understanding outcomes with real-world use will maximize the opportunities to prevent opioid overdose deaths.The work by McDonald and colleagues [1] is a welcome addition to what is known about naloxone bioavailability and pharmacokinetics, combined with the promise of a fit-for-purpose naloxone product for lay-person administration. Intranasal and other non-injectable naloxone formulations have clear benefits for community supply to carers and family members. Prison settings may also benefit given the potential barriers posed by injectable products.This healthy volunteers study demonstrates an intranasal product with comparable onset with the widely used 0.4 mg naloxone intramuscular dose. Data from healthy volunteers represent much of the data informing our knowledge about naloxone pharmacokinetics and bioavailability. A gap in our collective knowledge is how these data translate to clinical populations, including those who are opioid-dependent, those with poor physical health and those who may have consumed multiple substances. There is a need to extend knowledge of use of intranasal naloxone in real-world settings to understand how different route options may translate to clinical outcomes in overdose reversal. This is particularly relevant where small differences in onset-time can impact upon the damage due to an anoxic brain injury.There are other aspects of naloxone delivery that are also critical to understand more clearly. To date, only limited research has examined doses of naloxone required to reverse overdoses with higher potency opioids, such as fentanyl and fentanyl analogues. Naloxone is likely to be key in responding to increasing mortality with these higher potency opioids [2,3], yet little information exists to guide a public health response. Higher doses of naloxone will probably be required. Where products are packaged as a single-dose product, this may mean that programmes supplying naloxone need to consider supplying multiple units. Alternatively, multiple-dose products may represent a more rational way to supply naloxone, but may introduce infection risk if administered to multiple people. Cost implications of both options may impact upon the feasibility of naloxone supply.The availability of intranasal naloxone does not address all barriers to naloxone use. Macdonald et al.[1] highlight concerns with 'over-antagonism', which may pertain to higher doses. A dose-dependent reversal of fentanylinduced respiratory depression was demonstrated in a small study of anaesthetized patients [4], suggesting that dose is important. Concerns with withdrawal symptoms have been noted with higher doses, and in contrast, the emergence of withdrawal symptoms or aggression were rarely reported in a study using intramus...

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Opiate Receptors and Antagonists

Dean¹,

Bilsky²,

Negus³

2009

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Emergency Room Use of Opioid Antagonists in Drug Intoxication and Overdose

Cited by 3 publications

References 120 publications

Long‐term antagonism and allosteric regulation of mu opioid receptors by the novel ligand, methocinnamox

Long‐term antagonism and allosteric regulation of mu opioid receptors by the novel ligand, methocinnamox

Commentary on McDonald et al. (2018): Intranasal naloxone—from the laboratory to the real world

Opiate Receptors and Antagonists

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