The pattern of brain oxygen response induced by intravenous fentanyl limits the time window of therapeutic efficacy of naloxone

Curay, Carlos M.; Irwin, Matthew R.; Kiyatkin, Eugene A.

doi:10.1016/j.neuropharm.2023.109507

Cited by 7 publications

(5 citation statements)

References 42 publications

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“…When hypoxia occurs, rapid treatment is required; brain damage may occur within 3–6 min of oxygen deprivation, followed by bradycardia and other cardiac dysrhythmias, cardiac arrest, and death shortly after. Therefore, first responders or caregivers have a very narrow treatment window following the onset of hypoxia during which to prevent an OIRD death ( 44 , 45 ). The symptoms of opioid toxicity only occur when the product enters the bloodstream via ingestion, injection, or inhalation and cannot be experienced by touching the product.…”

Section: Treatment Of Oirdmentioning

confidence: 99%

Fact vs. fiction: naloxone in the treatment of opioid-induced respiratory depression in the current era of synthetic opioids

Dahan,

Franko,

Carroll

et al. 2024

Front. Public Health

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Opioid-induced respiratory depression (OIRD) deaths are ~80,000 a year in the US and are a major public health issue. Approximately 90% of fatal opioid-related deaths are due to synthetic opioids such as fentanyl, most of which is illicitly manufactured and distributed either on its own or as an adulterant to other drugs of abuse such as cocaine or methamphetamine. Other potent opioids such as nitazenes are also increasingly present in the illicit drug supply, and xylazine, a veterinary tranquilizer, is a prevalent additive to opioids and other drugs of abuse. Naloxone is the main treatment used to reverse OIRD and is available as nasal sprays, prefilled naloxone injection devices, and generic naloxone for injection. An overdose needs to be treated as soon as possible to avoid death, and synthetic opioids such as fentanyl are up to 50 times more potent than heroin, so the availability of new, higher-dose, 5-mg prefilled injection or 8-mg intranasal spray naloxone preparations are important additions for emergency treatment of OIRDs, especially by lay people in the community. Higher naloxone doses are expected to reverse a synthetic overdose more rapidly and the current formulations are ideal for use by untrained lay people in the community. There are potential concerns about severe withdrawal symptoms, or pulmonary edema from treatment with high-dose naloxone. However, from the perspective of first responders, the balance of risks would point to administration of naloxone at the dose required to combat the overdose where the risk of death is very high. The presence of xylazines as an adulterant complicates the treatment of OIRDs, as naloxone is probably ineffective, although it will reverse the respiratory depression due to the opioid. For these patients, hospitalization is particularly vital. Education about the benefits of naloxone remains important not only in informing people about how to treat emergency OIRDs but also how to obtain naloxone. A call to emergency services is also essential after administering naloxone because, although the patient may revive, they may overdose again later because of the short half-life of naloxone and the long-lasting potency of fentanyl and its analogs.

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Section: Treatment Of Oirdmentioning

confidence: 99%

Fact vs. fiction: naloxone in the treatment of opioid-induced respiratory depression in the current era of synthetic opioids

Dahan,

Franko,

Carroll

et al. 2024

Front. Public Health

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“…Filled symbols show values significantly different from pre-injection baseline. Original data were published in Thomas et al ( 37 ) and Curay et al ( 51 ).…”

Section: Brain Oxygen Responses Induced By IV Heroin and Fentanyl: Co...mentioning

confidence: 99%

“…We also examined the effect of naloxone on fentanyl-induced changes in oxygen levels in the NAc and SC space when administered after iv fentanyl injection ( 51 ). While it is known that naloxone should be delivered as early as possible, we picked a 10 min time interval between the onset of fentanyl delivery and start of naloxone injection to mimic a clinical response to overdose treatment.…”

Section: Interaction Of Heroin and Fentanyl With Other Neuroactive Su...mentioning

confidence: 99%

Brain oxygen responses induced by opioids: focus on heroin, fentanyl, and their adulterants

Kiyatkin,

Choi

2024

Front. Psychiatry

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Opioids are important tools for pain management, but abuse can result in serious health complications. Of these complications, respiratory depression that leads to brain hypoxia is the most dangerous, resulting in coma and death. Although all opioids at large doses induce brain hypoxia, danger is magnified with synthetic opioids such as fentanyl and structurally similar analogs. These drugs are highly potent, act rapidly, and are often not effectively treated by naloxone, the standard of care for opioid-induced respiratory depression. The goal of this review paper is to present and discuss brain oxygen responses induced by opioids, focusing on heroin and fentanyl. In contrast to studying drug-induced changes in respiratory activity, we used chronically implanted oxygen sensors coupled with high-speed amperometry to directly evaluate physiological and drug-induced fluctuations in brain oxygen levels in awake, freely moving rats. First, we provide an overview of brain oxygen responses to physiological stimuli and discuss the mechanisms regulating oxygen entry into brain tissue. Next, we present data on brain oxygen responses induced by heroin and fentanyl and review underlying mechanisms. These data allowed us to compare the effects of these drugs on brain oxygen in terms of their potency, time-dependent response pattern, and potentially lethal effect at high doses. Then, we present the interactive effects of opioids during polysubstance use (alcohol, ketamine, xylazine) on brain oxygenation. Finally, we consider factors that affect the therapeutic potential of naloxone, focusing on dosage, timing of drug delivery, and contamination of opioids by other neuroactive drugs. The latter issue is considered chiefly with respect to xylazine, which strongly potentiates the hypoxic effects of heroin and fentanyl. Although this work was done in rats, the data are human relevant and will aid in addressing the alarming rise in lethality associated with opioid misuse.

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“…Fentanyl is a synthetic μ opioid receptor agonist that has 50 to 100 times higher potency than morphine to depress respiration ( Harper et al, 1976 ). The primary cause of death from opioid overdose is hypoxia ( Solis et al, 2017 ; Curay et al, 2023 ) due to respiratory depression, characterized by bradypnea and a decrease in chemosensory drive ( White and Irvine, 1999 ; Pattinson, 2008 ). Opioid-induced respiratory depression results from activation of μ opioid receptors in the brainstem respiratory centres ( Dahan et al, 2001 ; Pattinson, 2008 ).…”

Section: Introductionmentioning

confidence: 99%

Comparison of the effects of fentanyls and other μ opioid receptor agonists on the electrical activity of respiratory muscles in the rat

Cavallo,

Kelly,

Henderson

et al. 2023

Front. Pharmacol.

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Introduction: Deaths due to overdose of fentanyls result primarily from depression of respiration. These potent opioids can also produce muscle rigidity in the diaphragm and the chest muscles, a phenomenon known as Wooden Chest Syndrome, which further limits ventilation.Methods: We have compared the depression of ventilation by fentanyl and morphine by directly measuring their ability to induce muscle rigidity using EMG recording from diaphragm and external and internal intercostal muscles, in the rat working heart-brainstem preparation.Results: At equipotent bradypnea-inducing concentrations fentanyl produced a greater increase in expiratory EMG amplitude than morphine in all three muscles examined. In order to understand whether this effect of fentanyl was a unique property of the phenylpiperidine chemical structure, or due to fentanyl’s high agonist intrinsic efficacy or its lipophilicity, we compared a variety of agonists with different properties at concentrations that were equipotent at producing bradypnea. We compared carfentanil and alfentanil (phenylpiperidines with relatively high efficacy and high to medium lipophilicity, respectively), norbuprenorphine (orvinolmorphinan with high efficacy and lipophilicity) and levorphanol (morphinan with relatively low efficacy and high lipophilicity).Discussion: We observed that, agonists with higher intrinsic efficacy were more likely to increase expiratory EMG amplitude (i.e., produce chest rigidity) than agonists with lower efficacy. Whereas lipophilicity and chemical structure did not appear to correlate with the ability to induce chest rigidity.

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The pattern of brain oxygen response induced by intravenous fentanyl limits the time window of therapeutic efficacy of naloxone

Cited by 7 publications

References 42 publications

Fact vs. fiction: naloxone in the treatment of opioid-induced respiratory depression in the current era of synthetic opioids

Fact vs. fiction: naloxone in the treatment of opioid-induced respiratory depression in the current era of synthetic opioids

Brain oxygen responses induced by opioids: focus on heroin, fentanyl, and their adulterants

Comparison of the effects of fentanyls and other μ opioid receptor agonists on the electrical activity of respiratory muscles in the rat

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