DARK Classics in Chemical Neuroscience: Fentanyl

Burns, Mallory; Cunningham, Christopher W.; Mercer, Susan L.

doi:10.1021/acschemneuro.8b00174

Cited by 65 publications

(90 citation statements)

References 92 publications

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“…The high receptor mu occupancy of fentanyl at the doses observed in this model without naloxone administration is consistent with reports of the potency of this synthetic opioid and its relation to a recent spike in overdoses and deaths. Fentanyl is known to be persistently lipophilic and has been described as having a rapid transport in and out of the CNS [31].…”

Section: Discussionmentioning

confidence: 99%

Higher naloxone dosing in a quantitative systems pharmacology model that predicts naloxone-fentanyl competition at the opioid mu receptor level

et al. 2020

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Rapid resuscitation of an opioid overdose with naloxone, an opioid antagonist, is critical. We developed an opioid receptor quantitative systems pharmacology (QSP) model for evaluation of naloxone dosing. In this model we examined three opioid exposure levels that have been reported in the literature (25 ng/ml, 50 ng/ml, and 75 ng/ml of fentanyl). The model predicted naloxone-fentanyl interaction at the mu opioid receptor over a range of three naloxone doses. For a 2 mg intramuscular (IM) dose of naloxone at lower fentanyl exposure levels (25 ng/ml and 50 ng/ml), the time to decreasing mu receptor occupancy by fentanyl to 50% was 3 and 10 minutes, respectively. However, at a higher fentanyl exposure level (75 ng/ml), a dose of 2 mg IM of the naloxone failed to reduce mu receptor occupancy by fentanyl to 50%. In contrast, naloxone doses of 5 mg and 10 mg IM reduced mu receptor occupancy by fentanyl to 50% in 5.5 and 4 minutes respectively. These results suggest that the current doses of naloxone (2 mg IM or 4 mg intranasal (IN)) may be inadequate for rapid reversal of toxicity due to fentanyl exposure and that increasing the dose of naloxone is likely to improve outcomes.

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Section: Discussionmentioning

confidence: 99%

Higher naloxone dosing in a quantitative systems pharmacology model that predicts naloxone-fentanyl competition at the opioid mu receptor level

et al. 2020

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“…Synthetic opioids present multiple challenges for first responders attempting to rescue overdose victims. High-potency synthetics [fentanyl and other synthetics identified in overdose victims can be $2 orders of magnitude more potent than morphine (Burns et al, 2018;Misailidi et al, 2018)] may require very high doses of the competitive antagonist naloxone (Sutter et al, 2017;Li et al, 2018;Uddayasankar et al, 2018), the only drug currently approved to treat opioid overdose, to effect a successful rescue. Not only are these high potencies problematic, but the long half-lives of fentanyl (7 to 8 hours) and analogs such as sufentanil (6-9 hours) (Ahonen et al, 2000;Kharasch, 2015) and carfentanil (∼5.7 hours) (Uddayasankar et al, 2018) further complicate rescue with naloxone.…”

Section: Discussionmentioning

confidence: 99%

“…Not only are these high potencies problematic, but the long half-lives of fentanyl (7 to 8 hours) and analogs such as sufentanil (6-9 hours) (Ahonen et al, 2000;Kharasch, 2015) and carfentanil (∼5.7 hours) (Uddayasankar et al, 2018) further complicate rescue with naloxone. Thus, therapeutically effective plasma concentrations of naloxone (t 1/2 5 1.3-2.4 hours; Ryan and Dunne, 2018) may not be sustained in the presence of long-duration synthetics, leading to a recurrence of symptoms (renarcotization) including respiratory depression (Kaplan and Marx, 1993;Burns et al, 2018) that complicate management of overdose and may require redosing with naloxone. Finally, synthetic opioids are orders of magnitude more lipophilic than morphine and related semisynthetic opiates such as oxycodone (Drewes et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Fighting Fire with Fire: Development of Intranasal Nalmefene to Treat Synthetic Opioid Overdose

Krieter

Gyaw

Crystal

et al. 2019

J Pharmacol Exp Ther

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The dramatic rise in overdose deaths linked to synthetic opioids (e.g., fentanyl, carfentanil) may require more potent, longerduration opiate antagonists than naloxone. Both the high affinity of nalmefene at m opiate receptors and its long half-life led us to examine the feasibility of developing an intranasal (IN) formulation as a rescue medication that could be especially useful in treating synthetic opioid overdose. In this study, the pharmacokinetic properties of IN nalmefene were compared with an intramuscular (i.m.) injection in a cohort of healthy volunteers. Nalmefene was absorbed slowly following IN administration, with a median time to reach C max (T max) of 2 hours. Addition of the absorption enhancer dodecyl maltoside (Intravail, Neurelis, Inc., Encinitas, CA) reduced T max to 0.25 hour and increased C max by ∼2.2-fold. The pharmacokinetic properties of IN nalmefene (3 mg) formulated with dodecyl maltoside has characteristics consistent with an effective rescue medication: its onset of action is comparable to an i.m. injection of nalmefene (1.5 mg) previously approved to treat opioid overdose. Furthermore, the C max following IN administration was ∼3-fold higher than following i.m. dosing, comparable to previously reported plasma concentrations of nalmefene observed 5 minutes following a 1-mg i.v. dose. The high affinity, very rapid onset, and long half-life (.7 hours) of IN nalmefene present distinct advantages as a rescue medication, particularly against longer-lived synthetic opioids.

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“…1 The surge in fentanyl is attributed to high potency (50-400 times more potent than the naturally occurring morphine), fast onset, straightforward synthesis, and low cost production. [2][3][4][5] Additionally, the fentanyl core is readily modified creating a vast chemical space of fentanyl analogs with abuse potential. 6 Fentanyl and morphine opioids produce strong analgesic responses through binding and subsequent activation of a class A G protein-coupled receptor (GPCR) µ-opioid receptor (mOR).…”

Section: Introductionmentioning

confidence: 99%

How mu-Opioid Receptor Recognizes Fentanyl

Mahinthichaichan

Shen

et al. 2020

Preprint

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The opioid crisis has escalated during the COVID-19 pandemic. More than half of the overdose-related deaths are related to synthetic opioids represented by fentanyl which is a potent agonist of mu-opioid receptor (mOR). In recent years, crystal structures of mOR complexed with morphine derivatives have been determined; however, structural basis of mOR activation by fentanyl-like synthetic opioids remains lacking. Exploiting the X-ray structure of mOR bound to a morphinan ligand and several state-of-the-art simulation techniques, including weighted ensemble and continuous constant pH molecular dynamics, we elucidated the detailed binding mechanism of fentanyl with mOR. Surprisingly, in addition to the orthosteric site common to morphinan opiates, fentanyl can move deeper and bind mOR through hydrogen bonding with a conserved histidine H297, which has been shown to modulate mOR's ligand affinity and pH dependence in mutagenesis experiments, but its precise role remains unclear. Intriguingly, the secondary binding mode is only accessible when H297 adopts a neutral HID tautomer. Alternative binding modes and involvement of tautomer states may represent general mechanisms in G protein-coupled receptor (GPCR)-ligand recognition. Our work provides a starting point for understanding mOR activation by fentanyl analogs that are emerging at a rapid pace and assisting the design of safer analgesics to combat the opioid crisis. Current protein simulation studies employ standard protonation and tautomer states; our work demonstrates the need to move beyond the practice to advance our understanding of protein-ligand recognition.

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DARK Classics in Chemical Neuroscience: Fentanyl

Cited by 65 publications

References 92 publications

Higher naloxone dosing in a quantitative systems pharmacology model that predicts naloxone-fentanyl competition at the opioid mu receptor level

Higher naloxone dosing in a quantitative systems pharmacology model that predicts naloxone-fentanyl competition at the opioid mu receptor level

Fighting Fire with Fire: Development of Intranasal Nalmefene to Treat Synthetic Opioid Overdose

How mu-Opioid Receptor Recognizes Fentanyl

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