The epidemic of fentanyl misuse and overdoses: challenges and strategies

Volkow, Nora D.

doi:10.1002/wps.20846

Cited by 49 publications

(35 citation statements)

References 6 publications

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“…Abstinence in individuals with OUD presents serious risks of fatal overdose on relapse, due to the rapid loss of tolerance that occurs during even brief periods of abstinence. This risk is particularly acute in countries where fentanyl is readily available: e.g., drug deaths have recently exceeded 100,000/year in the USA being further exacerbated by the COVID-19 pandemic [ 51 , 52 ]. Our findings also highlight the importance of the NVS as a target for new OUD treatments (e.g., partial MOR1 agonism, k-type opioid receptor antagonism, and α-2A adrenergic receptor agonism) [ 53 , 54 ].…”

Section: Discussionmentioning

confidence: 99%

Protracted abstinence in males with an opioid use disorder: partial recovery of nucleus accumbens function

et al. 2022

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Opioid use disorder (OUD) affects more than 27 million people globally accounting for more than 300,000 deaths annually. Protracted abstinence among individuals with OUD is rare due to a high relapse rate among those not receiving medications for OUD. Extensive preclinical studies form the basis of the allostasis theory, which proposes long-lasting functional brain abnormalities that persist after opioid withdrawal and contribute to relapse. Few studies have tested the allostasis theory in humans using neuroimaging. Here, we used fMRI and an instrumental learning task to test allostasis theory predictions (ATP) of functional abnormalities in both positive valence (PVS) and negative valence (NVS) accumbens systems in OUD patients with protracted abstinence (n = 15), comparing them with OUD patients receiving methadone treatment (MT) (n = 33), and with healthy controls (n = 23). As hypothesized, protracted abstinence OUD patients showed incomplete recovery of nucleus accumbens function, as evidenced by the blunted response to aversive events (NVS) during negative reinforcement, as observed in MT patients. In contrast, their accumbens response to rewarding events (PVS) during positive reinforcement was similar to that of controls and different from that in MT patients whose response was blunted. Protracted abstinence OUD patients also showed improvements in depression symptoms compared to MT patients. Residual depressive symptoms and pre-MT intravenous drug measures were associated with worse accumbens function in protracted abstinence. These results support the ATP of long-lasting dysfunction of NVS after withdrawal and show preliminary evidence of recovery of PVS function with protracted withdrawal. Therapeutic strategies that target NVS may facilitate recovery.

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Section: Discussionmentioning

confidence: 99%

Protracted abstinence in males with an opioid use disorder: partial recovery of nucleus accumbens function

et al. 2022

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“…Patients who receive fentanyl anesthesia also typically receive paralytics with mechanical ventilation for akinesia which conveniently prevents wooden chest syndrome and paralytics are listed as a treatment for fentanyl-induced muscle rigidity in the highlights of prescribing information for fentanyl citrate injection (Akorn Inc. 2019 ). A number of published reports outline concerns about the ability to treat non-opioid receptor-mediated F/FA-induced muscle rigidity during an overdose event (Pergolizzi et al 2021 ; Torralva and Janowsky 2019 ; Volkow 2021 ). However, the prevalence of wooden chest syndrome and vocal cord closure in people who are experiencing an overdose, the role it plays in F/FA overdose, and naloxone efficacy against wooden chest syndrome are largely unmeasured at this point.…”

Section: Naloxonementioning

confidence: 99%

Treatment of opioid overdose: current approaches and recent advances

Britch

Walsh

2022

Psychopharmacology

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Background The USA has recently entered the third decade of the opioid epidemic. Opioid overdose deaths reached a new record of over 74,000 in a 12-month period ending April 2021. Naloxone is the primary opioid overdose reversal agent, but concern has been raised that naloxone is not efficacious against the pervasive illicit high potency opioids (i.e., fentanyl and fentanyl analogs). Methods This narrative review provides a brief overview of naloxone, including its history and pharmacology, and the evidence regarding naloxone efficacy against fentanyl and fentanyl analogs. We also highlight current advances in overdose treatments and technologies that have been tested in humans. Results and conclusions The argument that naloxone is not efficacious against fentanyl and fentanyl analogs rests on case studies, retrospective analyses of community outbreaks, pharmacokinetics, and pharmacodynamics. No well-controlled studies have been conducted to test this argument, and the current literature provides limited evidence to suggest that naloxone is ineffective against fentanyl or fentanyl analog overdose. Rather a central concern for treating fentanyl/fentanyl analog overdose is the rapidity of overdose onset and the narrow window for treatment. It is also difficult to determine if other non-opioid substances are contributing to a drug overdose, for which naloxone is not an effective treatment. Alternative pharmacological approaches that are currently being studied in humans include other opioid receptor antagonists (e.g., nalmefene), respiratory stimulants, and buprenorphine. None of these approaches target polysubstance overdose and only one novel approach (a wearable naloxone delivery device) would address the narrow treatment window.

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“…Indeed, in the 12 months preceding March 2021 alone, the CDC estimated a total of 63,075 synthetic opioid overdose deaths, a 54.5% increase from the previous year 5 . This persistent increase in fentanyls-related overdose deaths reflects these synthetic compounds’ highly rewarding effects, potency in inducing respiratory depression, and widespread availability driven by ease of production and distribution 6 – 8 . Thus, such challenges are forcing health care providers to reconsider their strategies for treating overdoses caused by synthetic opioids 9 – 11 .…”

Section: Introductionmentioning

confidence: 99%

Naloxone’s dose-dependent displacement of [11C]carfentanil and duration of receptor occupancy in the rat brain

Kang

O'Conor

Kelleher

et al. 2022

Sci Rep

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The continuous rise in opioid overdoses in the United States is predominantly driven by very potent synthetic opioids, mostly fentanyl and its derivatives (fentanyls). Although naloxone (NLX) has been shown to effectively reverse overdoses by conventional opioids, there may be a need for higher or repeated doses of NLX to revert overdoses from highly potent fentanyls. Here, we used positron emission tomography (PET) to assess NLX’s dose-dependence on both its rate of displacement of [11C]carfentanil ([11C]CFN) binding and its duration of mu opioid receptor (MOR) occupancy in the male rat brain. We showed that clinically relevant doses of intravenously (IV) administered NLX (0.035 mg/kg, Human Equivalent Dose (HED) 0.4 mg; 0.17 mg/kg, HED 2 mg) rapidly displaced the specific binding of [11C]CFN in the thalamus in a dose-dependent manner. Brain MOR occupancy by IV NLX was greater than 90% at 5 min after NLX administration for both doses, but at 27.3 min after 0.035 mg/kg dose and at 85 min after 0.17 mg/kg NLX, only 50% occupancy remained. This indicates that the duration of NLX occupancy at MORs is short-lived. Overall, these results show that clinically relevant doses of IV NLX can promptly displace fentanyls at brain MORs, but repeated or higher NLX doses may be required to prevent re-narcotization following overdoses with long-acting fentanyls.

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The epidemic of fentanyl misuse and overdoses: challenges and strategies

Cited by 49 publications

References 6 publications

Protracted abstinence in males with an opioid use disorder: partial recovery of nucleus accumbens function

Protracted abstinence in males with an opioid use disorder: partial recovery of nucleus accumbens function

Treatment of opioid overdose: current approaches and recent advances

Naloxone’s dose-dependent displacement of [11C]carfentanil and duration of receptor occupancy in the rat brain

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