Oxycodone in the Opioid Epidemic: High ‘Liking’, ‘Wanting’, and Abuse Liability

Kibaly, Cherkaouia; Alderete, Jacob A.; Liu, Steven H.; Nasef, Hazem S.; Law, Ping Yee; Evans, Christopher J.; Cahill, Catherine M.

doi:10.1007/s10571-020-01013-y

Cited by 58 publications

(50 citation statements)

References 272 publications

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“…Codeine is a relatively safe opioid in the management of moderate pain with reduced respiratory liability, though it still presents a significant risk in terms of dependence and addiction (Nielsen et al, 2018). In contrast, management of moderate to severe pain using oxycodone has been associated with significant numbers of overdose deaths over the last 10–15 years (Kibaly et al, 2021). Interestingly, both agonists are metabolised by cytochrome P450 enzymes with codeine primarily metabolised by CYP2D6 (Crews et al, 2021) and oxycodone metabolised by both CYP2D6 and CYP3A (Umukoro et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

The respiratory depressant effects of mitragynine are limited by its conversion to 7‐OH mitragynine

Hill

Kruegel

Javitch

et al. 2022

British J Pharmacology

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Background and Purpose: Mitragynine, the major alkaloid in Mitragyna speciosa (kratom), is a partial agonist at the μ opioid receptor. CYP3A-dependent oxidation of mitragynine yields the metabolite 7-OH mitragynine, a more efficacious μ receptor agonist. While both mitragynine and 7-OH mitragynine can induce anti-nociception in mice, recent evidence suggests that 7-OH mitragynine formed as a metabolite is sufficient to explain the anti-nociceptive effects of mitragynine. However, the ability of 7-OH mitragynine to induce μ receptor-dependent respiratory depression has not yet been studied.Experimental Approach: Respiration was measured in awake, freely moving, male CD-1 mice, using whole body plethysmography. Anti-nociception was measured using the hot plate assay. Morphine, mitragynine, 7-OH mitragynine and the CYP3A inhibitor ketoconazole were administered orally.

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Section: Discussionmentioning

confidence: 99%

The respiratory depressant effects of mitragynine are limited by its conversion to 7‐OH mitragynine

Hill

Kruegel

Javitch

et al. 2022

British J Pharmacology

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“…This is evident for most abused drugs evaluated in primates and rats 7–9 . It has been claimed that delayed absorption of oxycodone reduces its abuse liability 10 . However, lessening behavioral effects by slowing drug release does not yield drugs that are no longer addictive.…”

Section: Introductionmentioning

confidence: 99%

Sex and heredity are determinants of drug intake in a novel model of rat oral oxycodone self‐administration

Sharp

Fan

Redei

et al. 2021

Genes Brain and Behavior

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The steady rise in prescription opioids such as oxycodone has led to a virulent epidemic of widespread abuse and deaths in the United States; approximately 80% of affected individuals initiate the habitual use of oxycodone by using prescription oral oxycodone. Given the importance of drug pharmacokinetics in determining abuse potential, we designed an oral operant oxycodone self‐administration (SA) procedure in rats to model drug intake by most human users/abusers of oxycodone. Key aspects of the model include limited initial drug intake followed by increasing drug concentrations during extended 4‐h sessions on alternating days. Sex and genetic predisposition are major determinants of human opiate abuse. Therefore, we studied females in seven inbred strains (WLI, WMI, LEW, DSS, F344, BN and SHR) and both sexes in three of these strains. All strains increased intake across serially increasing doses (0.025–0.2 mg/ml; p < 0.001): the range of intakes at the final concentration of oxycodone was 0.72 ± 0.17–4.84 ± 1.42 mg/kg (mean ± SEM) ‐ a 6.7‐fold difference across strains. In LEW, WLI and WMI strains, oxycodone intake increased significantly across all sessions in both sexes. However, in LEW and WMI male rats but not WLI, daily oxycodone intake was significantly lower across all 4‐h sessions than females (p < 0.005). The estimated heritability in oxycodone intake was in the range of 0.21–0.41. In summary, our novel operant oral oxycodone SA model captures the strong abuse potential of oral oxycodone and shows dose, sex and strain‐specific drug intake that is significantly dependent on heredity.

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“…Among the most widely misused opioids are prescription opioids, particularly oxycodone, hydrocodone, oxymorphone, and hydromorphone 18 . Prescription opioids are used for various moderate to severe pain conditions, although their extensive use was spurred by extended release formulations that emerged in the mid‐1990s, especially of oxycodone in the form of oxycodone ER 35 …”

Section: Prescription Opioidsmentioning

confidence: 99%

“…Despite unsubstantiated claims that an extended‐release formulation would decrease the abuse liability of oxycodone, patients self‐dosed with the medication at shorter than prescribed intervals developed tolerance and dependence with repeated withdrawal periods and were more likely to develop an opioid use disorder 35 . No other prescription opioid influenced the prescribing pattern to the same degree as extended formulations of oxycodone, with a rise in retail sales of 866% between 1997 and 2007 because of aggressive marketing and misleading safety claims by the manufacturer 36 .…”

Section: Prescription Opioidsmentioning

confidence: 99%

“…The distinction in signaling and activation may contribute to the higher dependence and abuse potential of oxycodone compared with other prescription opioids. The most common methods of abuse involve chewing or crushing extended‐release oxycodone tablets with subsequent oral administration or insufflation 35,41 . Because of oxycodone's high cost and limited availability as a prescription opioid, its users with an opioid use disorder may eventually transition to heroin or illicitly produced synthetic opioids that are often adulterated with fentanyl and its analogues 42,43 …”

Section: Prescription Opioidsmentioning

confidence: 99%

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Clinical Pharmacology, Toxicity, and Abuse Potential of Opioids

Vearrier

Grundmann

2021

The Journal of Clinical Pharma

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Opioids were the most common drug class resulting in overdose deaths in the United States in 2019. Widespread clinical use of prescription opioids for moderate to severe pain contributed to the ongoing opioid epidemic with the subsequent emergence of fentanyl‐laced heroin. More potent analogues of fentanyl and structurally diverse opioid receptor agonists such as AH‐7921 and MT‐45 are fueling an increasingly diverse illicit opioid supply. Overdose from synthetic opioids with high binding affinities may not respond to a typical naloxone dose, thereby rendering autoinjectors less effective, requiring higher antagonist doses or resulting in a confusing clinical picture for health care providers. Nonscheduled opioid drugs such as loperamide and dextromethorphan are associated with dependence and risk of overdose as easier access makes them attractive to opioid users. Despite a common opioid‐mediated pathway, several opioids present with unique pharmacodynamic properties leading to acute toxicity and dependence development. Pharmacokinetic considerations involve half‐life of the parent opioid and its metabolites as well as resulting toxicity, as is established for tramadol, codeine, and oxycodone. Pharmacokinetic considerations, toxicities, and treatment approaches for notable opioids are reviewed.

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Oxycodone in the Opioid Epidemic: High ‘Liking’, ‘Wanting’, and Abuse Liability

Cited by 58 publications

References 272 publications

The respiratory depressant effects of mitragynine are limited by its conversion to 7‐OH mitragynine

The respiratory depressant effects of mitragynine are limited by its conversion to 7‐OH mitragynine

Sex and heredity are determinants of drug intake in a novel model of rat oral oxycodone self‐administration

Clinical Pharmacology, Toxicity, and Abuse Potential of Opioids

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