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Review
. 2021 Jul;41(5):899-926.
doi: 10.1007/s10571-020-01013-y. Epub 2020 Nov 27.

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

Cherkaouia Kibaly #  1 , Jacob A Alderete #  2 , Steven H Liu #  2 , Hazem S Nasef #  2 , Ping-Yee Law #  2 , Christopher J Evans #  2 , Catherine M Cahill #  3
Affiliations
Review

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

Cherkaouia Kibaly et al. Cell Mol Neurobiol. 2021 Jul.

Abstract

It is estimated that nearly a third of people who abuse drugs started with prescription opioid medicines. Approximately, 11.5 million Americans used prescription drugs recreationally in 2016, and in 2018, 46,802 Americans died as the result of an opioid overdose, including prescription opioids, heroin, and illicitly manufactured fentanyl (National Institutes on Drug Abuse (2020) Opioid Overdose Crisis. https://www.drugabuse.gov/drugs-abuse/opioids/opioid-overdose-crisis . Accessed 06 June 2020). Yet physicians will continue to prescribe oral opioids for moderate-to-severe pain in the absence of alternative therapeutics, underscoring the importance in understanding how drug choice can influence detrimental outcomes. One of the opioid prescription medications that led to this crisis is oxycodone, where misuse of this drug has been rampant. Being one of the most highly prescribed opioid medications for treating moderate-to-severe pain as reflected in the skyrocketed increase in retail sales of 866% between 1997 and 2007, oxycodone was initially suggested to be less addictive than morphine. The false-claimed non-addictive formulation of oxycodone, OxyContin, further contributed to the opioid crisis. Abuse was often carried out by crushing the pills for immediate burst release, typically by nasal insufflation, or by liquefying the pills for intravenous injection. Here, we review oxycodone pharmacology and abuse liability as well as present the hypothesis that oxycodone may exhibit a unique pharmacology that contributes to its high likability and abuse susceptibility. We will discuss various mechanisms that likely contribute to the high abuse rate of oxycodone including clinical drug likability, pharmacokinetics, pharmacodynamics, differences in its actions within mesolimbic reward circuity compared to other opioids, and the possibility of differential molecular and cellular receptor interactions that contribute to its selective effects. We will also discuss marketing strategies and drug difference that likely contributes to the oxycodone opioid use disorders and addiction.

Keywords: Allosteric site; Dopamine; Incentive salience; Likability; Oxycodone.

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Conflict of interest statement

Conflict of interest: The authors declare no competing interests.

Figures

Fig. 1.
Fig. 1.. Metabolism of thebaine and oxycodone.
Oxycodone is derived from thebaine and is metabolized in humans by hepatic cytochrome P450 (CYP) isoenzymes into three major metabolites. Oxycodone is either N-demethylated by the cytochrome P450 CYP-3A4/5 to noroxycodone or O-demethylated by CYP-2D6 to oxymorphone. Then, oxymorphone is converted into noroxymorphone by CYP-3A4/5 (Lemberg et al. 2008).
Fig. 2.
Fig. 2.. Action of oxycodone and morphine on potential GABAergic neurons responsible for the difference in the extracellular dopamine (DA) within the reward system.
Oxycodone and morphine provoke distinct changes in DA release in the nucleus accumbens (NAc) that could potentially explain drug users’ selective preference for oxycodone over other opioids (Vander Weele et al. 2014). Intravenous infusion of oxycodone leads to greater global and phasic releases of DA in the NAc (especially in the shell), while morphine causes a short-lived DA release coupled to transient GABA release within the same structure (Vander Weele et al. 2014). Dopaminergic neurons of the mesolimbic pathway project from the VTA in the midbrain onto the GABAergic inhibitory medium spiny neurons (MSNs) in the NAc (Malenka et al. 2009; Ikemoto et al. 2010; Yager et al. 2015; Morales and Margolis 2017). These MSNs represent 95% of the striatum and express the D1 and/or D2 dopaminergic receptors (Kemp and Powell 1971; Yager et al. 2015; Morales and Margolis 2017). Besides DA, GABA is one of the principal neurotransmitters that mediate reward signaling within the NAc (Meredith et al. 1992; Shirayama et al. 2006). Terminals of dopaminergic neurons in the NAc from the VTA are presumed to express GABA receptors through which GABA released from the MSNs may induce tonic inhibition (Yang et al. 2018). MOR has been shown to be expressed on MSNs (Svingos et al. 1999; Shippenberg et al. 2008) and in an undetermined subset of GABAergic neurons within the mouse NAc (Ford et al. 2006; Margolis et al. 2012, 2014; Hinkle et al. 2019). Several lines of indirect functional evidence support the presence of MOR on GABAergic neurons in the VTA (Margolis et al. 2014). As posits the canonical model, opioids induce reward by disinhibiting VTA and NAc dopaminergic neurons through inhibition of GABAergic inputs (Johnson and North 1992; Labouèbe et al. 2007; Barrot et al. 2012; Bourdy and Barrot 2012; Margolis et al. 2012). Therefore, oxycodone may cause robust and stable DA release by decreasing the excitability of GABAergic MSNs (see label 1 on the figure), thus blocking their potential tonic inhibitory action on the DA terminals in the NAc. Oxycodone may also inhibit other NAc interneurons that innervate directly the dopaminergic terminals (label 1) and the GABAergic inputs on these dopaminergic neurons in the VTA (label 1). As our unpublished data suggest, the robust and stable increase in global and phasic releases of DA in the presence of oxycodone might involve the selective stimulation of putative opioid receptor heterodimers or potentially different signaling cascades compared to morphine. The morphine-dependent short-lived DA response could be caused by the additional surge of GABA release following morphine. One hypothesis for the transient rise of GABA is that inhibition of GABAergic neurons by morphine could be short-lived compared to oxycodone, thus leading to a brief inhibition of GABA release (bottom figure). However, this needs to be demonstrated. The surplus of GABA could also be secreted by VTA DA/GABAergic TH-expressing neurons that project to the NAc (labels 2 and 3). We speculate that these latter neurons could be activated to release GABA via disinhibition by morphine (label 2), whereas they would be inhibited in the presence of oxycodone via a potential selective agonist action on opioid receptor heterodimers-expressing GABAergic neurons (label 3).
Fig. 3.
Fig. 3.. Potential biased signaling of oxycodone and morphine.
Opioid receptors are both pre- and post-synaptic and are coupled to the Gi/Go proteins. In contrast to morphine, oxycodone is speculated in this review to interact with sodium (Na+) allosteric sites on the mu opioid-receptor (MOR) and to act as an “efficacy-switch” in the receptor signal transduction. In acute pain conditions, the activation of MOR by either morphine or oxycodone triggers the classical intracellular Gi/Go-protein signaling pathway that leads to analgesia (Law et al. 2000; Williams et al. 2013; Pena et al. 2018) and the Protein Kinase C (PKC)-mediated signaling pathway that is responsible for the receptor desensitization. The classical Go/Gi-protein signaling pathway has already been extensively described in the literature: it leads to (1) the inhibition of the adenylyl cyclase (AC)/cyclic AMP (cAMP)/ protein kinase A (PKA) or the exchange protein directly activated by cAMP (EPAC) pathways (Pena et al. 2018), (2) the stimulation of G protein-couple inwardly-rectifying potassium channels (GIRKs) and (3) the inhibition of voltage-gated calcium channels (Ca2+ conductance) causing a decreased neurotransmitter release from the pre-synaptic nerve terminal. After receptor activation, there is a progressive reduction in signal transduction which corresponds to MOR desensitization (Williams et al. 2013). MOR desensitization by morphine and oxycodone is mainly PKC-dependent as it minimally engages GRK-ß-arrestin regulation like fentanyl (Chu et al. 2010; Zheng et al. 2011). However, unlike morphine, we hypothesize that oxycodone requires other pathways in addition to that of PKC to induce MOR desensitization. These potential additional PKC-independent pathways need to be determined, although specific signal transduction activated by oxycodone has already been demonstrated, such as the Epithelial growth factor receptor (EGFR)/ERK/Akt pathway in the context of oxidative stress (Yu et al. 2020). The mechanism by which PKC mediates morphine- and oxycodone-promoted MOR desensitization is still not clear. Strong evidences suggest that morphine induces MOR desensitization through low level of receptor phosphorylation and activation of PKCα, γ and ε to induce ERK phosphorylation and tolerance (Smith et al. 2003; Song et al. 2010; Zheng et al. 2011). After MOR activation, PKC can be stimulated by second messengers such as DAG and calcium made available thanks to PLC activation by GBßγ subunit, non-coupled tyrosine kinases, or small G protein (Pena et al. 2018). Many substrates of PKC have been proposed including Phosphatidylethanolamine-binding protein 1 (PEBP1) which inhibits the MAPK/ERK pathway, scaffold proteins such as annexin 6 which also inhibits ERK activation, neurogranin and calmodulin whose stimulation by PKC leads to activation of CAMKII and TRPV1. These PKC-signaling signaling cascades of events are involved in the development of tolerance both in the spinal cord and the nucleus accumbens (NAc) (Song et al. 2010). PKC has also an important role in inhibition of receptor recycling (Bailey et al. 2006; Halls et al. 2016).
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