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Revisiting Oxycodone Analgesia
Revisiting Oxycodone Analgesia A Review and Hypothesis Xiulu Ruan,
MD*,
Ken F. Mancuso,
MD,
Alan David Kaye,
MD, PhD
KEYWORDS Oxycodone analgesia Morphine Pharmacology Peripheral opioid analgesia KEY POINTS Oxycodone, a semisynthetic opioid analgesic, is widely used in clinical practice. Oxycodone and morphine seem to be equally effective and equipotent when postoperatively administered intravenous via patient-controlled analgesia and in cancer pain. However, data have provided conflicting results. This article aims to provide an updated review on the basic pharmacology of oxycodone with a special focus on pharmacokinetic/pharmacodynamics properties. The controversy regarding oxycodone-mediated effects for visceral pain via agonism and the possible role of peripheral opioid analgesia are discussed to propose a plausible explanation to the perplexing question of oxycodone analgesia.
INTRODUCTION
Oxycodone, a semisynthetic opioid analgesic, is widely used in clinical practice. Oxycodone was first synthesized from thebaine in Germany in 1917.1 For decades, researchers have been challenged by results of a plethora of research studies in different animal models and in humans, related to oxycodone analgesia.2 Oxycodone and morphine seem to be equally effective and equipotent when postoperatively administered intravenously via patient-controlled analgesia and in patients with cancer pain.3,4 However, morphine has been found to be 10 times more potent than oxycodone when given epidurally after abdominal surgery.5 In rats, with intrathecal administration, morphine has been demonstrated to be 14 times more potent than oxycodone, whereas with subcutaneous and intraperitoneal administration,
External Funding: None. Conflict of Interest: None. Department of Anesthesiology, Louisiana State University Health Science Center, 1542 Tulane Avenue, New Orleans, LA 70112, USA * Corresponding author. E-mail address: [email protected] Anesthesiology Clin - (2017) -–http://dx.doi.org/10.1016/j.anclin.2017.01.022 1932-2275/17/ª 2017 Elsevier Inc. All rights reserved.
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oxycodone has been shown to be 2 to 4 times as potent as morphine.6 Thus, it remains largely unclear as to how these data have provided such conflicting results. This article provides an updated review on the basic pharmacology of oxycodone with a special focus on pharmacokinetic/pharmacodynamics properties. Additionally, a review is provided on the controversy regarding oxycodone-mediated or -modulated effects for visceral pain via k agonism and the possible role or roles of peripheral opioid analgesia are discussed in the present investigation in an attempt to determine a plausible explanation to the perplexing question of oxycodone analgesia. BASIC PHARMACOKINETICS
Oxycodone is relatively well-absorbed after oral administration. Approximately 40% of oxycodone is bound to plasma proteins in vitro, which is similar to the binding of morphine.7 The distribution volume at steady state is 2 to 5 L/kg in adults, which is comparable with that of morphine.2 Passive diffusion, a process whereby drugs or endogenous substances move across the blood–brain barrier (BBB),8 depends on the physicochemical properties of the drug and concentration gradient from blood to brain. Low-molecular-weight, lipid-soluble, and neutral agents may cross the BBB via passive diffusion. The lipid solubility of oxycodone has been found to be similar to that of morphine.9 In sheep and rats, after intravenous administration, the unbound concentration of oxycodone has been found to be 2.5 and 6 times higher in the brain than in the blood,10,11 suggesting an active transport of oxycodone across the BBB. Okura and colleagues12 postulated that oxycodone was transported into the central nervous system by an organic cation transporter in vitro and in vivo. However, how significant a role these transporters may plan in human BBB (assuming they exist) is largely unknown. The cerebral endothelium at the BBB has ATP-dependent efflux pumps, efflux transporters, which prevent brain penetration, as well as intracellular and extracellular distribution of a variety of endogenous and exogenous compounds.13 Morphine has been identified as a substrate of P-glycoprotein14; however, there have been conflicting studies regarding whether oxycodone is a substrate of P-glycoprotein. An early study in rats by Bostro¨m and colleagues15 has suggested that oxycodone is not a substrate of P-glycoprotein, unlike morphine. In contrast, these results were subsequently questioned by Hassan and colleagues,16 who reported that oxycodone was a P-glycoprotein substrate in various in vitro and in vivo models. Further, Hassan and colleagues16 also demonstrated that chronic administration of oxycodone induced overexpression of P-glycoprotein. In this regard, there is no information on the possible role of P-glycoprotein in regulating BBB transport of oxycodone in humans. PHARMACOGENETIC VARIATION OR METABOLITE CONTRIBUTION
The pharmacogenetic and pharmcodynamic properties of oxycodone and its metabolites have been reviewed extensively by Olkkola and colleagues.2 The m-opioid receptor binding affinity of nororoxycodone, the primary metabolite of oxycodone, is 4 times lower than that of oxycodone, and it produces 4 to 6 times lower G protein activation measured in a GTPg[35S] binding assay.17,18 The other primary oxidative metabolite, oxymorphone, has about a 50-fold higher affinity for the m-opioid receptor and can produce 8- to 30-fold higher G protein activation than oxycodone.17–19 The reduction products of oxymorphone, a- and b-oxymorphol, have been shown to be 2 to 3 times more potent than oxycodone17; however, after oral administration of oxycodone in humans, the plasma concentrations of a- and b-oxymorphol are low.17
Revisiting Oxycodone Analgesia
The most important secondary metabolite of oxycodone, noroxymorphone, has a 2to 3-fold higher affinity for the m-opioid receptor compared with oxycodone.7,17 The potency of noroxymorphone for m-opioid receptor-mediated G protein activation has been shown to be 3- to 7-fold higher than that of oxycodone.17,18 In a recent review, Klimas and colleagues20 demonstrated that oxycodone itself was responsible for the analgesic effect, despite its active metabolites, oxymorphone and noroxymorphone, possessing much higher m-receptor affinity than oxycodone, because the metabolites concentrations at the site of action, for example, the central nervous system, were too low. Andreassen and colleagues21 have reported in a cross-sectional study of 450 cancer patients genotyped for CYP2D6, which revealed 27 poor metabolizer, 413 extensive metabolizer, and 10 ultra-rapid metabolizer, oxycodone and noroxymorphone plasma concentrations did not differ between these phenotypes. In addition, the daily intake of oxycodone did not differ among patients, whether they were poor metabolizer, extensive metabolizer, or ultrarapid metabolizer (70–80 mg/d). Further, Andreassen and colleagues22 also reported the finding, after a multicenter cross-sectional study of 456 cancer patients, that no relationships were demonstrated between oxycodone or noroxymorphone concentrations and pain intensity, tiredness, nausea, or cognitive function. Oxycodone is primarily metabolized via CYP3A4/3A5 and to a lesser extent via CYP2D6.23 It is believed that CYP2D6 genotypes cause significant differences in pharmacokinetics without producing major pharmacodynamic consequences or clinical implications.23,24 PHARMACODYNAMIC DILEMMA
Oxycodone has been shown to be relatively selective at the m-opioid receptor.2 Depending on the assay properties, the affinity of oxycodone for the m-opioid receptor is 5 to 40 times lower compared with morphine.7,17,19 The potency of oxycodone in the m -opioid receptor-mediated activation of intracellular G proteins measured in the GTPg[35S] binding assay is 4- to 8-fold lower than the activity of morphine.17,19 In a radioligand displacement study, Lalovic and colleagues17 have shown that the m-receptor affinity of oxycodone is only one-fifth that of morphine, whereas its potency in activating GTPgS binding to the m-receptor is about one-third that of morphine. However, other observations have shown conflicting findings, for example, the antinociceptive potency of oxycodone in rodents is equal to that that of morphine6; oxycodone and morphine seem to be equally effective and equipotent when given intravenously for postoperative patient-controlled analgesia and in patients with cancer pain.3,4 In rats, with intrathecal administration, morphine has been shown to be 14 times more potent than oxycodone, whereas with subcutaneous and intraperitoneal administration, oxycodone has been demonstrated to be 2 to 4 times as potent as morphine.6 In a critical review on oxycodone pharmacology, Olkkola and colleagues2 opined, “We have still no explanation for the cerebral accumulation of oxycodone. Whether an active influx transporter explains the discrepancy between poor opioid receptor binding and analgesic efficacy remains to be elucidated. More research is also needed to understand why oxycodone is less effective after spinal than after intravenous administration.” Thus, using current opioid analgesic models, none of the hypotheses is able to provide a clear explanation for the conflicting findings in basic research and clinical practice. The apparent differences were hypothesized to be the result of either the involvement of active metabolites3,25 or the combined actions of oxycodone at the m- and k-opioid receptors.26,27
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Regardless of the underlying mechanism, it might be reasonable to consider, therefore, that there is a peripheral contribution from oxycodone and/or its active metabolites, in part, might be responsible for the observed pharmacologic differences. THE ROLE OF PERIPHERAL OPIOID RECEPTORS IN PERIPHERAL OXYCODONE ANALGESIA
Opioid receptors exist not only in the nervous system,28 but also in peripheral organs, such as the heart, lungs, liver, and gastrointestinal and reproductive tracts.29,30 However, the expression and distribution of these receptors vary significantly among different organs as well as among different animal species.28 Opioid receptors in the periphery can be a site for mediating analgesia.31–33 Peripheral analgesic effects of opioids are enhanced under inflammatory conditions and hyperalgesia.34,35 Inflammation increases the peripherally directed axonal transport of opioid receptors, which leads to upregulation of opioid receptors on peripheral nerve terminals,35 in particular, k-opioid receptors.36 In addition, the number of primary afferent neuron terminals is increased in inflamed tissues.31 Opioid receptors are classified into 3 major groups: m-opioid receptors, d-opioid receptors, and k-opioid receptors. Pharmacologically, the 3 classes of opioid receptors have been subdivided into 3 subtypes of m-opioid receptors, 2 subtypes of d-opioid receptors, and at least 3 subtypes of k-opioid receptors.37 All the receptor subtypes for m, d, and k-receptors have been proposed based on pharmacologic data; to date, there is only 1 known gene product for each subtype, which results in the expression of the functional receptor.38 It has also been demonstrated that characteristics of peripheral opioid receptors are very similar to those in the brain.31,39 Both m-opioid and k-opioid receptors have been found to be expressed in the stomach, duodenum, jejunum, and ileum as well as the proximal and distal colon, where their function is thought to include control of visceral pain, regulation of transit time of luminal contents, and mucosal transport of fluids and electrolytes.40,41 In contrast with m-opioid receptor and d-opioid receptor agonists, k-receptor agonists have long been recognized to be analgesics with no addiction and tolerance liability.42 However, almost all k-receptor agonists cause dysphoria, anhedonia, and hallucinations.43,44 Multiple lines of evidences suggest that the k-receptor modulates overlapping neurocircuits, connecting brainstem monoaminergic nuclei with forebrain limbic structures and thereby regulating the neurobiological effects of stress and psychostimulants. The emerging concept of “biased agonism” (also known as functional selectivity) for G-protein–coupled receptor ligands have provided new insights into overall response generated by a ligand.42 According to this concept, every ligand possesses the unique ability (coded in its structure) that dictates a distinct signaling pattern, and consequently beneficial or adverse response. Thus, the predominant signaling pattern of a G-protein–coupled receptor may differ from cell to cell in various tissues and organs. Finally, the promise of “biased agonism” lies in its ability to produce therapeutically beneficial signals while minimizing adverse effects.42 Peripheral k-opioid receptors in the gut have been suggested as an important feature of the visceral pain system.45–49 The k-receptors are more abundant in peripheral nerves than in central nerves.46 There are 3 subtypes of k-receptors that inhibit afferent firing and visceromotor responses to noxious colorectal distention in animal models.40 Analgesic development programs in the pharmaceutical industry for k1-opioid receptor selective ligands produced highly potent alternative analgesics to morphine in the late 1980s50; however, they failed in the clinical setting related to
Revisiting Oxycodone Analgesia
psychotomimetic side effects. The k2-opioid receptors are described as binding sites typically labeled by the nonselective benzomorphan ligand [3H]bremazocine in the presence of m-, d-, and k1-opioid receptor blocking ligands.50 Simonin and colleagues50 investigated the genetic origin of k2-opioid receptors, using homogenate binding experiments with [3H]bremazocine in brains of single, double, triple knockout mice. They found that no additional gene is required to explain the total population of [3H]bremazocine binding sites. Altogether the data demonstrate that the putative k2-opioid receptors are in fact a mixed population of receptor proteins produced by the 3 known opioid receptor genes.50 Findings in rodent experiments suggest that oxycodone is a partial k-opioid receptor agonist.26,51–54 Nielsen and colleagues26 proposed that oxycodone is a putative k2b agonist. In their study, rats pretreated with intracerebroventricular (ICV) nor-binaltorphimine (k-antagonist) prevented ICV oxycodone but not morphine antinociception. The opposite was shown with naloxonazine (putative m1 antagonist), suggesting an oxycodone analgesic effect mediated or modulated through k-opioid receptor binding.26 Further, Nielsen and colleagues26 demonstrated that, in animals tolerant to intravenous morphine, there is an absence of antinociceptive crosstolerance to ICV oxycodone. These investigators summarized that their findings provide support to the concept that oxycodone and morphine produce antinociception through distinctly different opioid receptor populations, that is, oxycodone seems to act as a k2b opioid agonist with a relatively low affinity for the m-opioid receptor. However, Nozaki and Kamei55 showed that the antinociceptive effect of subcutaneous oxycodone was completely antagonized by pretreatment with naloxonazine in both nondiabetic and diabetic mice. The selective k-opioid receptor antagonist norbinaltorphimine also antagonized oxycodone-induced antinociception in diabetic mice, but only had a partial effect in nondiabetic mice. Nozaki and Kamei55 allude that their findings suggest that, although oxycodone primarily interacts with m1-opioid receptor, k-opioid receptors are also strongly involved in oxycodone-induced antinociception.55 These studies imply a marked difference in the distribution of the putative k2 receptor subtypes and possibly an interaction with m receptors at different sites.56 In a recent review article by Gaveriaux-Ruff,57 entitled, “Opiate-induced analgesia: contributions from m-, d-, and k-opioid receptors mouse mutants,” the author summarized the findings regarding k-opioid receptor knockout mice, “Altogether, these findings indicate that m- and d-receptor proteins are necessary for the activity of k-2 opioid agonists, substantiating the idea that k-d heterodimers may mediate k-2 antinociceptive effects.” The regulation of opioid receptor system function in peripheral sensory neurons is still not well-understood. Opioid agonist efficacy to inhibit nociceptor function and promote antinociception is generally weak under basal conditions and frequently no response occurs.58 However, after injury or inflammation, the functional competence of m-, d-, and k-opioid receptor agonists to elicit antinociception via peripheral opioid receptors is increased markedly.39,59–62 Reichert and colleagues63 found that the intraperitoneal application of low doses of opioids produced antinociception in the writhing model via peripheral mechanisms. The k-opioids in animal models have been shown to reduce inflammation (colitis) nociceptive responses.36,64 The k-receptor gene “knocked-out” mice display increasing writhe to acetic acid peritonitis compared with wild-type mice.65 The k-opioid receptor agonists are particularly effective analgesics in experimental models of visceral pain.47 Their analgesic effects are mediated in the periphery. Smith and colleagues66 investigated the analgesic efficacy and systemic exposure of oxycodone administered topically in a novel tocopheryl phosphate mixture gel
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formulation to the inflamed hindpaws in a rat model of inflammatory pain. Topical application of oxycodone in a novel tocopheryl phosphate mixture gel formulation to the inflamed hindpaws of Freund’s complete adjuvant rats produced marked antihyperalgesia at a dose that produced insignificant systemic exposure to oxycodone or its major metabolite, noroxycodone. Smith and colleagues66 believe their findings suggest that topically applied oxycodone interacts with upregulated opioid receptors expressed on peripheral nerve terminals in inflamed tissue, to produce localized pain relief. Olesen and colleagues67 investigated the pharmacokinetic and pharmacodynamic profiles of oxycodone in a human experimental pain model of hyperalgesia. Twentyfour healthy subjects received oral oxycodone (15 mg) or placebo. Pharmacodynamics were assessed using a multimodal, multitissue paradigm where pain was assessed from skin (heat), muscle (pressure), and viscera (heat and electricity) where the induction of generalized hyperalgesia evoked by perfusion of acid and capsaicin in the esophagus.67 They found that there was a measurable effect of oxycodone, compared with placebo, on all pain measures, and a linear concentration–effect relationship without an effect delay was demonstrated. Olesen and colleagues67 concluded their findings indicate an initial peripheral analgesic effect of oxycodone on cutaneous, muscular, and visceral pain after the induction of hyperalgesia. However, Lalovic and colleagues17 previously studied the pupil diameter and found delay for the measure of central analgesia. Staahl and colleagues49 demonstrated that visceral analgesia of oxycodone was more directly correlated with plasma concentrations than somatic analgesia. Olesen and colleagues67 hypothesized that the peripherally located opioid receptor is the k-opioid receptor (assuming that oxycodone may interact with the k-opioid receptor, as shown in animal studies). Although results from in vitro opioid receptor-binding studies have raised questions about the k-opioid receptorbinding affinity of oxycodone,68 it has been shown that oxycodone interacts, at least in part, with a different population of opioid receptors or modulates m-opioid receptor signaling in inflammation in a way that is subtly different from that of other opioids.26,67,69 More recently, Olesen and colleagues70 conducted an investigation to compare the pharmacokinetic and pharmacodynamic profile of a novel peripherally selective k-opioid agonist, CR665, with oxycodone in a randomized, placebo-controlled, double-blind, 3-way crossover study in healthy volunteers. They found that the oxycodone kinetics were best described by a 1-compartment model with transit compartment absorption feeding directly into the central compartment. For both drugs, the plasma concentration effects on visceral pain tolerance threshold were best fit by a direct linear model, that is, without the concentration–analgesia delay characteristic of brain-penetrant opioids. Olesen and colleagues conclude that their results are consistent with the peripheral selectivity of CR665, as well as the possibility that peripheral actions of oxycodone contribute to its visceral analgesic efficacy.70 Lalovic and colleagues have demonstrated that the time course of central opioid effects of oxycodone can be explained by the pharmacokinetics–pharmacodynamics of the parent drug alone, not its metabolites.17 Klimas and colleagues20 have also demonstrated that oxycodone itself is responsible for the analgesic effect, despite its active metabolites oxymorphone and noroxymorphone having much higher m-receptor affinity than oxycodone. The concentrations of the metabolites at the site of action (central nervous system) are too low. OXYCODONE AND ITS ACTIVE METABOLITES BINDING SITES
Lalovic and colleagues have concluded that significant k-receptor activity is unlikely based on the substantially lower affinity of oxycodone and other metabolites
Revisiting Oxycodone Analgesia
to k-receptor in comparison with the m-receptor.17 Their data clearly demonstrate the m-receptor selectivity of oxycodone and all of its metabolites, as indicated by their nanomolar Ki values for the m-receptor compared with that for the k- and d-opioid receptors, for example, the affinity of noroxymorphone and oxymorphone toward k- and d-receptors was more than 15-fold lower than that at the m-opioid receptor.17 Kalso71 has concluded that oxycodone is a much weaker m-receptor agonist (m-receptor affinity 20 times less and the [35S]GTPgS activity 3–8 times weaker, comparing to that of morphine) and has summarized that oxycodone binding to k-receptor is unsubstantiated. He attributes the observed discrepancy of potency/efficacy of oxycodone versus morphine when given epidurally or spinally versus systemically to the production of active oxycodone metabolites, for example, oxymorphone.71 Khotib and colleagues72 demonstrated that repeated stimulation of k-opioid receptor markedly increased the functional m- and d-opioid receptors, whereas repeated stimulation of either the m- or d-opioid receptor had no direct effect on k-opioidergic function in mice. It is unclear if, in humans, such unique synergy between different types opioid receptor exists to mediate or modulate biologic functions. If so, it may partially explain the need for stimulation of k-receptor not only for k-receptor activation itself, but also for enhanced response of m- and d-receptors, therefore enhancing analgesia. Finally, it seems that the k-receptor activation is unique with oxycodone. Some research work with k-receptor knockout mice has ruled out the participation of k-receptors for analgesia induced by morphine65 and fentanyl.73 A study of human volunteers found that oxycodone significantly blocked visceral pain better than morphine, which has little kappa receptor activity.48 There is no dispute on oxycodone being responsible for its own central opioid effects, not its metabolites. Lalovic and colleagues17 have demonstrated that the time course of central opioid effects of oxycodone can be explained by the pharmacokinetics–pharmacodynamics of the parent drug alone. Although it has been shown that the potent active metabolite noroxymorphone is present at relatively high concentrations in circulation, it does not seem to penetrate the BBB to a significant extent. Other metabolites either demonstrate low potency (noroxycodone and b-noroxycodol) or are present in circulation at very low levels (oxymorphone and a- and b-oxycodol). In addition, all metabolites demonstrate restricted brain penetration as compared with the parent drug.17 Nevertheless, peripheral opioid receptors are readily accessible. At this point, there seems to be no literature that has clearly defined the role played by the active metabolites of oxycodone via peripheral mechanism. Recently, in a mouse model of bone cancer pain, Nakamura and colleagues74 showed that G protein activation induced by a m-opioid receptor agonist was attenuated significantly less (9%–26%) than the effect of morphine (46%–65%) in the periaqueductal gray matter and the region ventral to it, and in mediodorsal thalamus. Furthermore, ICV oxycodone at doses of 0.02 to 1.0 mg per mouse clearly inhibited pain-related behaviors, whereas ICV morphine (0.05–2.0 mg per mouse) had only partial or little analgesic effect on pain-related behavior. Nakamura and colleagues suggest that the modulation of m-opioid receptor function under bone cancer pain seems to be one of the mechanisms underlying the unique analgesic profile of oxycodone, that is, that modification of the m-opioid receptor is responsible for the distinct analgesic effect of oxycodone and morphine.74 Unfortunately, at present, there are too few clinical or even experimental studies that systematically compare the effects of different opioids in different pain models to draw meaningful conclusions on this issue.2 Recent evidence suggests that activation of these peripheral opioid receptors can contribute to analgesia produced by systemic opioid administration.75–77 Jagla and
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colleagues demonstrated that selective blockade of peripheral opioid receptors by methylnaltrexone significantly increased patients’ demand for morphine (about 40%) after knee replacement surgery, implying peripheral opioid analgesia plays a significant role in postoperative overall opioid analgesia. It seems that some newly formulated oxycodone formulation with added peripheral opioid antagonist such as methylnaltrexone or naloxegol would be less likely to affect oxycodone analgesia comparing to that of morphine because of both NNX and naloxegol have high selectivity for m-receptor, sparing k-receptor.78,79 As a matter of fact, both methylnaltrexone and naloxegaol have partial agonist activity at k-receptors and thus can activate k-receptors.78,80 Methadone, a potent and efficacious opioid, has been shown to be dependent on peripheral opioid receptors to mediate or to modulate antinociception in both rat and mouse. He and colleagues81 demonstrated that naloxone methiodide, a peripherally restricted opioid antagonist, when administered subcutaneously, blocked the antinociception of systemically and centrally administered methadone, although it had no effect on blocking antinociception to centrally administered morphine. Further, centrally administered naloxone methiodide blocked the antinociception of centrally administered morphine, but not centrally administered methadone. All of these data strongly support that the peripheral opioid receptors play crucial role in methadone antinociception.81 The finding of He and colleagues81 suggest that the dominance of opioid analgesia by centrally located opioid receptors may not be equally shared by all opioids. Thus, in summary, we theorize that the central antinociceptive effect of oxycodone is primarily via its interaction with the m-opioid receptor, while it engages in peripheral opioid analgesia through the interaction with primarily k-receptors, but also m-receptors, and possibly d-receptors in the peripheral tissue, in a not well-understood interaction. We further hypothesize that the active metabolites of oxycodone, such as oxymorphone and noroxymorphone, may contribute analgesia through interaction with peripheral opioid receptors, primarily k, but also m in the peripheral tissues. Finally, we speculate that peripheral contribution of oxycodone and its active metabolites may be responsible for making up the difference of centrally mediated opioid response, observed in preclinical and clinical studies. REFERENCES
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25. Lemberg KK, Kontinen VK, Siiskonen AO, et al. Antinociception by spinal and systemic oxycodone: why does the route make a difference? In vitro and in vivo studies in rats. Anesthesiology 2006;105:801–12. 26. Nielsen CK, Ross FB, Lotfipour S, et al. Oxycodone and morphine have distinctly different pharmacological profiles: radioligand binding and behavioural studies in two rat models of neuropathic pain. Pain 2007;132:289–300. 27. Smith JR, McSweeney A. Charitable giving: the effectiveness of a revised theory of planned behaviour model in predicting donating intentions and behaviour. J Community Appl Soc Psychol 2007;17:363–86. 28. Feng Y, He X, Yang Y, et al. Current research on opioid receptor function. Curr Drug Targets 2012;13:230. 29. Villemagne PS, Dannals RF, Ravert HT, et al. PET imaging of human cardiac opioid receptors. Eur J Nucl Med Mol Imaging 2002;29:1385–8. 30. Wittert G, Hope P, Pyle D. Tissue distribution of opioid receptor gene expression in the rat. Biochem Biophys Res Commun 1996;218:877–81. 31. Hassan AHS, Ableitner A, Stein C, et al. Inflammation of the rat paw enhances axonal transport of opioid receptors in the sciatic nerve and increases their density in the inflamed tissue. Neuroscience 1993;55:185–95. 32. Stein C, Millan MJ, Shippenberg TS, et al. Peripheral opioid receptors mediating antinociception in inflammation. Evidence for involvement of mu, delta and kappa receptors. J Pharmacol Exp Ther 1989;248:1269–75. 33. Vadivelu N, Mitra S, Hines RL. Peripheral opioid receptor agonists for analgesia: a comprehensive review. J Opioid Manag 2011;7:55–68. 34. Scha¨fer M. Peripheral opioid analgesia: from experimental to clinical studies. Curr Opin Anaesthesiol 1999;12:603–7. 35. Stein C, Machelska H, Scha¨fer M. Peripheral analgesic and antiinflammatory effects of opioids. Z Rheumatol 2001;60:416–24. 36. Sengupta JN, Snider A, Su X, et al. Effects of kappa opioids in the inflamed rat colon. Pain 1999;79:175–85. 37. Holzer P. Pharmacology of opioids and their effects on gastrointestinal function. Am J Gastroenterol Suppl 2014;2:9–16. 38. DeHaven-Hudkins DL, Dolle RE. Peripherally restricted opioid agonists as novel analgesic agents. Curr Pharm Des 2004;10:743–57. 39. Fields HL, Emson PC, Leigh BK, et al. Multiple opiate receptor sites on primary afferent fibres. Nature 1980;284:351–3. 40. Davis MP. Drug management of visceral pain: concepts from basic research. Pain Res Treat 2012;2012:265605. 41. Kapitzke D, Vetter I, Cabot PJ. Endogenous opioid analgesia in peripheral tissues and the clinical implications for pain control. Ther Clin Risk Manag 2005;1:279. 42. Dogra S, Yadav PN. Biased agonism at kappa opioid receptors: implication in pain and mood disorders. Eur J Pharmacol 2015;763:184–90. 43. Pfeiffer A, Brantl V, Herz A, et al. Psychotomimesis mediated by kappa opiate receptors. Science 1986;233:774–6. 44. Roth BL, Baner K, Westkaemper R, et al. Salvinorin A: a potent naturally occurring nonnitrogenous k opioid selective agonist. Proc Natl Acad Sci U S A 2002;99: 11934–9. 45. Burton MB, Gebhart GF. Effects of kappa-opioid receptor agonists on responses to colorectal distension in rats with and without acute colonic inflammation. J Pharmacol Exp Ther 1998;285:707–15.
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46. De Schepper HU, Cremonini F, Park M-I, et al. Opioids and the gut: pharmacology and current clinical experience. Neurogastroenterol Motil 2004;16: 383–94. 47. Rivie`re PJ-M. Peripheral kappa-opioid agonists for visceral pain. Br J Pharmacol 2004;141:1331–4. 48. Staahl C, Christrup LL, Andersen SD, et al. A comparative study of oxycodone and morphine in a multi-modal, tissue-differentiated experimental pain model. Pain 2006;123:28–36. 49. Staahl C, Upton R, Foster DJ, et al. Pharmacokinetic-Pharmacodynamic Modeling of Morphine and Oxycodone Concentrations and Analgesic Effect in a Multimodal Experimental Pain Model. J Clin Pharmacol 2008;48:619–31. 50. Simonin F, Slowe S, Becker JA, et al. Analysis of [3 H] bremazocine binding in single and combinatorial opioid receptor knockout mice. Eur J Pharmacol 2001;414:189–95. 51. Holtman JR, Wala EP. Characterization of the antinociceptive effect of oxycodone in male and female rats. Pharmacol Biochem Behav 2006;83:100–8. 52. Nozaki C, Saitoh A, Kamei J. Characterization of the antinociceptive effects of oxycodone in diabetic mice. Eur J Pharmacol 2006;535:145–51. 53. Nozaki C, Saitoh A, Tamura N, et al. Antinociceptive effect of oxycodone in diabetic mice. Eur J Pharmacol 2005;524:75–9. 54. Ross FB, Smith MT. The intrinsic antinociceptive effects of oxycodone appear to be k-opioid receptor mediated. Pain 1997;73:151–7. 55. Nozaki C, Kamei J. Involvement of m 1-opioid receptor on oxycodone-induced antinociception in diabetic mice. Eur J Pharmacol 2007;560:160–2. 56. Dietis N, Rowbotham DJ, Lambert DG. Opioid receptor subtypes: fact or artifact? Br J Anaesth 2011;107(1):8–18. 57. Gaveriaux-Ruff C. Opiate-induced analgesia: contributions from Mu, Delta and Kappa opioid receptors mouse mutants. Curr Pharm Des 2013;19:7373–81. 58. Sullivan LC, Berg KA, Clarke WP. Dual regulation of d-Opioid receptor function by arachidonic acid metabolites in rat peripheral sensory neurons. J Pharmacol Exp Ther 2015;353:44–51. 59. Chen JJ, Dymshitz J, Vasko MR. Regulation of opioid receptors in rat sensory neurons in culture. Mol Pharmacol 1997;51:666–73. 60. Obara I, Parkitna JR, Korostynski M, et al. Local peripheral opioid effects and expression of opioid genes in the spinal cord and dorsal root ganglia in neuropathic and inflammatory pain. Pain 2009;141:283–91. 61. Rowan MP, Ruparel NB, Patwardhan AM, et al. Peripheral delta opioid receptors require priming for functional competence in vivo. Eur J Pharmacol 2009;602: 283–7. 62. Stein C, Lang LJ. Peripheral mechanisms of opioid analgesia. Curr Opin Pharmacol 2009;9:3–8. 63. Reichert JA, Daughters RS, Rivard R, et al. Peripheral and preemptive opioid antinociception in a mouse visceral pain model. Pain 2001;89:221–7. 64. Ackley MA, Hurley RW, Virnich DE, et al. A cellular mechanism for the antinociceptive effect of a kappa opioid receptor agonist. Pain 2001;91:377–88. 65. Simonin F, Valverde O, Smadja C, et al. Disruption of the k-opioid receptor gene in mice enhances sensitivity to chemical visceral pain, impairs pharmacological actions of the selective k-agonist U-50,488 H and attenuates morphine withdrawal. EMBO J 1998;17:886–97. 66. Smith MT, Wyse BD, Edwards SR, et al. Topical application of a novel oxycodone gel formulation (tocopheryl phosphate mixture) in a rat model of peripheral
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inflammatory pain produces localized pain relief without significant systemic exposure. J Pharm Sci 2015;104(7):2388–96. Olesen AE, Upton R, Foster DJ, et al. A pharmacokinetic and pharmacodynamic study of oral oxycodone in a human experimental pain model of hyperalgesia. Clin Pharmacokinet 2010;49:817–27. Kalso E. Oxycodone. J Pain Symptom Manage 2005;29:47–56. Virk MS, Williams JT. Agonist-specific regulation of m-opioid receptor desensitization and recovery from desensitization. Mol Pharmacol 2008;73:1301–8. Olesen AE, Kristensen K, Staahl C, et al. A population pharmacokinetic and pharmacodynamic study of a peripheral k-opioid receptor agonist CR665 and oxycodone. Clin Pharmacokinet 2013;52:125–37. Kalso E. How different is oxycodone from morphine? Pain 2007;132:227–8. Khotib J, Narita M, Suzuki M, et al. Functional interaction among opioid receptor types: up-regulation of m-and d-opioid receptor functions after repeated stimulation of k-opioid receptors. Neuropharmacology 2004;46:531–40. Larsson MH, Bayati A, Lindstro¨m E, et al. Involvement of k-opioid receptors in visceral nociception in mice. Neurogastroenterol Motil 2008;20:1157–64. Nakamura A, Hasegawa M, Minami K, et al. Differential activation of the m-opioid receptor by oxycodone and morphine in pain-related brain regions in a bone cancer pain model. Br J Pharmacol 2013;168:375–88. Jagla C, Martus P, Stein C. Peripheral opioid receptor blockade increases postoperative morphine demands—A randomized, double-blind, placebo-controlled trial. Pain 2014;155:2056–62. Labuz D, Mousa SA, Scha¨fer M, et al. Relative contribution of peripheral versus central opioid receptors to antinociception. Brain Res 2007;1160:30–8. Weibel R, Reiss D, Karchewski L, et al. Mu opioid receptors on primary afferent nav1. 8 neurons contribute to opiate-induced analgesia: insight from conditional knockout mice. PLoS One 2013;8(9):e74706. Anantharamu T, Sharma S, Gupta AK, et al. Naloxegol: first oral peripherally acting mu opioid receptor antagonists for opioid-induced constipation. J Pharmacol Pharmacother 2015;6:188. Paech M, Sng B, Ng L, et al. Methylnaltrexone to prevent intrathecal morphineinduced pruritus after Caesarean delivery: a multicentre, randomized clinical trial. Br J Anaesth 2015;114(3):469–76. Viscusi ER, Gan TJ, Leslie JB, et al. Peripherally acting mu-opioid receptor antagonists and postoperative ileus: mechanisms of action and clinical applicability. Anesth Analg 2009;108:1811–22. He L, Kim J, Ou C, et al. Methadone antinociception is dependent on peripheral opioid receptors. J Pain 2009;10:369–79.
MD*,
Ken F. Mancuso,
MD,
Alan David Kaye,
MD, PhD
KEYWORDS Oxycodone analgesia Morphine Pharmacology Peripheral opioid analgesia KEY POINTS Oxycodone, a semisynthetic opioid analgesic, is widely used in clinical practice. Oxycodone and morphine seem to be equally effective and equipotent when postoperatively administered intravenous via patient-controlled analgesia and in cancer pain. However, data have provided conflicting results. This article aims to provide an updated review on the basic pharmacology of oxycodone with a special focus on pharmacokinetic/pharmacodynamics properties. The controversy regarding oxycodone-mediated effects for visceral pain via agonism and the possible role of peripheral opioid analgesia are discussed to propose a plausible explanation to the perplexing question of oxycodone analgesia.
INTRODUCTION
Oxycodone, a semisynthetic opioid analgesic, is widely used in clinical practice. Oxycodone was first synthesized from thebaine in Germany in 1917.1 For decades, researchers have been challenged by results of a plethora of research studies in different animal models and in humans, related to oxycodone analgesia.2 Oxycodone and morphine seem to be equally effective and equipotent when postoperatively administered intravenously via patient-controlled analgesia and in patients with cancer pain.3,4 However, morphine has been found to be 10 times more potent than oxycodone when given epidurally after abdominal surgery.5 In rats, with intrathecal administration, morphine has been demonstrated to be 14 times more potent than oxycodone, whereas with subcutaneous and intraperitoneal administration,
External Funding: None. Conflict of Interest: None. Department of Anesthesiology, Louisiana State University Health Science Center, 1542 Tulane Avenue, New Orleans, LA 70112, USA * Corresponding author. E-mail address: [email protected] Anesthesiology Clin - (2017) -–http://dx.doi.org/10.1016/j.anclin.2017.01.022 1932-2275/17/ª 2017 Elsevier Inc. All rights reserved.
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oxycodone has been shown to be 2 to 4 times as potent as morphine.6 Thus, it remains largely unclear as to how these data have provided such conflicting results. This article provides an updated review on the basic pharmacology of oxycodone with a special focus on pharmacokinetic/pharmacodynamics properties. Additionally, a review is provided on the controversy regarding oxycodone-mediated or -modulated effects for visceral pain via k agonism and the possible role or roles of peripheral opioid analgesia are discussed in the present investigation in an attempt to determine a plausible explanation to the perplexing question of oxycodone analgesia. BASIC PHARMACOKINETICS
Oxycodone is relatively well-absorbed after oral administration. Approximately 40% of oxycodone is bound to plasma proteins in vitro, which is similar to the binding of morphine.7 The distribution volume at steady state is 2 to 5 L/kg in adults, which is comparable with that of morphine.2 Passive diffusion, a process whereby drugs or endogenous substances move across the blood–brain barrier (BBB),8 depends on the physicochemical properties of the drug and concentration gradient from blood to brain. Low-molecular-weight, lipid-soluble, and neutral agents may cross the BBB via passive diffusion. The lipid solubility of oxycodone has been found to be similar to that of morphine.9 In sheep and rats, after intravenous administration, the unbound concentration of oxycodone has been found to be 2.5 and 6 times higher in the brain than in the blood,10,11 suggesting an active transport of oxycodone across the BBB. Okura and colleagues12 postulated that oxycodone was transported into the central nervous system by an organic cation transporter in vitro and in vivo. However, how significant a role these transporters may plan in human BBB (assuming they exist) is largely unknown. The cerebral endothelium at the BBB has ATP-dependent efflux pumps, efflux transporters, which prevent brain penetration, as well as intracellular and extracellular distribution of a variety of endogenous and exogenous compounds.13 Morphine has been identified as a substrate of P-glycoprotein14; however, there have been conflicting studies regarding whether oxycodone is a substrate of P-glycoprotein. An early study in rats by Bostro¨m and colleagues15 has suggested that oxycodone is not a substrate of P-glycoprotein, unlike morphine. In contrast, these results were subsequently questioned by Hassan and colleagues,16 who reported that oxycodone was a P-glycoprotein substrate in various in vitro and in vivo models. Further, Hassan and colleagues16 also demonstrated that chronic administration of oxycodone induced overexpression of P-glycoprotein. In this regard, there is no information on the possible role of P-glycoprotein in regulating BBB transport of oxycodone in humans. PHARMACOGENETIC VARIATION OR METABOLITE CONTRIBUTION
The pharmacogenetic and pharmcodynamic properties of oxycodone and its metabolites have been reviewed extensively by Olkkola and colleagues.2 The m-opioid receptor binding affinity of nororoxycodone, the primary metabolite of oxycodone, is 4 times lower than that of oxycodone, and it produces 4 to 6 times lower G protein activation measured in a GTPg[35S] binding assay.17,18 The other primary oxidative metabolite, oxymorphone, has about a 50-fold higher affinity for the m-opioid receptor and can produce 8- to 30-fold higher G protein activation than oxycodone.17–19 The reduction products of oxymorphone, a- and b-oxymorphol, have been shown to be 2 to 3 times more potent than oxycodone17; however, after oral administration of oxycodone in humans, the plasma concentrations of a- and b-oxymorphol are low.17
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The most important secondary metabolite of oxycodone, noroxymorphone, has a 2to 3-fold higher affinity for the m-opioid receptor compared with oxycodone.7,17 The potency of noroxymorphone for m-opioid receptor-mediated G protein activation has been shown to be 3- to 7-fold higher than that of oxycodone.17,18 In a recent review, Klimas and colleagues20 demonstrated that oxycodone itself was responsible for the analgesic effect, despite its active metabolites, oxymorphone and noroxymorphone, possessing much higher m-receptor affinity than oxycodone, because the metabolites concentrations at the site of action, for example, the central nervous system, were too low. Andreassen and colleagues21 have reported in a cross-sectional study of 450 cancer patients genotyped for CYP2D6, which revealed 27 poor metabolizer, 413 extensive metabolizer, and 10 ultra-rapid metabolizer, oxycodone and noroxymorphone plasma concentrations did not differ between these phenotypes. In addition, the daily intake of oxycodone did not differ among patients, whether they were poor metabolizer, extensive metabolizer, or ultrarapid metabolizer (70–80 mg/d). Further, Andreassen and colleagues22 also reported the finding, after a multicenter cross-sectional study of 456 cancer patients, that no relationships were demonstrated between oxycodone or noroxymorphone concentrations and pain intensity, tiredness, nausea, or cognitive function. Oxycodone is primarily metabolized via CYP3A4/3A5 and to a lesser extent via CYP2D6.23 It is believed that CYP2D6 genotypes cause significant differences in pharmacokinetics without producing major pharmacodynamic consequences or clinical implications.23,24 PHARMACODYNAMIC DILEMMA
Oxycodone has been shown to be relatively selective at the m-opioid receptor.2 Depending on the assay properties, the affinity of oxycodone for the m-opioid receptor is 5 to 40 times lower compared with morphine.7,17,19 The potency of oxycodone in the m -opioid receptor-mediated activation of intracellular G proteins measured in the GTPg[35S] binding assay is 4- to 8-fold lower than the activity of morphine.17,19 In a radioligand displacement study, Lalovic and colleagues17 have shown that the m-receptor affinity of oxycodone is only one-fifth that of morphine, whereas its potency in activating GTPgS binding to the m-receptor is about one-third that of morphine. However, other observations have shown conflicting findings, for example, the antinociceptive potency of oxycodone in rodents is equal to that that of morphine6; oxycodone and morphine seem to be equally effective and equipotent when given intravenously for postoperative patient-controlled analgesia and in patients with cancer pain.3,4 In rats, with intrathecal administration, morphine has been shown to be 14 times more potent than oxycodone, whereas with subcutaneous and intraperitoneal administration, oxycodone has been demonstrated to be 2 to 4 times as potent as morphine.6 In a critical review on oxycodone pharmacology, Olkkola and colleagues2 opined, “We have still no explanation for the cerebral accumulation of oxycodone. Whether an active influx transporter explains the discrepancy between poor opioid receptor binding and analgesic efficacy remains to be elucidated. More research is also needed to understand why oxycodone is less effective after spinal than after intravenous administration.” Thus, using current opioid analgesic models, none of the hypotheses is able to provide a clear explanation for the conflicting findings in basic research and clinical practice. The apparent differences were hypothesized to be the result of either the involvement of active metabolites3,25 or the combined actions of oxycodone at the m- and k-opioid receptors.26,27
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Regardless of the underlying mechanism, it might be reasonable to consider, therefore, that there is a peripheral contribution from oxycodone and/or its active metabolites, in part, might be responsible for the observed pharmacologic differences. THE ROLE OF PERIPHERAL OPIOID RECEPTORS IN PERIPHERAL OXYCODONE ANALGESIA
Opioid receptors exist not only in the nervous system,28 but also in peripheral organs, such as the heart, lungs, liver, and gastrointestinal and reproductive tracts.29,30 However, the expression and distribution of these receptors vary significantly among different organs as well as among different animal species.28 Opioid receptors in the periphery can be a site for mediating analgesia.31–33 Peripheral analgesic effects of opioids are enhanced under inflammatory conditions and hyperalgesia.34,35 Inflammation increases the peripherally directed axonal transport of opioid receptors, which leads to upregulation of opioid receptors on peripheral nerve terminals,35 in particular, k-opioid receptors.36 In addition, the number of primary afferent neuron terminals is increased in inflamed tissues.31 Opioid receptors are classified into 3 major groups: m-opioid receptors, d-opioid receptors, and k-opioid receptors. Pharmacologically, the 3 classes of opioid receptors have been subdivided into 3 subtypes of m-opioid receptors, 2 subtypes of d-opioid receptors, and at least 3 subtypes of k-opioid receptors.37 All the receptor subtypes for m, d, and k-receptors have been proposed based on pharmacologic data; to date, there is only 1 known gene product for each subtype, which results in the expression of the functional receptor.38 It has also been demonstrated that characteristics of peripheral opioid receptors are very similar to those in the brain.31,39 Both m-opioid and k-opioid receptors have been found to be expressed in the stomach, duodenum, jejunum, and ileum as well as the proximal and distal colon, where their function is thought to include control of visceral pain, regulation of transit time of luminal contents, and mucosal transport of fluids and electrolytes.40,41 In contrast with m-opioid receptor and d-opioid receptor agonists, k-receptor agonists have long been recognized to be analgesics with no addiction and tolerance liability.42 However, almost all k-receptor agonists cause dysphoria, anhedonia, and hallucinations.43,44 Multiple lines of evidences suggest that the k-receptor modulates overlapping neurocircuits, connecting brainstem monoaminergic nuclei with forebrain limbic structures and thereby regulating the neurobiological effects of stress and psychostimulants. The emerging concept of “biased agonism” (also known as functional selectivity) for G-protein–coupled receptor ligands have provided new insights into overall response generated by a ligand.42 According to this concept, every ligand possesses the unique ability (coded in its structure) that dictates a distinct signaling pattern, and consequently beneficial or adverse response. Thus, the predominant signaling pattern of a G-protein–coupled receptor may differ from cell to cell in various tissues and organs. Finally, the promise of “biased agonism” lies in its ability to produce therapeutically beneficial signals while minimizing adverse effects.42 Peripheral k-opioid receptors in the gut have been suggested as an important feature of the visceral pain system.45–49 The k-receptors are more abundant in peripheral nerves than in central nerves.46 There are 3 subtypes of k-receptors that inhibit afferent firing and visceromotor responses to noxious colorectal distention in animal models.40 Analgesic development programs in the pharmaceutical industry for k1-opioid receptor selective ligands produced highly potent alternative analgesics to morphine in the late 1980s50; however, they failed in the clinical setting related to
Revisiting Oxycodone Analgesia
psychotomimetic side effects. The k2-opioid receptors are described as binding sites typically labeled by the nonselective benzomorphan ligand [3H]bremazocine in the presence of m-, d-, and k1-opioid receptor blocking ligands.50 Simonin and colleagues50 investigated the genetic origin of k2-opioid receptors, using homogenate binding experiments with [3H]bremazocine in brains of single, double, triple knockout mice. They found that no additional gene is required to explain the total population of [3H]bremazocine binding sites. Altogether the data demonstrate that the putative k2-opioid receptors are in fact a mixed population of receptor proteins produced by the 3 known opioid receptor genes.50 Findings in rodent experiments suggest that oxycodone is a partial k-opioid receptor agonist.26,51–54 Nielsen and colleagues26 proposed that oxycodone is a putative k2b agonist. In their study, rats pretreated with intracerebroventricular (ICV) nor-binaltorphimine (k-antagonist) prevented ICV oxycodone but not morphine antinociception. The opposite was shown with naloxonazine (putative m1 antagonist), suggesting an oxycodone analgesic effect mediated or modulated through k-opioid receptor binding.26 Further, Nielsen and colleagues26 demonstrated that, in animals tolerant to intravenous morphine, there is an absence of antinociceptive crosstolerance to ICV oxycodone. These investigators summarized that their findings provide support to the concept that oxycodone and morphine produce antinociception through distinctly different opioid receptor populations, that is, oxycodone seems to act as a k2b opioid agonist with a relatively low affinity for the m-opioid receptor. However, Nozaki and Kamei55 showed that the antinociceptive effect of subcutaneous oxycodone was completely antagonized by pretreatment with naloxonazine in both nondiabetic and diabetic mice. The selective k-opioid receptor antagonist norbinaltorphimine also antagonized oxycodone-induced antinociception in diabetic mice, but only had a partial effect in nondiabetic mice. Nozaki and Kamei55 allude that their findings suggest that, although oxycodone primarily interacts with m1-opioid receptor, k-opioid receptors are also strongly involved in oxycodone-induced antinociception.55 These studies imply a marked difference in the distribution of the putative k2 receptor subtypes and possibly an interaction with m receptors at different sites.56 In a recent review article by Gaveriaux-Ruff,57 entitled, “Opiate-induced analgesia: contributions from m-, d-, and k-opioid receptors mouse mutants,” the author summarized the findings regarding k-opioid receptor knockout mice, “Altogether, these findings indicate that m- and d-receptor proteins are necessary for the activity of k-2 opioid agonists, substantiating the idea that k-d heterodimers may mediate k-2 antinociceptive effects.” The regulation of opioid receptor system function in peripheral sensory neurons is still not well-understood. Opioid agonist efficacy to inhibit nociceptor function and promote antinociception is generally weak under basal conditions and frequently no response occurs.58 However, after injury or inflammation, the functional competence of m-, d-, and k-opioid receptor agonists to elicit antinociception via peripheral opioid receptors is increased markedly.39,59–62 Reichert and colleagues63 found that the intraperitoneal application of low doses of opioids produced antinociception in the writhing model via peripheral mechanisms. The k-opioids in animal models have been shown to reduce inflammation (colitis) nociceptive responses.36,64 The k-receptor gene “knocked-out” mice display increasing writhe to acetic acid peritonitis compared with wild-type mice.65 The k-opioid receptor agonists are particularly effective analgesics in experimental models of visceral pain.47 Their analgesic effects are mediated in the periphery. Smith and colleagues66 investigated the analgesic efficacy and systemic exposure of oxycodone administered topically in a novel tocopheryl phosphate mixture gel
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formulation to the inflamed hindpaws in a rat model of inflammatory pain. Topical application of oxycodone in a novel tocopheryl phosphate mixture gel formulation to the inflamed hindpaws of Freund’s complete adjuvant rats produced marked antihyperalgesia at a dose that produced insignificant systemic exposure to oxycodone or its major metabolite, noroxycodone. Smith and colleagues66 believe their findings suggest that topically applied oxycodone interacts with upregulated opioid receptors expressed on peripheral nerve terminals in inflamed tissue, to produce localized pain relief. Olesen and colleagues67 investigated the pharmacokinetic and pharmacodynamic profiles of oxycodone in a human experimental pain model of hyperalgesia. Twentyfour healthy subjects received oral oxycodone (15 mg) or placebo. Pharmacodynamics were assessed using a multimodal, multitissue paradigm where pain was assessed from skin (heat), muscle (pressure), and viscera (heat and electricity) where the induction of generalized hyperalgesia evoked by perfusion of acid and capsaicin in the esophagus.67 They found that there was a measurable effect of oxycodone, compared with placebo, on all pain measures, and a linear concentration–effect relationship without an effect delay was demonstrated. Olesen and colleagues67 concluded their findings indicate an initial peripheral analgesic effect of oxycodone on cutaneous, muscular, and visceral pain after the induction of hyperalgesia. However, Lalovic and colleagues17 previously studied the pupil diameter and found delay for the measure of central analgesia. Staahl and colleagues49 demonstrated that visceral analgesia of oxycodone was more directly correlated with plasma concentrations than somatic analgesia. Olesen and colleagues67 hypothesized that the peripherally located opioid receptor is the k-opioid receptor (assuming that oxycodone may interact with the k-opioid receptor, as shown in animal studies). Although results from in vitro opioid receptor-binding studies have raised questions about the k-opioid receptorbinding affinity of oxycodone,68 it has been shown that oxycodone interacts, at least in part, with a different population of opioid receptors or modulates m-opioid receptor signaling in inflammation in a way that is subtly different from that of other opioids.26,67,69 More recently, Olesen and colleagues70 conducted an investigation to compare the pharmacokinetic and pharmacodynamic profile of a novel peripherally selective k-opioid agonist, CR665, with oxycodone in a randomized, placebo-controlled, double-blind, 3-way crossover study in healthy volunteers. They found that the oxycodone kinetics were best described by a 1-compartment model with transit compartment absorption feeding directly into the central compartment. For both drugs, the plasma concentration effects on visceral pain tolerance threshold were best fit by a direct linear model, that is, without the concentration–analgesia delay characteristic of brain-penetrant opioids. Olesen and colleagues conclude that their results are consistent with the peripheral selectivity of CR665, as well as the possibility that peripheral actions of oxycodone contribute to its visceral analgesic efficacy.70 Lalovic and colleagues have demonstrated that the time course of central opioid effects of oxycodone can be explained by the pharmacokinetics–pharmacodynamics of the parent drug alone, not its metabolites.17 Klimas and colleagues20 have also demonstrated that oxycodone itself is responsible for the analgesic effect, despite its active metabolites oxymorphone and noroxymorphone having much higher m-receptor affinity than oxycodone. The concentrations of the metabolites at the site of action (central nervous system) are too low. OXYCODONE AND ITS ACTIVE METABOLITES BINDING SITES
Lalovic and colleagues have concluded that significant k-receptor activity is unlikely based on the substantially lower affinity of oxycodone and other metabolites
Revisiting Oxycodone Analgesia
to k-receptor in comparison with the m-receptor.17 Their data clearly demonstrate the m-receptor selectivity of oxycodone and all of its metabolites, as indicated by their nanomolar Ki values for the m-receptor compared with that for the k- and d-opioid receptors, for example, the affinity of noroxymorphone and oxymorphone toward k- and d-receptors was more than 15-fold lower than that at the m-opioid receptor.17 Kalso71 has concluded that oxycodone is a much weaker m-receptor agonist (m-receptor affinity 20 times less and the [35S]GTPgS activity 3–8 times weaker, comparing to that of morphine) and has summarized that oxycodone binding to k-receptor is unsubstantiated. He attributes the observed discrepancy of potency/efficacy of oxycodone versus morphine when given epidurally or spinally versus systemically to the production of active oxycodone metabolites, for example, oxymorphone.71 Khotib and colleagues72 demonstrated that repeated stimulation of k-opioid receptor markedly increased the functional m- and d-opioid receptors, whereas repeated stimulation of either the m- or d-opioid receptor had no direct effect on k-opioidergic function in mice. It is unclear if, in humans, such unique synergy between different types opioid receptor exists to mediate or modulate biologic functions. If so, it may partially explain the need for stimulation of k-receptor not only for k-receptor activation itself, but also for enhanced response of m- and d-receptors, therefore enhancing analgesia. Finally, it seems that the k-receptor activation is unique with oxycodone. Some research work with k-receptor knockout mice has ruled out the participation of k-receptors for analgesia induced by morphine65 and fentanyl.73 A study of human volunteers found that oxycodone significantly blocked visceral pain better than morphine, which has little kappa receptor activity.48 There is no dispute on oxycodone being responsible for its own central opioid effects, not its metabolites. Lalovic and colleagues17 have demonstrated that the time course of central opioid effects of oxycodone can be explained by the pharmacokinetics–pharmacodynamics of the parent drug alone. Although it has been shown that the potent active metabolite noroxymorphone is present at relatively high concentrations in circulation, it does not seem to penetrate the BBB to a significant extent. Other metabolites either demonstrate low potency (noroxycodone and b-noroxycodol) or are present in circulation at very low levels (oxymorphone and a- and b-oxycodol). In addition, all metabolites demonstrate restricted brain penetration as compared with the parent drug.17 Nevertheless, peripheral opioid receptors are readily accessible. At this point, there seems to be no literature that has clearly defined the role played by the active metabolites of oxycodone via peripheral mechanism. Recently, in a mouse model of bone cancer pain, Nakamura and colleagues74 showed that G protein activation induced by a m-opioid receptor agonist was attenuated significantly less (9%–26%) than the effect of morphine (46%–65%) in the periaqueductal gray matter and the region ventral to it, and in mediodorsal thalamus. Furthermore, ICV oxycodone at doses of 0.02 to 1.0 mg per mouse clearly inhibited pain-related behaviors, whereas ICV morphine (0.05–2.0 mg per mouse) had only partial or little analgesic effect on pain-related behavior. Nakamura and colleagues suggest that the modulation of m-opioid receptor function under bone cancer pain seems to be one of the mechanisms underlying the unique analgesic profile of oxycodone, that is, that modification of the m-opioid receptor is responsible for the distinct analgesic effect of oxycodone and morphine.74 Unfortunately, at present, there are too few clinical or even experimental studies that systematically compare the effects of different opioids in different pain models to draw meaningful conclusions on this issue.2 Recent evidence suggests that activation of these peripheral opioid receptors can contribute to analgesia produced by systemic opioid administration.75–77 Jagla and
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colleagues demonstrated that selective blockade of peripheral opioid receptors by methylnaltrexone significantly increased patients’ demand for morphine (about 40%) after knee replacement surgery, implying peripheral opioid analgesia plays a significant role in postoperative overall opioid analgesia. It seems that some newly formulated oxycodone formulation with added peripheral opioid antagonist such as methylnaltrexone or naloxegol would be less likely to affect oxycodone analgesia comparing to that of morphine because of both NNX and naloxegol have high selectivity for m-receptor, sparing k-receptor.78,79 As a matter of fact, both methylnaltrexone and naloxegaol have partial agonist activity at k-receptors and thus can activate k-receptors.78,80 Methadone, a potent and efficacious opioid, has been shown to be dependent on peripheral opioid receptors to mediate or to modulate antinociception in both rat and mouse. He and colleagues81 demonstrated that naloxone methiodide, a peripherally restricted opioid antagonist, when administered subcutaneously, blocked the antinociception of systemically and centrally administered methadone, although it had no effect on blocking antinociception to centrally administered morphine. Further, centrally administered naloxone methiodide blocked the antinociception of centrally administered morphine, but not centrally administered methadone. All of these data strongly support that the peripheral opioid receptors play crucial role in methadone antinociception.81 The finding of He and colleagues81 suggest that the dominance of opioid analgesia by centrally located opioid receptors may not be equally shared by all opioids. Thus, in summary, we theorize that the central antinociceptive effect of oxycodone is primarily via its interaction with the m-opioid receptor, while it engages in peripheral opioid analgesia through the interaction with primarily k-receptors, but also m-receptors, and possibly d-receptors in the peripheral tissue, in a not well-understood interaction. We further hypothesize that the active metabolites of oxycodone, such as oxymorphone and noroxymorphone, may contribute analgesia through interaction with peripheral opioid receptors, primarily k, but also m in the peripheral tissues. Finally, we speculate that peripheral contribution of oxycodone and its active metabolites may be responsible for making up the difference of centrally mediated opioid response, observed in preclinical and clinical studies. REFERENCES
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