The Toxicology of Oxycontin

By Ken Niemann

Oxycodone is a synthetic opiate derivative classified as a Schedule II Controlled Substance and about 59 tons of the drug were consumed in the United States in 2010. Each year, a growing number of deaths occur from semi-synthetic opioids such as oxycodone, hydrocodone, and morphine. This essay will describe the manufacturing process, biochemistry, commercial uses, pharmacokinetics, pharmacodynamics, toxicological properties, and risk assessment data of the pharmaceutical oxycontin.

The National Institute of Drug Abuse cites 207 million opioid prescriptions in the United States in 2013 and estimates that over 2 million Americans are prescription opioid substance abusers (National Institute of Drug Abuse, n.d., Prescription and Over-the-Counter Medications). Opioid deaths have nearly quadrupled from 1.4 to 5.4 per 100,000, from 1999 to 2011 with the greatest increase in the 55-64 age bracket. According to Chen et al., “In 2011, there were 41,340 deaths due to drug poisoning; 41% (16,917 deaths) of them involved opioid analgesics.” and of these 16,917 deaths 70% “involved natural and semisynthetic opioid analgesics such as hydrocodone, morphine, and oxycodone” (Chen L., Hedegaard, H., Warner, M., n.d.) The authors present the numbers graphically:

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Opioid abuse is also thought to increase healthcare costs by $72.5 billion annually (Rinaldo, S., & Rinaldo, D., 2013) and thirty-six states have responded to this crisis by enacting prescription drug monitoring programs (Policy Impact: Prescription Painkiller Overdoses, n.d.). Given the enormity of the human and financial burden of opiate overdose and toxicity, investigations into such are warranted. Here, the focus will remain on the toxicological nature of oxycodone in particular.

First synthesized in 1916 by Freund and Speyer at the University of Frankfurt, oxycodone is a semi-synthetic opiate derivative in use since the World War I era. With a molecular weight of 315.36364 g/mol and chemical formula of C18H21NO4.HCl, oxycodone or (5α)-4,5-Epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one-hydrochloride (CAS number: 124-90-3) is soluble in water to a concentration of 100 mM. The compound has a melting point of 220 degrees Celsius and an estimated pKa of 8.28 (Oxycodone, n.d., PubChem). Its fat solubility is comparable to that of morphine (Kalso, 2005) and the water n-octanol partition coefficient is 0.7 at a pH of 7 (Korjamo, T., Tolonen, A., Ranta, V., Turpeinen, M., & Kokki, H., 2012).

Oxycodone is an alkaloid drug belonging to a class of compounds termed morphinans of which the three ring aromatic phenanthrene molecule is a substructure. Thebaine, an opium derived phenanthrene, is a common precursor to oxycontin (Kalso, 2005). PubChem summarizes the oxidation-reduction manufacturing process: “Thebaine is oxidized with hydrogen peroxide to 14-hydroxycodeinone, which is hydrogenated directly or via its oxime, or its bromination products to oxycodone”. (Oxycodone, n.d., PubChem).

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Opium from cultivated poppy plants only produce 0.3-1.5% thebaine, however, and the compound is highly toxic and does not produce narcotic effects (Thebaine, n.d., PubChem). Therefore, oxycodone synthesis often takes place from morphine, for example, via 12, codeine, 11, codeinone, and 23, 14-hydroxycodeinone intermediates (Wong, 2008). Alternatively, Thodey et al. describe a novel process of baker’s yeast conversion of thebaine into codeine, morphine, hydromorphone, hydrocodone, and oxycodone.   (Thodey, K., Galanie, S., & Smolke, C., 2014). Genes from the opium poppy Papaver somniferum and the bacteria Escherichia coli and Pseudomonas putida are engineered into Saccharomyces cerevisiae giving yields of up to 70 mg/L of oxycodone. The biochemical cascade is pictured below:

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Brand names include OxyContin, Roxicodone, Roxicodone Intensol, OxyIR, Oxanest, and Oxecta and the drug may also present as various mixtures of acetaminophen, aspirin, or ibuprofen. Oxycodone is classified as a Schedule II Controlled Substance and in 2010 about 122.5 tons were produced globally of which the United States accounted for 83 percent (Narcotic Drugs, n.d., Comments on the reported statistics on narcotic drugs). Manufacturers include Actavis Elizabeth, Acura Pharms, Alvogen, Impax Labs, Amneal Pharms, Aurolife Pharma, Avanthi, Teva, Coastal Pharms, Corepharma, Endo Pharms, Impax Pharms, Mallinckrodt, Nesher Pharms, Purdue Pharma, Rhodes Pharms, Roxane, Sun Pharm Inds, Vintage Pharms, and Vistapharm (Oxycodone, n.d., PubChem).

Generally, the drug is used for moderate to severe chronic pain such as that in cancer patients through time released tablets but may also be used for acute pain (Kalso, 2005). Contraindications exist for known hypersensitivity, respiratory depression, hypercapnia, paralytic ileus, and severe or acute asthma The warnings and cautions for the drug are extensive and include concomitant alcohol use or toxicity, convulsive disorders, CNS depression, toxic psychosis, Addison’s Disease, myxedema or hypothyroidism, acute abdominal conditions, head injuries, hypotensive conditions, urethral stricture, and impaired heart, liver, kidney, or pulmonary function (Oxycodone, n.d., FDA).

The routes of administration are intravenous, intramuscular, intranasal, subcutaneously, rectally, epidurally, and orally using immediate release solutions and immediate and controlled-release tablets (Kalso, 2005). Preparations typically come in 5mg, 15mg, or 30mg tablets, 5mg/mL and 20mg/mL oral solutions with 8% alcohol or propylene glycol, or extended release tablets up to 80mg (HSDB: ToxNet, n.d.). The minimum effective dose will vary significantly between patients and with increasing tolerance. For analgesia, a typical prescription is 5 mg every 6 hours p.r.n. for adults. Steady-state plasma concentrations may be reached within 18 hours given a half-life of over three hours and in steady state, the volume of distribution (Vss) is 2.6 L/kg. First pass metabolism of an oral dose allows for up to 87% bioavailability compared to intramuscular injections. (Oxycodone, n.d., FDA). Bioavailibility of oxycodone is significantly higher (60-90%) than the roughly 60% bioavailibility of morphine and increases in cases of liver disease. Exposure is further increased in the elderly and those with kidney disease. In the gut, the efflux pump P-glycoprotein (P-gp) transports the absorbed oxycodone back into the intestine thus decreasing bioavailability Generally, the pump has the same substrates as CYP3A4 which is also present in the gut and degrades the substrates further limiting bioavailibility (Löfdal, K., Andersson, M., & Gustafsson, L., 2013). Post absorbtion, about 45% of oxycodone binds plasma proteins at physiological pH (Kalso, 2005).

Early and inconclusive studies suggested that cytochrome P450 (CYP) 2D6 mediated O-demethylation of oxycodone to oxymorphone accounted for the significant physiological and clinical effects of oxycodone adminsitration (Lalovic, B., Kharasch, E., Hoffer, C., Risler, L., Liuchen, L., & Shen, D., 2006). The conjectures were plausible as a similar bioconversion of codeine to morphine accounted for the analgesic properties of codeine administration. Moreover, oxymorphone has a 2-5 times greater binding affinity to the μ opiate receptor and analgesic effects than morphine. However, other investigators found that the introduction of the CYP2D6 inhibitor quinine (which decreased the oxymorphone area under the curve (AUC) by 50 fold) did not decrease the pain relieving effects of oxycodone (Lalovic et al., 2006). Further, when Lalovic et al. performed in vitro liver microsome studies, they found that metabolism to oxymorphone only accounted for 13% of the dose. These findings lead to reconsidering which metabolite or, perhaps, whether the parent compound, is responsible for the analgesic effects of oxycodone.

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Lalovic et al. then investigated the pharmacokinetics of oxycodone and found a cytochrome P450 (CYP)3A mediated N-demethylation of oxycodone as the primary metabolic pathway. That is, the CYP3A degradation of oxycodone produced noroxycodone, noroxymorphone, and α and β norxycodol which accounted for 45% +/- 21% of the administered dose (Lalovic et al., 2006). Kalso concurred in stating “Oxycodone hydrochloride is extensively metabolized to noroxycodone, oxymorphone, and their glucuronides. The major circulating metabolite is noroxycodone with an AUC ratio of 0.6 relative to that of Oxycodone. Oxymorphone is present in the plasma only in low concentrations” (Kalso, 2005). While noroxycodone is the most abundant metabolite of oxycodone, it has been shown to be a weak pain reliever in rat studies. Noroxycodone, however, is further metabolized to noroxymorphone which displaces tritium labeled enkephalin from μ receptors to a greater extent than oxycodone (Lalovic et al., 2006). Lalovic et al. employed a series of both in vitro and in vivo experiments to determine which of the metabolites or oxycodone itself was responsible for the clinical effects. Initially, the team surmised that, based on receptor binding affinities and G-protein activation, noroxymorphone seemed to be the best candidate to account for the efficacy of the drug. However, it was found that the half-life of noroxymorphone could not account for the duration of clinical effects (i.e. pupil dilation and analgesic effects) and, most importantly, noroxymorphone “has an extremely low brain to plasma portioning” (Lalovic et al., 2006). Lipophilicity (i.e. the water-octanol partition coefficient, LogD) is a key determinant of efficacy. The brain to plasma concentration ratio is about 10 fold higher for oxycodone than for oxymorphone, noroxycodone, and morphine and noroxymorphone is only 1% that of oxycodone (Lalovic et al., 2006). Lalovic’s team attributes this to the comparable in vivo efficacy of morphine and oxycodone. The former has higher binding capacities but less lipophilicity making it perform better in in vitro studies. Further, both N-demethylation and O-demethylation decreases transport into brain tissue. Therefore, it is most likely oxycodone which accounts for the analgesic effects rather than its metabolites (Lalovic et al., 2006).

Elimination of oxycodone and its metabolites takes place through the kidneys and the plasma clearance is about 0.8 L/min (Löfdal, 2013). According to Korjamo et al. only about 10% of un-metabolized oxycodone is excreted in urine. (Korjamo, T., Tolonen, A., Ranta, V., Turpeinen, M., & Kokki, H., 2012). Villesen et al. report that “Drug disposition of both morphine and oxycodone followed a biexpontential decline with an initial rapid distribution phase followed by a slower elimination phase. The corresponding elimination half-life t½ was 2.7 ± 3.6 (range 0.8–11.6) and 3.1 ± 1.3 (range 1.1–4.8) hr for morphine and oxycodone, respectively” (Villesen, H., Banning, A., Petersen, R., Weinelt, S., Poulsen, J., Hansen, S., & Christrup, L., 2007). How polymorphism affects rates of metabolism is a reflection of the pathways described above. For example, variations CYP2D6 genotypes giving rise to poor metabolizers (PM) have little difference in circulating oxycodone given the predominant CYP3A metabolic pathway. However, variations CYP2D6 genotypes giving rise to ultrarapid metabolizers (UM) have decreased concentrations of oxycodone. Conversely, noroxycodone formation is affected by CYP3A polymorphism.

Endogenous and exogenous opiates bind to one of three very widely distributed (i.e. central and peripheral) opiate receptors: Mu (μ), kappa (κ), and delta (δ), abbreviated MOP-r (i.e. mu opioid peptide receptor), KOP-r, and DOP-r respectively. Brunton points out that “each derives from a distinct large precursor protein, prepro-opiomelanocortin, (PMOC), preproenkephalin, and preprodynorphin respectively” (Brunton, L., Chabner, B., Knollman, B., 2011). Oxycodone has agonist effects primarily at MOP-r receptors though it was earlier thought it mainly exerts action at the kappa receptors. Borg et al. observe that “MOP-r are members of the G-protein–coupled 7-transmembrane domain superfamily; they are coupled to Gi and Go proteins, and thus MOP-r agonists typically acutely result in a downstream decrease in adenylate cyclase activity” (Borg, L., Buonora, M., Butelman, E., Ducat, E., Ray, B., & Kreek, M., 2014). Thus, the receptor’s structure “consists of an extracellular N-terminus, seven transmembrane helices, three, extra- and intracellular loops, and an intracellular C-terminus characteristic of the GPCRs” and is pictured as follows (Brunton, L., Chabner, B., Knollman, B., 2011):

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Selectivity is conferred by the loops and transmembrane helices. Ligands such as morphine and oxycodone bind within the core of the transmembrane portion of the protein and larger ligands bind to the loops which “show the greatest structural diversity across receptors” (Brunton, L., Chabner, B., Knollman, B., 2011). Binding of the ligand results in the conversion of GDP to GTP causing conformational changes within the α, β, and γ subunits. Brunton et al. note the outcomes of receptor activation:

  • Inhibition of adenylyl cyclase activity
  • Reduced opening of voltage gated Ca+ channels
  • Stimulation of K+ current through several channels
  • Activation of PKC and PLCβ

The systemic diversity of these receptors, the MOP-r in particular, explains the wide range of clinical and adverse effects of oxycodone. The receptors may found in a host of different tissues including brain, lung, heart, vascular, gut, immune, and other tissues. However, given that most deaths from oxycodone overdose occur from respiratory depression, the focus of the toxicity of the drug will remain here.

Oxycodone will affect each parameter of respiration such as breaths per minute, tidal exchange, minute volume, rhythm & regularity, etc. With the respiratory depressive properties of oxycodone being as potent as they are, the drug must be used with caution in the presence of diseases and conditions such as hypoxia, hypercapnia, asthma, COPD, cor pulmonale, and other cardiorespiratory pathologies. Critically, the ventrolateral medulla, which is the primary site of respiratory rhythm and drive, has MOP-receptors and is very opiate sensitive. This region receives “afferent input reflecting the partial pressure of arterial O2 as measured by chemosensors in the carotid and aortic bodies and CO2 as measured by chemosensors in the brainstem” (Brunton, L., Chabner, B., Knollman, B., 2011). As opiates depress the excitability of chemosensory neurons, normal ventilatory responses to increased levels of CO2 and low levels of O2 then become pathological. Caution in O2 administration, however, is warranted in that the effect of opioids on CO2 chemosensors is predominant. That is, the drive to breathe in response to CO2 levels is markedly depressed while a hypoxic state may still stimulate a drive to breathe. Increasing O2 levels, may remove the drive to breathe even more. Further, the drug has the potential to block airways exacerbating depressed respiration and hypoxia may result in capillary damage causing shock. With or without blood pressure decreases in blood pressure, pulmonary edema may develop (Brunton, L., Chabner, B., Knollman, B., 2011).

Pulmonary edema may be treated with positive pressure respiration. Treatment for oxycodone overdose includes establishing patent airways and the administration of opioid antagonists such as naloxone which is the treatment of choice. Effective treatment entails reversal of respiratory depression while avoiding withdrawal syndrome. 0.4mg of naloxone given intravenously while monitoring respiration and withdrawal is a common approach. Monitoring for a rebound sympathetic response and pulmonary edema is also necessary (Brunton, L., Chabner, B., Knollman, B., 2011).

Purdue Pharma, a manufacturer of oxycodone, lists the following in its MSDS for oxycodone: LD50 Acute Exposures: Oral: 482 mg/kg (mouse) LD50: IP: 250 mg/kg (mouse) LDL: IV: 20 mg/kg (rat). Further, in a 28 day sub-acute trial using a canine model, it was found that “doses of 4, 8, or 20 mg/kg/day were associated with decreased activity, sedation, ataxia, and pale color and slow capillary refill of the oral mucosa. One dog given 20 mg/kg/day did not survive past 3 days of dosing and one animal given 20 mg/kg/day had convulsions”. (Material Safety Data Sheet, Purdue Pharma, n.d.).

Mutagenicity and genotoxicity testing revealed a negative test for bacterial mutagenicity and mouse micronucleus, but weakly positive for human lymphocyte chromosome aberration and positive for mouse lymphoma. For reproductive and developmental toxicity, rats fed 6 mg/kg/day gave birth to low weight pups and the NOAEL for the study was 2 mg/kg/day. However, another study on rats and rabbits demonstrated no effects at 125 mg/kg/day (Material Safety Data Sheet, Purdue Pharma, n.d.).

Oxycodone, therefore, is a toxic pharmaceutical and may cause death due to respiratory depression at doses that vary widely from individual to individual and with age, diseased states, enzymatic genotype, and drug interactions.

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