Pharmacodynamics +<unk>  (and metabolite) at opioid receptors Compound Affinities () Ratio MOR:DOR:KOR<unk>  18 nM 958 nM 677 nM 1:53:38 Oxymorphone 0.78 nM 50 nM 137 nM 1:64:176 + Equianalgesic doses Compound Route Dose Codeine 200 mg Hydrocodone 20–30 mg Hydromorphone 7.5 mg Hydromorphone 1.5 mg Morphine 30 mg Morphine 10 mg<unk>  20 mg<unk>  10 mg Oxymorphone 10 mg Oxymorphone 1 mg<unk> , a semi-synthetic opioid, is a highly selective full agonist of the μ-opioid receptor (MOR). This is the main biological target of the endogenous opioid neuropeptide β-endorphin.<unk>  has low affinity for the δ-opioid receptor (DOR) and the κ-opioid receptor (KOR), where it is an agonist similarly. After<unk>  binds to the MOR, a G protein-complex is released, which inhibits the release of neurotransmitters by the cell by decreasing the amount of cAMP produced, closing calcium channels, and opening potassium channels. Opioids like<unk>  are thought to produce their analgesic effects via activation of the MOR in the midbrain periaqueductal gray (PAG) and rostral ventromedial medulla (RVM). Conversely, they are thought to produce reward and addiction via activation of the MOR in the mesolimbic reward pathway, including in the ventral tegmental area, nucleus accumbens, and ventral pallidum. Tolerance to the analgesic and rewarding effects of opioids is complex and occurs due to receptor-level tolerance (e.g., MOR downregulation), cellular-level tolerance (e.g., cAMP upregulation), and system-level tolerance (e.g., neural adaptation due to induction of ΔFosB expression). Taken orally, 20 mg of immediate-release<unk>  is considered to be equivalent in analgesic effect to 30 mg of morphine, while extended release<unk>  is considered to be twice as potent as oral morphine. Similarly to most other opioids,<unk>  increases prolactin secretion, but its influence on testosterone levels is unknown. Unlike morphine,<unk>  lacks immunosuppressive activity (measured by natural killer cell activity and interleukin 2 production in vitro); the clinical relevance of this has not been clarified. Active metabolites A few of the metabolites of<unk>  have also been found to be active as MOR agonists, some of which notably have much higher affinity for (as well as higher efficacy at) the MOR in comparison. Oxymorphone possesses 3- to 5-fold higher affinity for the MOR than does<unk> , while noroxycodone and noroxymorphone possess one-third of and 3-fold higher affinity for the MOR, respectively, and MOR activation is 5- to 10-fold less with noroxycodone but 2-fold higher with noroxymorphone relative to<unk> . Noroxycodone, noroxymorphone, and oxymorphone also have longer biological half-lives than<unk> . + Pharmacology of<unk>  and metabolites Compound<unk>  16.0 nM 343 nM 23.2 ± 8.6 ng/mL 236 ± 102 ng/h/mL Oxymorphone 0.36 nM 42.8 nM 0.82 ± 0.85 ng/mL 12.3 ± 12 ng/h/mL Noroxycodone 57.1 nM 1930 nM 15.2 ± 4.5 ng/mL 233 ± 102 ng/h/mL Noroxymorphone 5.69 nM 167 nM However, despite the greater in vitro activity of some of its metabolites, it has been determined that<unk>  itself is responsible for 83.0% and 94.8% of its analgesic effect following oral and intravenous administration, respectively. Oxymorphone plays only a minor role, being responsible for 15.8% and 4.5% of the analgesic effect of<unk>  after oral and intravenous administration, respectively. Although the CYP2D6 genotype and the route of administration result in differential rates of oxymorphone formation, the unchanged parent compound remains the major contributor to the overall analgesic effect of<unk> . In contrast to<unk>  and oxymorphone, noroxycodone and noroxymorphone, while also potent MOR agonists, poorly cross the blood–brain barrier into the central nervous system, and for this reason are only minimally analgesic in comparison. κ-opioid receptor In 1997, a group of Australian researchers proposed (based on a study in rats) that<unk>  acts on KORs, unlike morphine, which acts upon MORs. Further research by this group indicated the drug appears to be a high-affinity κ2b-opioid receptor agonist. However, this conclusion has been disputed, primarily on the basis that<unk>  produces effects that are typical of MOR agonists. In 2006, research by a Japanese group suggested the effect of<unk>  is mediated by different receptors in different situations. Specifically in diabetic mice, the KOR appears to be involved in the antinociceptive effects of<unk> , while in nondiabetic mice, the μ1-opioid receptor seems to be primarily responsible for these effects. Pharmacokinetics Instant-release absorption profile<unk>  can be administered orally, intranasally, via intravenous, intramuscular, or subcutaneous injection, or rectally. The bioavailability of oral administration of<unk>  averages within a range of 60 to 87%, with rectal administration yielding the same results; intranasal varies between individuals with a mean of 46%. After a dose of conventional (immediate-release) oral<unk> , the onset of action is 10 to 30 minutes, and peak plasma levels of the drug are attained within roughly 30 to 60 minutes; in contrast, after a dose of OxyContin (an oral controlled-release formulation), peak plasma levels of<unk>  occur in about three hours. The duration of instant-release<unk>  is 3 to 6 hours, although this can be variable depending on the individual. Distribution<unk>  has a volume of distribution of 2.6L/kg, in the blood it is distributed to skeletal muscle, liver, intestinal tract, lungs, spleen, and brain. At equilibrium the unbound concentration in the brain is threefold higher than the unbound concentration in blood Conventional oral preparations start to reduce pain within 10 to 15 minutes on an empty stomach; in contrast, OxyContin starts to reduce pain within one hour. Metabolism The metabolism of<unk>  in humans occurs in the liver mainly via the cytochrome P450 system and is extensive (about 95%) and complex, with many minor pathways and resulting metabolites. Around 10% (range 8–14%) of a dose of<unk>  is excreted essentially unchanged (unconjugated or conjugated) in the urine. The major metabolites of<unk>  are noroxycodone (70%), noroxymorphone ("relatively high concentrations"), and oxymorphone (5%). The immediate metabolism of<unk>  in humans is as follows: * N-Demethylation to noroxycodone predominantly via CYP3A4 * O-Demethylation to oxymorphone predominantly via CYP2D6 * 6-Ketoreduction to 6α- and 6β-oxycodol * N-Oxidation to<unk> -N-oxide In humans, N-demethylation of<unk>  to noroxycodone by CYP3A4 is the major metabolic pathway, accounting for 45% ± 21% of a dose of<unk> , while O-demethylation of<unk>  into oxymorphone by CYP2D6 and 6-ketoreduction of<unk>  into 6-oxycodols represent relatively minor metabolic pathways, accounting for 11% ± 6% and 8% ± 6% of a dose of<unk> , respectively. Several of the immediate metabolites of<unk>  are subsequently conjugated with glucuronic acid and excreted in the urine. 6α-Oxycodol and 6β-oxycodol are further metabolized by N-demethylation to nor-6α-oxycodol and nor-6β-oxycodol, respectively, and by N-oxidation to 6α-oxycodol-N-oxide and 6β-oxycodol-N-oxide (which can subsequently be glucuronidated as well). Oxymorphone is also further metabolized, as follows: * 3-Glucuronidation to oxymorphone-3-glucuronide predominantly via UGT2B7 * 6-Ketoreduction to 6α-oxymorphol and 6β-oxymorphol * N-Demethylation to noroxymorphone The first pathway of the above three accounts for 40% of the metabolism of oxymorphone, making oxymorphone-3-glucuronide the main metabolite of oxymorphone, while the latter two pathways account for less than 10% of the metabolism of oxymorphone. After N-demethylation of oxymorphone, noroxymorphone is further glucuronidated to noroxymorphone-3-glucuronide. Because<unk>  is metabolized by the cytochrome P450 system in the liver, its pharmacokinetics can be influenced by genetic polymorphisms and drug interactions concerning this system, as well as by liver function. Some people are fast metabolizers of<unk> , while others are slow metabolizers, resulting in polymorphism-dependent alterations in relative analgesia and toxicity. While higher CYP2D6 activity increases the effects of<unk>  (owing to increased conversion into oxymorphone), higher CYP3A4 activity has the opposite effect and decreases the effects of<unk>  (owing to increased metabolism into noroxycodone and noroxymorphone). The dose of<unk>  must be reduced in patients with reduced liver function. Elimination The clearance of<unk>  is 0.8 L/min.<unk>  and its metabolites are mainly excreted in urine. Therefore,<unk>  accumulates in patients with kidney impairment.<unk>  is eliminated in the urine 10% as unchanged<unk> , 45% ± 21% as N-demethylated metabolites (noroxycodone, noroxymorphone, noroxycodols), 11 ± 6% as O-demethylated metabolites (oxymorphone, oxymorphols), and 8% ± 6% as 6-keto-reduced metabolites (oxycodols). Duration of action<unk>  has a half-life of 4.5 hours. It is available as a generic medication. The manufacturer of OxyContin, a controlled-release preparation of<unk> , Purdue Pharma, claimed in their 1992 patent application that the duration of action of OxyContin is 12 hours in "90% of patients." It has never performed any clinical studies in which OxyContin was given at more frequent intervals. In a separate filing, Purdue claims that controlled-release<unk>  "provides pain relief in said patient for at least 12 hours after administration." However, in 2016 an investigation by the Los Angeles Times found that "the drug weans off hours early in many people," inducing symptoms of opiate withdrawal and intense cravings for OxyContin. One doctor, Lawrence Robbins, told journalists that over 70% of his patients would report that OxyContin would only provide 4–7 hours of relief. Doctors in the 1990s often would switch their patients to a dosing schedule of once every eight hours when they complained that the duration of action for OxyContin was too short to be taken only
Oxycodone
Hydrocodone
Codeine
Morphine
Noroxycodone
Norhydrocodone
Tramadol
Piperoxan