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Oxycodone

January 27, 2024

For the naturally occurring peptide hormone, see Oxytocin.

Oxycodone, sold under various brand names such as Roxicodone and OxyContin (which is the extended release form), is a semi-synthetic opioid used medically for treatment of moderate to severe pain. It is highly addictive[14] and is a commonly abused drug.[15][16] It is usually taken by mouth, and is available in immediate-release and controlled-release formulations.[15] Onset of pain relief typically begins within fifteen minutes and lasts for up to six hours with the immediate-release formulation.[15] In the United Kingdom, it is available by injection.[17] Combination products are also available with paracetamol (acetaminophen), ibuprofen, naloxone, naltrexone, and aspirin.[15]

Oxycodone
Clinical data
Pronunciationɒksɪˈkəʊdəʊn
Trade namesOxyContin, Endone, others
Other namesEukodal, eucodal; dihydrohydroxycodeinone, 7,8-dihydro-14-hydroxycodeinone, 6-deoxy-7,8-dihydro-14-hydroxy-3-O-methyl-6-oxomorphine[1]
AHFS/Drugs.comMonograph
MedlinePlusa682132
License data
Pregnancy
category
Dependence
liability		High[3]
Addiction
liability		High[4]
Routes of
administration		By mouth, sublingual, intramuscular, intravenous, intranasal, subcutaneous, transdermal, rectal, epidural[5]
Drug classOpioid
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityBy mouth: 60–87%[7][8]
Protein binding45%[7]
MetabolismLiver: mainly CYP3A, and, to a much lesser extent, CYP2D6 (~5%);[7] 95% metabolized (i.e., 5% excreted unchanged)[10]
Metabolites• Noroxycodone (25%)[9][10]
• Noroxymorphone (15%, free and conjugated)[9][10]
• Oxymorphone (11%, conjugated)[9][10]
• Others (e.g., minor metabolites)[10]
Onset of actionIRTooltip Instant release: 10–30 minutes[8][10]
CRTooltip controlled release: 1 hour[11]
Elimination half-lifeBy mouth (IR): 2–3 hrs (same t1/2Tooltip biological half-life for all ROAsTooltip routes of administration)[10][8]
By mouth (CR): 4.5 hrs[12]
Duration of actionBy mouth (IR): 3–6 hrs[10]
By mouth (CR): 10–12 hrs[13]
ExcretionUrine (83%)[7]
Identifiers
  • (5R,9R,13S,14S)-4,5α-Epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one
CAS Number
  • 76-42-6 Y
PubChem CID
  • 5284603
IUPHAR/BPS
  • 7093
DrugBank
  • DB00497 Y
ChemSpider
  • 4447649 Y
UNII
  • CD35PMG570
KEGG
  • D05312 Y
  • as HCl: D00847 Y
ChEBI
  • CHEBI:7852 Y
ChEMBL
  • ChEMBL656 Y
CompTox Dashboard (EPA)
  • DTXSID5023407
ECHA InfoCard100.000.874
Chemical and physical data
FormulaC18H21NO4
Molar mass315.369 g·mol−1
3D model (JSmol)
  • Interactive image
Melting point219 °C (426 °F)
Solubility in water166 (HCl)
  • O=C4[C@@H]5Oc1c2c(ccc1OC)C[C@H]3N(CC[C@]25[C@@]3(O)CC4)C
  • InChI=1S/C18H21NO4/c1-19-8-7-17-14-10-3-4-12(22-2)15(14)23-16(17)11(20)5-6-18(17,21)13(19)9-10/h3-4,13,16,21H,5-9H2,1-2H3/t13-,16+,17+,18-/m1/s1 Y
  • Key:BRUQQQPBMZOVGD-XFKAJCMBSA-N Y
  (verify)

Common side effects include euphoria, constipation, nausea, vomiting, loss of appetite, drowsiness, dizziness, itching, dry mouth, and sweating.[15] Side effects may also include addiction and dependence, substance abuse, irritability, depression or mania, delirium, hallucinations, hypoventilation, gastroparesis, bradycardia, and hypotension.[15] Those allergic to codeine may also be allergic to oxycodone.[15] Use of oxycodone in early pregnancy appears relatively safe.[15] Opioid withdrawal may occur if rapidly stopped from withdrawal.[15] Oxycodone acts by activating the μ-opioid receptor.[18] When taken by mouth, it has roughly 1.5 times the effect of the equivalent amount of morphine.[19]

Oxycodone was originally produced from the opium poppy opiate alkaloid thebaine in 1916. It was first used medically in Germany in 1917.[20] It is on the World Health Organization's List of Essential Medicines.[21] It is available as a generic medication.[15] In 2021, it was the 59th most commonly prescribed medication in the United States, with more than 11 million prescriptions.[22][23] A number of abuse-deterrent formulations are available, such as in combination with naloxone or naltrexone.[16][24]

Medical uses edit

Oxycodone is used for managing moderate to severe acute or chronic pain when other treatments are not sufficient.[15] It may improve quality of life in certain types of pain.[25] Numerous studies have been completed, and the appropriate use of this compound does improve the quality of life of patients with long term chronic pain syndromes.[26][27][28]

Oxycodone is available as a controlled-release tablet, intended to be taken every 12 hours.[29] A 2006 review found that controlled-release oxycodone is comparable to immediate-release oxycodone, morphine, and hydromorphone in management of moderate to severe cancer pain, with fewer side effects than morphine. The author concluded that the controlled-release form is a valid alternative to morphine and a first-line treatment for cancer pain.[29] In 2014, the European Association for Palliative Care recommended oxycodone by mouth as a second-line alternative to morphine by mouth for cancer pain.[30]

In children between 11 and 16, the extended release formulation is FDA approved for the relief of cancer pain, trauma pain, or pain due to major surgery (for those already treated with opioids, who can tolerate at least 20 mg per day of oxycodone) - this provides an alternative to Duragesic (fentanyl), the only other extended-release opioid analgesic approved for children.[31]

Oxycodone, in its extended-release form and/or in combination with naloxone, is sometimes used off-label in the treatment of severe and refractory restless legs syndrome.[32]

Available forms edit

See also: Oxycodone/paracetamol, Oxycodone/aspirin, Oxycodone/ibuprofen, and Oxycodone/naloxone
 
 
Both sides of a single 10mg OxyContin pill.

Oxycodone is available in a variety of formulations for by mouth or under the tongue:[8][33][34][35]

  • Immediate-release oxycodone (OxyFast, OxyIR, OxyNorm, Roxicodone)
  • Controlled-release oxycodone (OxyContin, Xtampza ER) – 10–12 hour duration[13]
  • Oxycodone tamper-resistant (OxyContin OTR)[36]
  • Immediate-release oxycodone with paracetamol (acetaminophen) (Percocet, Endocet, Roxicet, Tylox)
  • Immediate-release oxycodone with aspirin (Endodan, Oxycodan, Percodan, Roxiprin)
  • Immediate-release oxycodone with ibuprofen (Combunox)[37]
  • Controlled-release oxycodone with naloxone (Targin, Targiniq, Targinact)[38] – 10–12 hour duration[13]
  • Controlled-release oxycodone with naltrexone (Troxyca) – 10–12 hour duration[13][39]
 
A liquid solution containing 10mg of oxycodone per 1ml

In the US, oxycodone is only approved for use by mouth, available as tablets and oral solutions. Parenteral formulations of oxycodone (brand name OxyNorm) are also available in other parts of the world, however, and are widely used in the European Union.[40][41][42] In Spain, the Netherlands and the United Kingdom, oxycodone is approved for intravenous (IV) and intramuscular (IM) use. When first introduced in Germany during World War I, both IV and IM administrations of oxycodone were commonly used for postoperative pain management of Central Powers soldiers.[5]

Side effects edit

 
Main side effects of oxycodone[43]
 
Two tablets (10 mg) of oxycodone and safety blisters

Most common side effects of oxycodone include reduced sensitivity to pain, delayed gastric emptying, euphoria, anxiolysis, feelings of relaxation, and respiratory depression.[44] Common side effects of oxycodone include constipation (23%), nausea (23%), vomiting (12%), somnolence (23%), dizziness (13%), itching (13%), dry mouth (6%), and sweating (5%).[44][45] Less common side effects (experienced by less than 5% of patients) include loss of appetite, nervousness, abdominal pain, diarrhea, urinary retention, dyspnea, and hiccups.[46]

Most side effects generally become less intense over time, although issues related to constipation are likely to continue for the duration of use.[47] Chronic use of this compound and associated constipation issues can become very serious, and have been implicated in life-threatening bowel perforations,[48] a number of specific medications including naloxegol[49] have been developed to address opioid induced constipation.

Oxycodone in combination with naloxone in managed-release tablets, has been formulated to both deter abuse and reduce opioid-induced constipation.[50]

Dependence and withdrawal edit

See also: Opioid dependence

The risk of experiencing severe withdrawal symptoms is high if a patient has become physically dependent and discontinues oxycodone abruptly. Medically, when the drug has been taken regularly over an extended period, it is withdrawn gradually rather than abruptly. People who regularly use oxycodone recreationally or at higher than prescribed doses are at even higher risk of severe withdrawal symptoms. The symptoms of oxycodone withdrawal, as with other opioids, may include "anxiety, panic attack, nausea, insomnia, muscle pain, muscle weakness, fevers, and other flu-like symptoms".[51][52]

Withdrawal symptoms have also been reported in newborns whose mothers had been either injecting or orally taking oxycodone during pregnancy.[53]

Hormone levels edit

See also: Opioid § Low sex hormone levels

As with other opioids, chronic use of oxycodone (particularly with higher doses) can often cause concurrent hypogonadism (low sex hormone levels).[54][55]

Overdose edit

In high doses, overdoses, or in some persons not tolerant to opioids, oxycodone can cause shallow breathing, slowed heart rate, cold/clammy skin, pauses in breathing, low blood pressure, constricted pupils, circulatory collapse, respiratory arrest, and death.[46]

In 2011, it was the leading cause of drug-related deaths in the U.S.[56] However, from 2012 onwards, heroin and fentanyl have become more common causes of drug-related deaths.[56]

Oxycodone overdose has also been described to cause spinal cord infarction in high doses and ischemic damage to the brain, due to prolonged hypoxia from suppressed breathing.[57]

Interactions edit

Oxycodone is metabolized by the enzymes CYP3A4 and CYP2D6. Therefore, its clearance can be altered by inhibitors and inducers of these enzymes, increasing and decreasing half-life, respectively.[41] (For lists of CYP3A4 and CYP2D6 inhibitors and inducers, see here and here, respectively.) Natural genetic variation in these enzymes can also influence the clearance of oxycodone, which may be related to the wide inter-individual variability in its half-life and potency.[41]

Ritonavir or lopinavir/ritonavir greatly increase plasma concentrations of oxycodone in healthy human volunteers due to inhibition of CYP3A4 and CYP2D6.[58] Rifampicin greatly reduces plasma concentrations of oxycodone due to strong induction of CYP3A4.[59] There is also a case report of fosphenytoin, a CYP3A4 inducer, dramatically reducing the analgesic effects of oxycodone in a chronic pain patient.[60] Dosage or medication adjustments may be necessary in each case.[58][59][60]

Pharmacology edit

Pharmacodynamics edit

Oxycodone (and metabolite) at opioid receptors
Compound Affinities (KiTooltip Inhibitor constant) Ratio Ref.
MORTooltip μ-Opioid receptor DORTooltip δ-Opioid receptor KORTooltip κ-Opioid receptor MOR:DOR:KOR
Oxycodone 18 nM 958 nM 677 nM 1:53:38 [5]
Oxymorphone 0.78 nM 50 nM 137 nM 1:64:176 [61]

Equianalgesic doses[62][63][64]
Compound Route Dose
Codeine PO 200 mg
Hydrocodone PO 20–30 mg
Hydromorphone PO 7.5 mg
Hydromorphone IV 1.5 mg
Morphine PO 30 mg
Morphine IV 10 mg
Oxycodone PO 20 mg
Oxycodone IV 10 mg
Oxymorphone PO 10 mg
Oxymorphone IV 1 mg

Oxycodone, a semi-synthetic opioid, is a highly selective full agonist of the μ-opioid receptor (MOR).[40][41] This is the main biological target of the endogenous opioid neuropeptide β-endorphin.[18] Oxycodone has low affinity for the δ-opioid receptor (DOR) and the κ-opioid receptor (KOR), where it is an agonist similarly.[40][41] After oxycodone 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.[65] Opioids like oxycodone are thought to produce their analgesic effects via activation of the MOR in the midbrain periaqueductal gray (PAG) and rostral ventromedial medulla (RVM).[66] 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.[67][68] 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).[69]

Taken orally, 20 mg of immediate-release oxycodone is considered to be equivalent in analgesic effect to 30 mg of morphine,[70][71] while extended release oxycodone is considered to be twice as potent as oral morphine.[72]

Similarly to most other opioids, oxycodone increases prolactin secretion, but its influence on testosterone levels is unknown.[40] Unlike morphine, oxycodone lacks immunosuppressive activity (measured by natural killer cell activity and interleukin 2 production in vitro); the clinical relevance of this has not been clarified.[40]

Active metabolites edit

A few of the metabolites of oxycodone 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.[73][74][75] Oxymorphone possesses 3- to 5-fold higher affinity for the MOR than does oxycodone,[10] while noroxycodone and noroxymorphone possess one-third of and 3-fold higher affinity for the MOR, respectively,[10][75] and MOR activation is 5- to 10-fold less with noroxycodone but 2-fold higher with noroxymorphone relative to oxycodone.[76] Noroxycodone, noroxymorphone, and oxymorphone also have longer biological half-lives than oxycodone.[73][77]

Pharmacology of oxycodone and metabolites[44][76]
Compound KiTooltip Inhibitor constant EC50Tooltip Half-maximal effective concentration Cmax AUC
Oxycodone 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 ND ND
Ki is for [3H]diprenorphine displacement. (Note that diprenorphine is a non-selective opioid receptor ligand, so this is not MOR-specific.) EC50 is for hMOR1 GTPyS binding. Cmax and AUC levels are for 20 mg CR oxycodone.

However, despite the greater in vitro activity of some of its metabolites, it has been determined that oxycodone itself is responsible for 83.0% and 94.8% of its analgesic effect following oral and intravenous administration, respectively.[74] Oxymorphone plays only a minor role, being responsible for 15.8% and 4.5% of the analgesic effect of oxycodone after oral and intravenous administration, respectively.[74] 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 oxycodone.[74] In contrast to oxycodone 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.[73][76][74][75]

κ-opioid receptor edit

In 1997, a group of Australian researchers proposed (based on a study in rats) that oxycodone acts on KORs, unlike morphine, which acts upon MORs.[78] Further research by this group indicated the drug appears to be a high-affinity κ2b-opioid receptor agonist.[79] However, this conclusion has been disputed, primarily on the basis that oxycodone produces effects that are typical of MOR agonists.[80] In 2006, research by a Japanese group suggested the effect of oxycodone is mediated by different receptors in different situations.[81] Specifically in diabetic mice, the KOR appears to be involved in the antinociceptive effects of oxycodone, while in nondiabetic mice, the μ1-opioid receptor seems to be primarily responsible for these effects.[81][82]

Pharmacokinetics edit

Instant-release absorption profile edit

Oxycodone can be administered orally, intranasally, via intravenous, intramuscular, or subcutaneous injection, or rectally. The bioavailability of oral administration of oxycodone averages within a range of 60 to 87%, with rectal administration yielding the same results; intranasal varies between individuals with a mean of 46%.[83]

After a dose of conventional (immediate-release) oral oxycodone, the onset of action is 10 to 30 minutes,[10][8] and peak plasma levels of the drug are attained within roughly 30 to 60 minutes;[10][8][73] in contrast, after a dose of OxyContin (an oral controlled-release formulation), peak plasma levels of oxycodone occur in about three hours.[46] The duration of instant-release oxycodone is 3 to 6 hours, although this can be variable depending on the individual.[10]

Distribution edit

Oxycodone has a volume of distribution of 2.6L/kg,[84] in the blood it is distributed to skeletal muscle, liver, intestinal tract, lungs, spleen, and brain.[46] At equilibrium the unbound concentration in the brain is threefold higher than the unbound concentration in blood.[85] 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.[15]

Metabolism edit

The metabolism of oxycodone 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.[10][86] Around 10% (range 8–14%) of a dose of oxycodone is excreted essentially unchanged (unconjugated or conjugated) in the urine.[10] The major metabolites of oxycodone are noroxycodone (70%), noroxymorphone ("relatively high concentrations"),[44] and oxymorphone (5%).[73][76] The immediate metabolism of oxycodone in humans is as follows:[10][12][87]

In humans, N-demethylation of oxycodone to noroxycodone by CYP3A4 is the major metabolic pathway, accounting for 45% ± 21% of a dose of oxycodone, while O-demethylation of oxycodone into oxymorphone by CYP2D6 and 6-ketoreduction of oxycodone into 6-oxycodols represent relatively minor metabolic pathways, accounting for 11% ± 6% and 8% ± 6% of a dose of oxycodone, respectively.[10][40]

Several of the immediate metabolites of oxycodone are subsequently conjugated with glucuronic acid and excreted in the urine.[10] 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).[10][12] Oxymorphone is also further metabolized, as follows:[10][12][87]

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.[87] After N-demethylation of oxymorphone, noroxymorphone is further glucuronidated to noroxymorphone-3-glucuronide.[87]

Because oxycodone 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.[46] Some people are fast metabolizers of oxycodone, while others are slow metabolizers, resulting in polymorphism-dependent alterations in relative analgesia and toxicity.[88][89] While higher CYP2D6 activity increases the effects of oxycodone (owing to increased conversion into oxymorphone), higher CYP3A4 activity has the opposite effect and decreases the effects of oxycodone (owing to increased metabolism into noroxycodone and noroxymorphone).[90] The dose of oxycodone must be reduced in patients with reduced liver function.[91]

Elimination edit

The clearance of oxycodone is 0.8 L/min.[84] Oxycodone and its metabolites are mainly excreted in urine.[92] Therefore, oxycodone accumulates in patients with kidney impairment.[91] Oxycodone is eliminated in the urine 10% as unchanged oxycodone, 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).[92][73]

Duration of action edit

Oxycodone has a half-life of 4.5 hours.[84] It is available as a generic medication.[15] The manufacturer of OxyContin, a controlled-release preparation of oxycodone, 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 oxycodone "provides pain relief in said patient for at least 12 hours after administration".[93] However, in 2016 an investigation by the Los Angeles Times found that "the drug wears 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 twice a day.[93][94]

Purdue strongly discouraged the practice: Purdue's medical director Robert Reder wrote to one doctor in 1995 that "OxyContin has been developed for [12-hour] dosing...I request that you not use a [8-hourly] dosing regimen." Purdue repeatedly released memos to its sales representatives ordering them to remind doctors not to deviate from a 12-hour dosing schedule. One such memo read, "There is no Q8 dosing with OxyContin... [8-hour dosing] needs to be nipped in the bud. NOW!!"[93] The journalists who covered the investigation argued that Purdue Pharma has insisted on a 12-hour duration of action for nearly all patients, despite evidence to the contrary, to protect the reputation of OxyContin as a 12-hour drug and the willingness of health insurance and managed care companies to cover OxyContin despite its high cost relative to generic opiates such as morphine.[93]

Purdue sales representatives were instructed to encourage doctors to write prescriptions for larger 12-hour doses instead of more frequent dosing. An August 1996 memo to Purdue sales representatives in Tennessee entitled "$$$$$$$$$$$$$ It's Bonus Time in the Neighborhood!" reminded the representatives that their commissions would dramatically increase if they were successful in convincing doctors to prescribe larger doses. Los Angeles Times journalists argue using interviews from opioid addiction experts that such high doses of OxyContin spaced 12 hours apart create a combination of agony during opiate withdrawal (lower lows) and a schedule of reinforcement that relieves this agony, fostering addiction.[93]

Chemistry edit

See also: List of opioids

Oxycodone's chemical name is derived from codeine. The chemical structures are very similar, differing only in that

  • Oxycodone has a hydroxy group at carbon-14 (codeine has just a hydrogen in its place)
  • Oxycodone has a 7,8-dihydro feature. Codeine has a double bond between those two carbons; and
  • Oxycodone has a carbonyl group (as in ketones) in place of the hydroxyl group of codeine.

It is also similar to hydrocodone, differing only in that it has a hydroxyl group at carbon-14.[91]

Biosynthesis edit

In terms of biosynthesis, oxycodone has been found naturally in nectar extracts from the orchid family Epipactis helleborine; together along with another opioid: 3-{2-{3-{3-benzyloxypropyl}-3-indol, 7,8-didehydro- 4,5-epoxy-3,6-d-morphinan.[95]

Thodey et al., 2014 introduces a microbial compound manufacturing system for compounds including oxycodone.[96] The Thodey platform produces both natural and semisynthetic opioids including this one.[96] This system uses Saccharomyces cerevisiae with transgenes from Papaver somniferum (the opium poppy) and Pseudomonas putida to turn a thebaine input into other opiates and opioids.[96]

Detection in biological fluids edit

Oxycodone and/or its major metabolites may be measured in blood or urine to monitor for clearance, non-medical use, confirm a diagnosis of poisoning, or assist in a medicolegal death investigation. Many commercial opiate screening tests cross-react appreciably with oxycodone and its metabolites, but chromatographic techniques can easily distinguish oxycodone from other opiates.[97]

History edit

Martin Freund and (Jakob) Edmund Speyer of the University of Frankfurt in Germany published the first synthesis of oxycodone from thebaine in 1916.[98][99] When Freund died, in 1920, Speyer wrote his obituary for the German Chemical Society.[100] Speyer, born to a Jewish family in Frankfurt am Main in 1878, became a victim of the Holocaust. He died on 5 May 1942, the second day of deportations from the Lodz Ghetto; his death was noted in the ghetto's chronicle.[101]

The first clinical use of the drug was documented in 1917, the year after it was first developed.[99][13] It was first introduced to the U.S. market in May 1939. In early 1928, Merck introduced a combination product containing scopolamine, oxycodone, and ephedrine under the German initials for the ingredients SEE, which was later renamed Scophedal (SCOpolamine, ePHEDrine, and eukodAL) in 1942. It was last manufactured in 1987, but can be compounded. This combination is essentially an oxycodone analogue of the morphine-based "twilight sleep", with ephedrine added to reduce circulatory and respiratory effects.[102] The drug became known as the "Miracle Drug of the 1930s" in Continental Europe and elsewhere and it was the Wehrmacht's choice for a battlefield analgesic for a time. The drug was expressly designed to provide what the patent application and package insert referred to as "very deep analgesia and profound and intense euphoria" as well as tranquillisation and anterograde amnesia useful for surgery and battlefield wounding cases. Oxycodone was allegedly chosen over other common opiates for this product because it had been shown to produce less sedation at equianalgesic doses compared to morphine, hydromorphone (Dilaudid), and hydrocodone (Dicodid).[103]

During Operation Himmler, Skophedal was also reportedly injected in massive overdose into the prisoners dressed in Polish Army uniforms in the staged incident on 1 September 1939 which opened the Second World War.[102][104]

The personal notes of Adolf Hitler's physician, Theodor Morell, indicate Hitler received repeated injections of "Eukodal" (oxycodone; produced by Merck) and Scophedal, as well as Dolantin (pethidine) codeine, and morphine less frequently; oxycodone could not be obtained after late January 1945.[105][106]

In the United States, the Controlled Substances Act (CSA) was passed by the United States Congress and signed into law by President Richard Nixon on 27 October 1970.[107] The passing of the CSA resulted in all products containing oxycodone to be classified as a Schedule II controlled substance.[108]

Purdue Pharma, a privately held company based in Stamford, Connecticut, developed the prescription painkiller OxyContin. It was approved by the FDA in 1995 after no long-term studies and no assessment of its addictive capabilities.[109] David Kessler, FDA commissioner at the time, later said of the approval of OxyContin: "No doubt it was a mistake. It was certainly one of the worst medical mistakes, a major mistake."[110] Upon its release in 1995, OxyContin was hailed as a medical breakthrough, a long-lasting narcotic that could help patients with moderate to severe pain. The drug became a blockbuster and has reportedly generated some US$35 billion in revenue for Purdue.[111]

Opioid epidemic edit

See also: Opioid epidemic

Oxycodone, like other opioid analgesics, tends to induce feelings of euphoria, relaxation and reduced anxiety in those who are occasional users.[112] These effects make it one of the most commonly abused pharmaceutical drugs in the United States.[113] The abuse of Oxycodone, as well as related opioids more broadly, is not unique to the United States and is a common drug of abuse globally.[114][115]

United States edit

See also: Opioid epidemic in the United States

Oxycodone is the most widely recreationally used opioid in America. In the United States, more than 12 million people use opioid drugs recreationally.[116] The U.S. Department of Health and Human Services estimates that about 11 million people in the U.S. consume oxycodone in a non-medical way annually.[117]

Opioids were responsible for 49,000 of the 72,000 drug overdose deaths in the U.S. in 2017.[118] In 2007, about 42,800 emergency room visits occurred due to "episodes" involving oxycodone.[119] In 2008, recreational use of oxycodone and hydrocodone was involved in 14,800 deaths. Some of the cases were due to overdoses of the acetaminophen component, resulting in fatal liver damage.[120]

In September 2013, the FDA released new labeling guidelines for long acting and extended release opioids requiring manufacturers to remove moderate pain as indication for use, instead stating the drug is for "pain severe enough to require daily, around-the-clock, long term opioid treatment".[121] The updated labeling will not restrict physicians from prescribing opioids for moderate pain, as needed.[116]

Reformulated OxyContin is causing some recreational users to change to heroin, which is cheaper and easier to obtain.[122]

Lawsuits edit

In October 2017, The New Yorker published a story on Mortimer Sackler and Purdue Pharma regarding their ties to the production and manipulation of the oxycodone markets.[111] The article links Raymond and Arthur Sackler's business practices with the rise of direct pharmaceutical marketing and eventually to the rise of addiction to oxycodone in the United States. The article implies that the Sackler family bears some responsibility for the opioid epidemic in the United States.[123] In 2019, The New York Times ran a piece confirming that Richard Sackler, the son of Raymond Sackler, told company officials in 2008 to "measure our performance by Rx's by strength, giving higher measures to higher strengths".[124] This was verified with documents tied to a lawsuit – which was filed by the Massachusetts attorney general, Maura Healey – claiming that Purdue Pharma and members of the Sackler family knew that high doses of OxyContin over long periods would increase the risk of serious side effects, including addiction.[125] Despite Purdue Pharma's proposal for a US$12 billion settlement of the lawsuit, the attorneys general of 23 states, including Massachusetts, rejected the settlement offer in September 2019.[126]

Australia edit

The non-medical use of oxycodone existed from the early 1970s, but by 2015, 91% of a national sample of injecting drug users in Australia had reported using oxycodone, and 27% had injected it in the last six months.[127]

Canada edit

Opioid-related deaths in Ontario had increased by 242% from 1969 to 2014.[128] By 2009 in Ontario there were more deaths from oxycodone overdoses than from cocaine overdoses.[129] Deaths from opioid pain relievers had increased from 13.7 deaths per million residents in 1991 to 27.2 deaths per million residents in 2004.[130] The non-medical use of oxycodone in Canada became a problem. Areas where oxycodone is most problematic are Atlantic Canada and Ontario, where its non-medical use is prevalent in rural towns, and in many smaller to medium-sized cities.[131] Oxycodone is also widely available across Western Canada, but methamphetamine and heroin are more serious problems in larger cities, while oxycodone is more common in rural towns. Oxycodone is diverted through doctor shopping, prescription forgery, pharmacy theft, and overprescription.[131][132]

The recent formulations of oxycodone, particularly Purdue Pharma's crush-, chew-, injection- and dissolve-resistant OxyNEO[133] which replaced the banned OxyContin product in Canada in early 2012, have led to a decline in the recreational use of this opiate but have increased the recreational use of the more potent drug fentanyl.[134] According to a Canadian Centre on Substance Abuse study quoted in Maclean's magazine, there were at least 655 fentanyl-related deaths in Canada in a five-year period.[135]

In Alberta, the Blood Tribe police claimed that from the fall of 2014 through January 2015, oxycodone pills or a lethal fake variation referred to as Oxy 80s[136] containing fentanyl made in illegal labs by members of organized crime were responsible for ten deaths on the Blood Reserve, which is located southwest of Lethbridge, Alberta.[137] Province-wide, approximately 120 Albertans died from fentanyl-related overdoses in 2014.[136]

United Kingdom edit

Prescriptions of Oxycodone rose in Scotland by 430% between 2002 and 2008, prompting fears of usage problems that would mirror those of the United States.[138] The first known death due to overdose in the UK occurred in 2002.[139]

Preventive measures edit

In August 2010, Purdue Pharma reformulated their long-acting oxycodone line, marketed as OxyContin, using a polymer, Intac,[140] to make the pills more difficult to crush or dissolve in water[141] to reduce non-medical use of OxyContin.[142] The FDA approved relabeling the reformulated version as abuse-resistant in April 2013.[143]

Pfizer manufactures a preparation of short-acting oxycodone, marketed as Oxecta, which contains inactive ingredients, referred to as tamper-resistant Aversion Technology.[144] Approved by the FDA in the U.S. in June 2011, the new formulation, while not being able to deter oral recreational use, makes crushing, chewing, snorting, or injecting the opioid impractical because of a change in its chemical properties.[145]

Legal status edit

Oxycodone is subject to international conventions on narcotic drugs. In addition, oxycodone is subject to national laws that differ by country. The 1931 Convention for Limiting the Manufacture and Regulating the Distribution of Narcotic Drugs of the League of Nations included oxycodone.[146] The 1961 Single Convention on Narcotic Drugs of the United Nations, which replaced the 1931 convention, categorized oxycodone in Schedule I.[147] Global restrictions on Schedule I drugs include "limit[ing] exclusively to medical and scientific purposes the production, manufacture, export, import, distribution of, trade in, use and possession of" these drugs; "requir[ing] medical prescriptions for the supply or dispensation of [these] drugs to individuals"; and "prevent[ing] the accumulation" of quantities of these drugs "in excess of those required for the normal conduct of business".[147]

Australia edit

Oxycodone is in Schedule I (derived from the Single Convention on Narcotic Drugs) of the Commonwealth's Narcotic Drugs Act 1967.[148] In addition, it is in Schedule 8 of the Australian Standard for the Uniform Scheduling of Drugs and Poisons ("Poisons Standard"), meaning it is a "controlled drug... which should be available for use but require[s] restriction of manufacture, supply, distribution, possession and use to reduce abuse, misuse and physical or psychological dependence".[149]

Canada edit

Oxycodone is a controlled substance under Schedule I of the Controlled Drugs and Substances Act (CDSA).[150]

 
Canadian oxycodone HCL/acetaminophen 5/325 mg tablet

In February 2012, Ontario passed legislation to allow the expansion of an already existing drug-tracking system for publicly funded drugs to include those that are privately insured. This database will function to identify and monitor patient's attempts to seek prescriptions from multiple doctors or retrieve them from multiple pharmacies. Other provinces have proposed similar legislation, while some, such as Nova Scotia, have legislation already in effect for monitoring prescription drug use. These changes have coincided with other changes in Ontario's legislation to target the misuse of painkillers and high addiction rates to drugs such as oxycodone. As of 29 February 2012, Ontario passed legislation delisting oxycodone from the province's public drug benefit program. This was a first for any province to delist a drug based on addictive properties. The new law prohibits prescriptions for OxyNeo except to certain patients under the Exceptional Access Program including palliative care and in other extenuating circumstances. Patients already prescribed oxycodone will receive coverage for an additional year for OxyNeo, and after that, it will be disallowed unless designated under the exceptional access program.[151]

Much of the legislative activity has stemmed from Purdue Pharma's decision in 2011 to begin a modification of Oxycontin's composition to make it more difficult to crush for snorting or injecting. The new formulation, OxyNeo, is intended to be preventive in this regard and retain its effectiveness as a painkiller. Since introducing its Narcotics Safety and Awareness Act, Ontario has committed to focusing on drug addiction, particularly in the monitoring and identification of problem opioid prescriptions, as well as the education of patients, doctors, and pharmacists.[152] This Act, introduced in 2010, commits to the establishment of a unified database to fulfil this intention.[153] Both the public and medical community have received the legislation positively, though concerns about the ramifications of legal changes have been expressed. Because laws are largely provincially regulated, many speculate a national strategy is needed to prevent smuggling across provincial borders from jurisdictions with looser restrictions.[154]

In 2015, Purdue Pharma's abuse-resistant OxyNEO and six generic versions of OxyContin had been on the Canada-wide approved list for prescriptions since 2012. In June 2015, then federal Minister of Health Rona Ambrose announced that within three years all oxycodone products sold in Canada would need to be tamper-resistant. Some experts warned that the generic product manufacturers may not have the technology to achieve that goal, possibly giving Purdue Pharma a monopoly on this opiate.[155]

Several class-action suits across Canada have been launched against the Purdue group of companies and affiliates. Claimants argue the pharmaceutical manufacturers did not meet a standard of care and were negligent in doing so. These lawsuits reference earlier judgments in the United States, which held that Purdue was liable for wrongful marketing practices and misbranding. Since 2007, the Purdue companies have paid over CAN$650 million in settling litigation or facing criminal fines.

Germany edit

The drug is in Appendix III of the Narcotics Act (Betäubungsmittelgesetz or BtMG).[156] The law allows only physicians, dentists, and veterinarians to prescribe oxycodone and the federal government to regulate the prescriptions (e.g., by requiring reporting).[156]

Hong Kong edit

Oxycodone is regulated under Part I of Schedule 1 of Hong Kong's Chapter 134 Dangerous Drugs Ordinance.[157]

Japan edit

Oxycodone is a restricted drug in Japan. Its import and export are strictly restricted to specially designated organizations having a prior permit to import it. In a high-profile case an American who was a top Toyota executive living in Tokyo, who claimed to be unaware of the law, was arrested for importing oxycodone into Japan.[158][159]

Singapore edit

Oxycodone is listed as a Class A drug in the Misuse of Drugs Act of Singapore, which means offences concerning the drug attract the most severe level of punishment. A conviction for unauthorized manufacture of the drug attracts a minimum sentence of 10 years of imprisonment and corporal punishment of 5 strokes of the cane, and a maximum sentence of life imprisonment or 30 years of imprisonment and 15 strokes of the cane.[160] The minimum and maximum penalties for unauthorized trafficking in the drug are respectively 5 years of imprisonment and 5 strokes of the cane, and 20 years of imprisonment and 15 strokes of the cane.[161]

United Kingdom edit

Oxycodone is a Class A drug under the Misuse of Drugs Act 1971.[162] For Class A drugs, which are "considered to be the most likely to cause harm", possession without a prescription is punishable by up to seven years in prison, an unlimited fine, or both.[163] Dealing of the drug illegally is punishable by up to life imprisonment, an unlimited fine, or both.[163] Oxycodone is a Schedule 2 drug per the Misuse of Drugs Regulations 2001 which "provide certain exemptions from the provisions of the Misuse of Drugs Act 1971".[164]

United States edit

Under the Controlled Substances Act, oxycodone is a Schedule II controlled substance whether by itself or part of a multi-ingredient medication.[165] The DEA lists oxycodone both for sale and for use in manufacturing other opioids as ACSCN 9143 and in 2013 approved the following annual aggregate manufacturing quotas: 131.5 metric tons for sale, down from 153.75 in 2012, and 10.25 metric tons for conversion, unchanged from the previous year.[166] In 2020, oxycodone possession was decriminalized in the U.S. state of Oregon.[167]

Economics edit

The International Narcotics Control Board estimated 11.5 short tons (10.4 t) of oxycodone were manufactured worldwide in 1998;[168] by 2007 this figure had grown to 75.2 short tons (68.2 t).[168] United States accounted for 82% of consumption in 2007 at 51.6 short tons (46.8 t). Canada, Germany, Australia, and France combined accounted for 13% of consumption in 2007.[168][169] In 2010, 1.3 short tons (1.2 t) of oxycodone were illegally manufactured using a fake pill imprint. This accounted for 0.8% of consumption. These illicit tablets were later seized by the U.S. Drug Enforcement Administration, according to the International Narcotics Control Board.[170] The board also reported 122.5 short tons (111.1 t) manufactured in 2010. This number had decreased from a record high of 135.9 short tons (123.3 t) in 2009.[171]

Names edit

Expanded expressions for the compound oxycodone in the academic literature include "dihydrohydroxycodeinone",[1][172][173] "Eucodal",[172][173] "Eukodal",[5][13] "14-hydroxydihydrocodeinone",[1][172] and "Nucodan".[172][173] In a UNESCO convention, the translations of "oxycodone" are oxycodon (Dutch), oxycodone (French), oxicodona (Spanish), الأوكسيكودون‎ (Arabic), 羟考酮 (Chinese), and оксикодон (Russian).[174]

The word "oxycodone" should not be confused with "oxandrolone", "oxazepam", "oxybutynin", "oxytocin", or "Roxanol".[175]

Other brand names include Longtec and Shortec.[176]

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Further reading edit

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January 27, 2024
oxycodone, naturally, occurring, peptide, hormone, oxytocin, sold, under, various, brand, names, such, roxicodone, oxycontin, which, extended, release, form, semi, synthetic, opioid, used, medically, treatment, moderate, severe, pain, highly, addictive, common. For the naturally occurring peptide hormone see Oxytocin Oxycodone sold under various brand names such as Roxicodone and OxyContin which is the extended release form is a semi synthetic opioid used medically for treatment of moderate to severe pain It is highly addictive 14 and is a commonly abused drug 15 16 It is usually taken by mouth and is available in immediate release and controlled release formulations 15 Onset of pain relief typically begins within fifteen minutes and lasts for up to six hours with the immediate release formulation 15 In the United Kingdom it is available by injection 17 Combination products are also available with paracetamol acetaminophen ibuprofen naloxone naltrexone and aspirin 15 OxycodoneClinical dataPronunciationɒksɪˈkeʊdeʊnTrade namesOxyContin Endone othersOther namesEukodal eucodal dihydrohydroxycodeinone 7 8 dihydro 14 hydroxycodeinone 6 deoxy 7 8 dihydro 14 hydroxy 3 O methyl 6 oxomorphine 1 AHFS Drugs comMonographMedlinePlusa682132License dataUS DailyMed OxycodonePregnancycategoryAU C 2 DependenceliabilityHigh 3 AddictionliabilityHigh 4 Routes ofadministrationBy mouth sublingual intramuscular intravenous intranasal subcutaneous transdermal rectal epidural 5 Drug classOpioidATC codeN02AA05 WHO N02AA55 WHO N02AJ18 WHO N02AJ19 WHO N02AA56 WHO N02AJ17 WHO Legal statusLegal statusAU S8 Controlled drug BR Class A1 Narcotic drugs CA Schedule I DE Anlage III Special prescription form required UK Class A US WARNING 6 Schedule II UN Narcotic Schedule IPharmacokinetic dataBioavailabilityBy mouth 60 87 7 8 Protein binding45 7 MetabolismLiver mainly CYP3A and to a much lesser extent CYP2D6 5 7 95 metabolized i e 5 excreted unchanged 10 Metabolites Noroxycodone 25 9 10 Noroxymorphone 15 free and conjugated 9 10 Oxymorphone 11 conjugated 9 10 Others e g minor metabolites 10 Onset of actionIRTooltip Instant release 10 30 minutes 8 10 CRTooltip controlled release 1 hour 11 Elimination half lifeBy mouth IR 2 3 hrs same t1 2Tooltip biological half life for all ROAsTooltip routes of administration 10 8 By mouth CR 4 5 hrs 12 Duration of actionBy mouth IR 3 6 hrs 10 By mouth CR 10 12 hrs 13 ExcretionUrine 83 7 IdentifiersIUPAC name 5R 9R 13S 14S 4 5a Epoxy 14 hydroxy 3 methoxy 17 methylmorphinan 6 oneCAS Number76 42 6 YPubChem CID5284603IUPHAR BPS7093DrugBankDB00497 YChemSpider4447649 YUNIICD35PMG570KEGGD05312 Yas HCl D00847 YChEBICHEBI 7852 YChEMBLChEMBL656 YCompTox Dashboard EPA DTXSID5023407ECHA InfoCard100 000 874Chemical and physical dataFormulaC 18H 21N O 4Molar mass315 369 g mol 13D model JSmol Interactive imageMelting point219 C 426 F Solubility in water166 HCl SMILES O C4 C H 5Oc1c2c ccc1OC C C H 3N CC C 25 C 3 O CC4 CInChI InChI 1S C18H21NO4 c1 19 8 7 17 14 10 3 4 12 22 2 15 14 23 16 17 11 20 5 6 18 17 21 13 19 9 10 h3 4 13 16 21H 5 9H2 1 2H3 t13 16 17 18 m1 s1 YKey BRUQQQPBMZOVGD XFKAJCMBSA N Y verify Common side effects include euphoria constipation nausea vomiting loss of appetite drowsiness dizziness itching dry mouth and sweating 15 Side effects may also include addiction and dependence substance abuse irritability depression or mania delirium hallucinations hypoventilation gastroparesis bradycardia and hypotension 15 Those allergic to codeine may also be allergic to oxycodone 15 Use of oxycodone in early pregnancy appears relatively safe 15 Opioid withdrawal may occur if rapidly stopped from withdrawal 15 Oxycodone acts by activating the m opioid receptor 18 When taken by mouth it has roughly 1 5 times the effect of the equivalent amount of morphine 19 Oxycodone was originally produced from the opium poppy opiate alkaloid thebaine in 1916 It was first used medically in Germany in 1917 20 It is on the World Health Organization s List of Essential Medicines 21 It is available as a generic medication 15 In 2021 it was the 59th most commonly prescribed medication in the United States with more than 11 million prescriptions 22 23 A number of abuse deterrent formulations are available such as in combination with naloxone or naltrexone 16 24 Contents 1 Medical uses 1 1 Available forms 2 Side effects 2 1 Dependence and withdrawal 2 2 Hormone levels 3 Overdose 4 Interactions 5 Pharmacology 5 1 Pharmacodynamics 5 1 1 Active metabolites 5 1 2 k opioid receptor 5 2 Pharmacokinetics 5 2 1 Instant release absorption profile 5 2 2 Distribution 5 2 3 Metabolism 5 2 4 Elimination 5 2 5 Duration of action 6 Chemistry 6 1 Biosynthesis 6 2 Detection in biological fluids 7 History 8 Opioid epidemic 8 1 United States 8 1 1 Lawsuits 8 2 Australia 8 3 Canada 8 4 United Kingdom 8 5 Preventive measures 9 Legal status 9 1 Australia 9 2 Canada 9 3 Germany 9 4 Hong Kong 9 5 Japan 9 6 Singapore 9 7 United Kingdom 9 8 United States 10 Economics 11 Names 12 References 13 Further readingMedical uses editOxycodone is used for managing moderate to severe acute or chronic pain when other treatments are not sufficient 15 It may improve quality of life in certain types of pain 25 Numerous studies have been completed and the appropriate use of this compound does improve the quality of life of patients with long term chronic pain syndromes 26 27 28 Oxycodone is available as a controlled release tablet intended to be taken every 12 hours 29 A 2006 review found that controlled release oxycodone is comparable to immediate release oxycodone morphine and hydromorphone in management of moderate to severe cancer pain with fewer side effects than morphine The author concluded that the controlled release form is a valid alternative to morphine and a first line treatment for cancer pain 29 In 2014 the European Association for Palliative Care recommended oxycodone by mouth as a second line alternative to morphine by mouth for cancer pain 30 In children between 11 and 16 the extended release formulation is FDA approved for the relief of cancer pain trauma pain or pain due to major surgery for those already treated with opioids who can tolerate at least 20 mg per day of oxycodone this provides an alternative to Duragesic fentanyl the only other extended release opioid analgesic approved for children 31 Oxycodone in its extended release form and or in combination with naloxone is sometimes used off label in the treatment of severe and refractory restless legs syndrome 32 Available forms edit See also Oxycodone paracetamol Oxycodone aspirin Oxycodone ibuprofen and Oxycodone naloxone nbsp nbsp Both sides of a single 10mg OxyContin pill Oxycodone is available in a variety of formulations for by mouth or under the tongue 8 33 34 35 Immediate release oxycodone OxyFast OxyIR OxyNorm Roxicodone Controlled release oxycodone OxyContin Xtampza ER 10 12 hour duration 13 Oxycodone tamper resistant OxyContin OTR 36 Immediate release oxycodone with paracetamol acetaminophen Percocet Endocet Roxicet Tylox Immediate release oxycodone with aspirin Endodan Oxycodan Percodan Roxiprin Immediate release oxycodone with ibuprofen Combunox 37 Controlled release oxycodone with naloxone Targin Targiniq Targinact 38 10 12 hour duration 13 Controlled release oxycodone with naltrexone Troxyca 10 12 hour duration 13 39 nbsp A liquid solution containing 10mg of oxycodone per 1mlIn the US oxycodone is only approved for use by mouth available as tablets and oral solutions Parenteral formulations of oxycodone brand name OxyNorm are also available in other parts of the world however and are widely used in the European Union 40 41 42 In Spain the Netherlands and the United Kingdom oxycodone is approved for intravenous IV and intramuscular IM use When first introduced in Germany during World War I both IV and IM administrations of oxycodone were commonly used for postoperative pain management of Central Powers soldiers 5 Side effects edit nbsp Main side effects of oxycodone 43 nbsp Two tablets 10 mg of oxycodone and safety blistersMost common side effects of oxycodone include reduced sensitivity to pain delayed gastric emptying euphoria anxiolysis feelings of relaxation and respiratory depression 44 Common side effects of oxycodone include constipation 23 nausea 23 vomiting 12 somnolence 23 dizziness 13 itching 13 dry mouth 6 and sweating 5 44 45 Less common side effects experienced by less than 5 of patients include loss of appetite nervousness abdominal pain diarrhea urinary retention dyspnea and hiccups 46 Most side effects generally become less intense over time although issues related to constipation are likely to continue for the duration of use 47 Chronic use of this compound and associated constipation issues can become very serious and have been implicated in life threatening bowel perforations 48 a number of specific medications including naloxegol 49 have been developed to address opioid induced constipation Oxycodone in combination with naloxone in managed release tablets has been formulated to both deter abuse and reduce opioid induced constipation 50 Dependence and withdrawal edit See also Opioid dependence The risk of experiencing severe withdrawal symptoms is high if a patient has become physically dependent and discontinues oxycodone abruptly Medically when the drug has been taken regularly over an extended period it is withdrawn gradually rather than abruptly People who regularly use oxycodone recreationally or at higher than prescribed doses are at even higher risk of severe withdrawal symptoms The symptoms of oxycodone withdrawal as with other opioids may include anxiety panic attack nausea insomnia muscle pain muscle weakness fevers and other flu like symptoms 51 52 Withdrawal symptoms have also been reported in newborns whose mothers had been either injecting or orally taking oxycodone during pregnancy 53 Hormone levels edit See also Opioid Low sex hormone levels As with other opioids chronic use of oxycodone particularly with higher doses can often cause concurrent hypogonadism low sex hormone levels 54 55 Overdose editIn high doses overdoses or in some persons not tolerant to opioids oxycodone can cause shallow breathing slowed heart rate cold clammy skin pauses in breathing low blood pressure constricted pupils circulatory collapse respiratory arrest and death 46 In 2011 it was the leading cause of drug related deaths in the U S 56 However from 2012 onwards heroin and fentanyl have become more common causes of drug related deaths 56 Oxycodone overdose has also been described to cause spinal cord infarction in high doses and ischemic damage to the brain due to prolonged hypoxia from suppressed breathing 57 Interactions editOxycodone is metabolized by the enzymes CYP3A4 and CYP2D6 Therefore its clearance can be altered by inhibitors and inducers of these enzymes increasing and decreasing half life respectively 41 For lists of CYP3A4 and CYP2D6 inhibitors and inducers see here and here respectively Natural genetic variation in these enzymes can also influence the clearance of oxycodone which may be related to the wide inter individual variability in its half life and potency 41 Ritonavir or lopinavir ritonavir greatly increase plasma concentrations of oxycodone in healthy human volunteers due to inhibition of CYP3A4 and CYP2D6 58 Rifampicin greatly reduces plasma concentrations of oxycodone due to strong induction of CYP3A4 59 There is also a case report of fosphenytoin a CYP3A4 inducer dramatically reducing the analgesic effects of oxycodone in a chronic pain patient 60 Dosage or medication adjustments may be necessary in each case 58 59 60 Pharmacology editThis section s equianalgesic table appears to contradict the article Equianalgesic Please discuss at the talk page and do not remove this message until the contradictions are resolved October 2023 Pharmacodynamics edit Oxycodone and metabolite at opioid receptors Compound Affinities KiTooltip Inhibitor constant Ratio Ref MORTooltip m Opioid receptor DORTooltip d Opioid receptor KORTooltip k Opioid receptor MOR DOR KOROxycodone 18 nM 958 nM 677 nM 1 53 38 5 Oxymorphone 0 78 nM 50 nM 137 nM 1 64 176 61 Equianalgesic doses 62 63 64 Compound Route DoseCodeine PO 200 mgHydrocodone PO 20 30 mgHydromorphone PO 7 5 mgHydromorphone IV 1 5 mgMorphine PO 30 mgMorphine IV 10 mgOxycodone PO 20 mgOxycodone IV 10 mgOxymorphone PO 10 mgOxymorphone IV 1 mgOxycodone a semi synthetic opioid is a highly selective full agonist of the m opioid receptor MOR 40 41 This is the main biological target of the endogenous opioid neuropeptide b endorphin 18 Oxycodone has low affinity for the d opioid receptor DOR and the k opioid receptor KOR where it is an agonist similarly 40 41 After oxycodone 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 65 Opioids like oxycodone are thought to produce their analgesic effects via activation of the MOR in the midbrain periaqueductal gray PAG and rostral ventromedial medulla RVM 66 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 67 68 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 DFosB expression 69 Taken orally 20 mg of immediate release oxycodone is considered to be equivalent in analgesic effect to 30 mg of morphine 70 71 while extended release oxycodone is considered to be twice as potent as oral morphine 72 Similarly to most other opioids oxycodone increases prolactin secretion but its influence on testosterone levels is unknown 40 Unlike morphine oxycodone lacks immunosuppressive activity measured by natural killer cell activity and interleukin 2 production in vitro the clinical relevance of this has not been clarified 40 Active metabolites edit A few of the metabolites of oxycodone 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 73 74 75 Oxymorphone possesses 3 to 5 fold higher affinity for the MOR than does oxycodone 10 while noroxycodone and noroxymorphone possess one third of and 3 fold higher affinity for the MOR respectively 10 75 and MOR activation is 5 to 10 fold less with noroxycodone but 2 fold higher with noroxymorphone relative to oxycodone 76 Noroxycodone noroxymorphone and oxymorphone also have longer biological half lives than oxycodone 73 77 Pharmacology of oxycodone and metabolites 44 76 Compound KiTooltip Inhibitor constant EC50Tooltip Half maximal effective concentration Cmax AUCOxycodone 16 0 nM 343 nM 23 2 8 6 ng mL 236 102 ng h mLOxymorphone 0 36 nM 42 8 nM 0 82 0 85 ng mL 12 3 12 ng h mLNoroxycodone 57 1 nM 1930 nM 15 2 4 5 ng mL 233 102 ng h mLNoroxymorphone 5 69 nM 167 nM ND NDKi is for 3H diprenorphine displacement Note that diprenorphine is a non selective opioid receptor ligand so this is not MOR specific EC50 is for hMOR1 GTPyS binding Cmax and AUC levels are for 20 mg CR oxycodone However despite the greater in vitro activity of some of its metabolites it has been determined that oxycodone itself is responsible for 83 0 and 94 8 of its analgesic effect following oral and intravenous administration respectively 74 Oxymorphone plays only a minor role being responsible for 15 8 and 4 5 of the analgesic effect of oxycodone after oral and intravenous administration respectively 74 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 oxycodone 74 In contrast to oxycodone 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 73 76 74 75 k opioid receptor edit In 1997 a group of Australian researchers proposed based on a study in rats that oxycodone acts on KORs unlike morphine which acts upon MORs 78 Further research by this group indicated the drug appears to be a high affinity k2b opioid receptor agonist 79 However this conclusion has been disputed primarily on the basis that oxycodone produces effects that are typical of MOR agonists 80 In 2006 research by a Japanese group suggested the effect of oxycodone is mediated by different receptors in different situations 81 Specifically in diabetic mice the KOR appears to be involved in the antinociceptive effects of oxycodone while in nondiabetic mice the m1 opioid receptor seems to be primarily responsible for these effects 81 82 Pharmacokinetics edit Instant release absorption profile edit Oxycodone can be administered orally intranasally via intravenous intramuscular or subcutaneous injection or rectally The bioavailability of oral administration of oxycodone averages within a range of 60 to 87 with rectal administration yielding the same results intranasal varies between individuals with a mean of 46 83 After a dose of conventional immediate release oral oxycodone the onset of action is 10 to 30 minutes 10 8 and peak plasma levels of the drug are attained within roughly 30 to 60 minutes 10 8 73 in contrast after a dose of OxyContin an oral controlled release formulation peak plasma levels of oxycodone occur in about three hours 46 The duration of instant release oxycodone is 3 to 6 hours although this can be variable depending on the individual 10 Distribution edit Oxycodone has a volume of distribution of 2 6L kg 84 in the blood it is distributed to skeletal muscle liver intestinal tract lungs spleen and brain 46 At equilibrium the unbound concentration in the brain is threefold higher than the unbound concentration in blood 85 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 15 Metabolism edit The metabolism of oxycodone 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 10 86 Around 10 range 8 14 of a dose of oxycodone is excreted essentially unchanged unconjugated or conjugated in the urine 10 The major metabolites of oxycodone are noroxycodone 70 noroxymorphone relatively high concentrations 44 and oxymorphone 5 73 76 The immediate metabolism of oxycodone in humans is as follows 10 12 87 N Demethylation to noroxycodone predominantly via CYP3A4 O Demethylation to oxymorphone predominantly via CYP2D6 6 Ketoreduction to 6a and 6b oxycodol N Oxidation to oxycodone N oxideIn humans N demethylation of oxycodone to noroxycodone by CYP3A4 is the major metabolic pathway accounting for 45 21 of a dose of oxycodone while O demethylation of oxycodone into oxymorphone by CYP2D6 and 6 ketoreduction of oxycodone into 6 oxycodols represent relatively minor metabolic pathways accounting for 11 6 and 8 6 of a dose of oxycodone respectively 10 40 Several of the immediate metabolites of oxycodone are subsequently conjugated with glucuronic acid and excreted in the urine 10 6a Oxycodol and 6b oxycodol are further metabolized by N demethylation to nor 6a oxycodol and nor 6b oxycodol respectively and by N oxidation to 6a oxycodol N oxide and 6b oxycodol N oxide which can subsequently be glucuronidated as well 10 12 Oxymorphone is also further metabolized as follows 10 12 87 3 Glucuronidation to oxymorphone 3 glucuronide predominantly via UGT2B7 6 Ketoreduction to 6a oxymorphol and 6b oxymorphol N Demethylation to noroxymorphoneThe 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 87 After N demethylation of oxymorphone noroxymorphone is further glucuronidated to noroxymorphone 3 glucuronide 87 Because oxycodone 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 46 Some people are fast metabolizers of oxycodone while others are slow metabolizers resulting in polymorphism dependent alterations in relative analgesia and toxicity 88 89 While higher CYP2D6 activity increases the effects of oxycodone owing to increased conversion into oxymorphone higher CYP3A4 activity has the opposite effect and decreases the effects of oxycodone owing to increased metabolism into noroxycodone and noroxymorphone 90 The dose of oxycodone must be reduced in patients with reduced liver function 91 Elimination edit The clearance of oxycodone is 0 8 L min 84 Oxycodone and its metabolites are mainly excreted in urine 92 Therefore oxycodone accumulates in patients with kidney impairment 91 Oxycodone is eliminated in the urine 10 as unchanged oxycodone 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 92 73 Duration of action edit Oxycodone has a half life of 4 5 hours 84 It is available as a generic medication 15 The manufacturer of OxyContin a controlled release preparation of oxycodone 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 oxycodone provides pain relief in said patient for at least 12 hours after administration 93 However in 2016 an investigation by the Los Angeles Times found that the drug wears 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 twice a day 93 94 Purdue strongly discouraged the practice Purdue s medical director Robert Reder wrote to one doctor in 1995 that OxyContin has been developed for 12 hour dosing I request that you not use a 8 hourly dosing regimen Purdue repeatedly released memos to its sales representatives ordering them to remind doctors not to deviate from a 12 hour dosing schedule One such memo read There is no Q8 dosing with OxyContin 8 hour dosing needs to be nipped in the bud NOW 93 The journalists who covered the investigation argued that Purdue Pharma has insisted on a 12 hour duration of action for nearly all patients despite evidence to the contrary to protect the reputation of OxyContin as a 12 hour drug and the willingness of health insurance and managed care companies to cover OxyContin despite its high cost relative to generic opiates such as morphine 93 Purdue sales representatives were instructed to encourage doctors to write prescriptions for larger 12 hour doses instead of more frequent dosing An August 1996 memo to Purdue sales representatives in Tennessee entitled It s Bonus Time in the Neighborhood reminded the representatives that their commissions would dramatically increase if they were successful in convincing doctors to prescribe larger doses Los Angeles Times journalists argue using interviews from opioid addiction experts that such high doses of OxyContin spaced 12 hours apart create a combination of agony during opiate withdrawal lower lows and a schedule of reinforcement that relieves this agony fostering addiction 93 Chemistry editSee also List of opioids Oxycodone s chemical name is derived from codeine The chemical structures are very similar differing only in that Oxycodone has a hydroxy group at carbon 14 codeine has just a hydrogen in its place Oxycodone has a 7 8 dihydro feature Codeine has a double bond between those two carbons and Oxycodone has a carbonyl group as in ketones in place of the hydroxyl group of codeine It is also similar to hydrocodone differing only in that it has a hydroxyl group at carbon 14 91 Biosynthesis edit In terms of biosynthesis oxycodone has been found naturally in nectar extracts from the orchid family Epipactis helleborine together along with another opioid 3 2 3 3 benzyloxypropyl 3 indol 7 8 didehydro 4 5 epoxy 3 6 d morphinan 95 Thodey et al 2014 introduces a microbial compound manufacturing system for compounds including oxycodone 96 The Thodey platform produces both natural and semisynthetic opioids including this one 96 This system uses Saccharomyces cerevisiae with transgenes from Papaver somniferum the opium poppy and Pseudomonas putida to turn a thebaine input into other opiates and opioids 96 Detection in biological fluids edit Oxycodone and or its major metabolites may be measured in blood or urine to monitor for clearance non medical use confirm a diagnosis of poisoning or assist in a medicolegal death investigation Many commercial opiate screening tests cross react appreciably with oxycodone and its metabolites but chromatographic techniques can easily distinguish oxycodone from other opiates 97 History editMartin Freund and Jakob Edmund Speyer of the University of Frankfurt in Germany published the first synthesis of oxycodone from thebaine in 1916 98 99 When Freund died in 1920 Speyer wrote his obituary for the German Chemical Society 100 Speyer born to a Jewish family in Frankfurt am Main in 1878 became a victim of the Holocaust He died on 5 May 1942 the second day of deportations from the Lodz Ghetto his death was noted in the ghetto s chronicle 101 The first clinical use of the drug was documented in 1917 the year after it was first developed 99 13 It was first introduced to the U S market in May 1939 In early 1928 Merck introduced a combination product containing scopolamine oxycodone and ephedrine under the German initials for the ingredients SEE which was later renamed Scophedal SCOpolamine ePHEDrine and eukodAL in 1942 It was last manufactured in 1987 but can be compounded This combination is essentially an oxycodone analogue of the morphine based twilight sleep with ephedrine added to reduce circulatory and respiratory effects 102 The drug became known as the Miracle Drug of the 1930s in Continental Europe and elsewhere and it was the Wehrmacht s choice for a battlefield analgesic for a time The drug was expressly designed to provide what the patent application and package insert referred to as very deep analgesia and profound and intense euphoria as well as tranquillisation and anterograde amnesia useful for surgery and battlefield wounding cases Oxycodone was allegedly chosen over other common opiates for this product because it had been shown to produce less sedation at equianalgesic doses compared to morphine hydromorphone Dilaudid and hydrocodone Dicodid 103 During Operation Himmler Skophedal was also reportedly injected in massive overdose into the prisoners dressed in Polish Army uniforms in the staged incident on 1 September 1939 which opened the Second World War 102 104 The personal notes of Adolf Hitler s physician Theodor Morell indicate Hitler received repeated injections of Eukodal oxycodone produced by Merck and Scophedal as well as Dolantin pethidine codeine and morphine less frequently oxycodone could not be obtained after late January 1945 105 106 In the United States the Controlled Substances Act CSA was passed by the United States Congress and signed into law by President Richard Nixon on 27 October 1970 107 The passing of the CSA resulted in all products containing oxycodone to be classified as a Schedule II controlled substance 108 Purdue Pharma a privately held company based in Stamford Connecticut developed the prescription painkiller OxyContin It was approved by the FDA in 1995 after no long term studies and no assessment of its addictive capabilities 109 David Kessler FDA commissioner at the time later said of the approval of OxyContin No doubt it was a mistake It was certainly one of the worst medical mistakes a major mistake 110 Upon its release in 1995 OxyContin was hailed as a medical breakthrough a long lasting narcotic that could help patients with moderate to severe pain The drug became a blockbuster and has reportedly generated some US 35 billion in revenue for Purdue 111 Opioid epidemic editSee also Opioid epidemic Oxycodone like other opioid analgesics tends to induce feelings of euphoria relaxation and reduced anxiety in those who are occasional users 112 These effects make it one of the most commonly abused pharmaceutical drugs in the United States 113 The abuse of Oxycodone as well as related opioids more broadly is not unique to the United States and is a common drug of abuse globally 114 115 United States edit See also Opioid epidemic in the United States Oxycodone is the most widely recreationally used opioid in America In the United States more than 12 million people use opioid drugs recreationally 116 The U S Department of Health and Human Services estimates that about 11 million people in the U S consume oxycodone in a non medical way annually 117 Opioids were responsible for 49 000 of the 72 000 drug overdose deaths in the U S in 2017 118 In 2007 about 42 800 emergency room visits occurred due to episodes involving oxycodone 119 In 2008 recreational use of oxycodone and hydrocodone was involved in 14 800 deaths Some of the cases were due to overdoses of the acetaminophen component resulting in fatal liver damage 120 In September 2013 the FDA released new labeling guidelines for long acting and extended release opioids requiring manufacturers to remove moderate pain as indication for use instead stating the drug is for pain severe enough to require daily around the clock long term opioid treatment 121 The updated labeling will not restrict physicians from prescribing opioids for moderate pain as needed 116 Reformulated OxyContin is causing some recreational users to change to heroin which is cheaper and easier to obtain 122 Lawsuits edit In October 2017 The New Yorker published a story on Mortimer Sackler and Purdue Pharma regarding their ties to the production and manipulation of the oxycodone markets 111 The article links Raymond and Arthur Sackler s business practices with the rise of direct pharmaceutical marketing and eventually to the rise of addiction to oxycodone in the United States The article implies that the Sackler family bears some responsibility for the opioid epidemic in the United States 123 In 2019 The New York Times ran a piece confirming that Richard Sackler the son of Raymond Sackler told company officials in 2008 to measure our performance by Rx s by strength giving higher measures to higher strengths 124 This was verified with documents tied to a lawsuit which was filed by the Massachusetts attorney general Maura Healey claiming that Purdue Pharma and members of the Sackler family knew that high doses of OxyContin over long periods would increase the risk of serious side effects including addiction 125 Despite Purdue Pharma s proposal for a US 12 billion settlement of the lawsuit the attorneys general of 23 states including Massachusetts rejected the settlement offer in September 2019 126 Australia edit The non medical use of oxycodone existed from the early 1970s but by 2015 91 of a national sample of injecting drug users in Australia had reported using oxycodone and 27 had injected it in the last six months 127 Canada edit Opioid related deaths in Ontario had increased by 242 from 1969 to 2014 128 By 2009 in Ontario there were more deaths from oxycodone overdoses than from cocaine overdoses 129 Deaths from opioid pain relievers had increased from 13 7 deaths per million residents in 1991 to 27 2 deaths per million residents in 2004 130 The non medical use of oxycodone in Canada became a problem Areas where oxycodone is most problematic are Atlantic Canada and Ontario where its non medical use is prevalent in rural towns and in many smaller to medium sized cities 131 Oxycodone is also widely available across Western Canada but methamphetamine and heroin are more serious problems in larger cities while oxycodone is more common in rural towns Oxycodone is diverted through doctor shopping prescription forgery pharmacy theft and overprescription 131 132 The recent formulations of oxycodone particularly Purdue Pharma s crush chew injection and dissolve resistant OxyNEO 133 which replaced the banned OxyContin product in Canada in early 2012 have led to a decline in the recreational use of this opiate but have increased the recreational use of the more potent drug fentanyl 134 According to a Canadian Centre on Substance Abuse study quoted in Maclean s magazine there were at least 655 fentanyl related deaths in Canada in a five year period 135 In Alberta the Blood Tribe police claimed that from the fall of 2014 through January 2015 oxycodone pills or a lethal fake variation referred to as Oxy 80s 136 containing fentanyl made in illegal labs by members of organized crime were responsible for ten deaths on the Blood Reserve which is located southwest of Lethbridge Alberta 137 Province wide approximately 120 Albertans died from fentanyl related overdoses in 2014 136 United Kingdom edit Prescriptions of Oxycodone rose in Scotland by 430 between 2002 and 2008 prompting fears of usage problems that would mirror those of the United States 138 The first known death due to overdose in the UK occurred in 2002 139 Preventive measures edit In August 2010 Purdue Pharma reformulated their long acting oxycodone line marketed as OxyContin using a polymer Intac 140 to make the pills more difficult to crush or dissolve in water 141 to reduce non medical use of OxyContin 142 The FDA approved relabeling the reformulated version as abuse resistant in April 2013 143 Pfizer manufactures a preparation of short acting oxycodone marketed as Oxecta which contains inactive ingredients referred to as tamper resistant Aversion Technology 144 Approved by the FDA in the U S in June 2011 the new formulation while not being able to deter oral recreational use makes crushing chewing snorting or injecting the opioid impractical because of a change in its chemical properties 145 Legal status editOxycodone is subject to international conventions on narcotic drugs In addition oxycodone is subject to national laws that differ by country The 1931 Convention for Limiting the Manufacture and Regulating the Distribution of Narcotic Drugs of the League of Nations included oxycodone 146 The 1961 Single Convention on Narcotic Drugs of the United Nations which replaced the 1931 convention categorized oxycodone in Schedule I 147 Global restrictions on Schedule I drugs include limit ing exclusively to medical and scientific purposes the production manufacture export import distribution of trade in use and possession of these drugs requir ing medical prescriptions for the supply or dispensation of these drugs to individuals and prevent ing the accumulation of quantities of these drugs in excess of those required for the normal conduct of business 147 Australia edit Oxycodone is in Schedule I derived from the Single Convention on Narcotic Drugs of the Commonwealth s Narcotic Drugs Act 1967 148 In addition it is in Schedule 8 of the Australian Standard for the Uniform Scheduling of Drugs and Poisons Poisons Standard meaning it is a controlled drug which should be available for use but require s restriction of manufacture supply distribution possession and use to reduce abuse misuse and physical or psychological dependence 149 Canada edit Oxycodone is a controlled substance under Schedule I of the Controlled Drugs and Substances Act CDSA 150 nbsp Canadian oxycodone HCL acetaminophen 5 325 mg tabletIn February 2012 Ontario passed legislation to allow the expansion of an already existing drug tracking system for publicly funded drugs to include those that are privately insured This database will function to identify and monitor patient s attempts to seek prescriptions from multiple doctors or retrieve them from multiple pharmacies Other provinces have proposed similar legislation while some such as Nova Scotia have legislation already in effect for monitoring prescription drug use These changes have coincided with other changes in Ontario s legislation to target the misuse of painkillers and high addiction rates to drugs such as oxycodone As of 29 February 2012 Ontario passed legislation delisting oxycodone from the province s public drug benefit program This was a first for any province to delist a drug based on addictive properties The new law prohibits prescriptions for OxyNeo except to certain patients under the Exceptional Access Program including palliative care and in other extenuating circumstances Patients already prescribed oxycodone will receive coverage for an additional year for OxyNeo and after that it will be disallowed unless designated under the exceptional access program 151 Much of the legislative activity has stemmed from Purdue Pharma s decision in 2011 to begin a modification of Oxycontin s composition to make it more difficult to crush for snorting or injecting The new formulation OxyNeo is intended to be preventive in this regard and retain its effectiveness as a painkiller Since introducing its Narcotics Safety and Awareness Act Ontario has committed to focusing on drug addiction particularly in the monitoring and identification of problem opioid prescriptions as well as the education of patients doctors and pharmacists 152 This Act introduced in 2010 commits to the establishment of a unified database to fulfil this intention 153 Both the public and medical community have received the legislation positively though concerns about the ramifications of legal changes have been expressed Because laws are largely provincially regulated many speculate a national strategy is needed to prevent smuggling across provincial borders from jurisdictions with looser restrictions 154 In 2015 Purdue Pharma s abuse resistant OxyNEO and six generic versions of OxyContin had been on the Canada wide approved list for prescriptions since 2012 In June 2015 then federal Minister of Health Rona Ambrose announced that within three years all oxycodone products sold in Canada would need to be tamper resistant Some experts warned that the generic product manufacturers may not have the technology to achieve that goal possibly giving Purdue Pharma a monopoly on this opiate 155 Several class action suits across Canada have been launched against the Purdue group of companies and affiliates Claimants argue the pharmaceutical manufacturers did not meet a standard of care and were negligent in doing so These lawsuits reference earlier judgments in the United States which held that Purdue was liable for wrongful marketing practices and misbranding Since 2007 the Purdue companies have paid over CAN 650 million in settling litigation or facing criminal fines Germany edit The drug is in Appendix III of the Narcotics Act Betaubungsmittelgesetz or BtMG 156 The law allows only physicians dentists and veterinarians to prescribe oxycodone and the federal government to regulate the prescriptions e g by requiring reporting 156 Hong Kong edit Oxycodone is regulated under Part I of Schedule 1 of Hong Kong s Chapter 134 Dangerous Drugs Ordinance 157 Japan edit Oxycodone is a restricted drug in Japan Its import and export are strictly restricted to specially designated organizations having a prior permit to import it In a high profile case an American who was a top Toyota executive living in Tokyo who claimed to be unaware of the law was arrested for importing oxycodone into Japan 158 159 Singapore edit Oxycodone is listed as a Class A drug in the Misuse of Drugs Act of Singapore which means offences concerning the drug attract the most severe level of punishment A conviction for unauthorized manufacture of the drug attracts a minimum sentence of 10 years of imprisonment and corporal punishment of 5 strokes of the cane and a maximum sentence of life imprisonment or 30 years of imprisonment and 15 strokes of the cane 160 The minimum and maximum penalties for unauthorized trafficking in the drug are respectively 5 years of imprisonment and 5 strokes of the cane and 20 years of imprisonment and 15 strokes of the cane 161 United Kingdom edit Oxycodone is a Class A drug under the Misuse of Drugs Act 1971 162 For Class A drugs which are considered to be the most likely to cause harm possession without a prescription is punishable by up to seven years in prison an unlimited fine or both 163 Dealing of the drug illegally is punishable by up to life imprisonment an unlimited fine or both 163 Oxycodone is a Schedule 2 drug per the Misuse of Drugs Regulations 2001 which provide certain exemptions from the provisions of the Misuse of Drugs Act 1971 164 United States edit Under the Controlled Substances Act oxycodone is a Schedule II controlled substance whether by itself or part of a multi ingredient medication 165 The DEA lists oxycodone both for sale and for use in manufacturing other opioids as ACSCN 9143 and in 2013 approved the following annual aggregate manufacturing quotas 131 5 metric tons for sale down from 153 75 in 2012 and 10 25 metric tons for conversion unchanged from the previous year 166 In 2020 oxycodone possession was decriminalized in the U S state of Oregon 167 Economics editThe International Narcotics Control Board estimated 11 5 short tons 10 4 t of oxycodone were manufactured worldwide in 1998 168 by 2007 this figure had grown to 75 2 short tons 68 2 t 168 United States accounted for 82 of consumption in 2007 at 51 6 short tons 46 8 t Canada Germany Australia and France combined accounted for 13 of consumption in 2007 168 169 In 2010 1 3 short tons 1 2 t of oxycodone were illegally manufactured using a fake pill imprint This accounted for 0 8 of consumption These illicit tablets were later seized by the U S Drug Enforcement Administration according to the International Narcotics Control Board 170 The board also reported 122 5 short tons 111 1 t manufactured in 2010 This number had decreased from a record high of 135 9 short tons 123 3 t in 2009 171 Names editExpanded expressions for the compound oxycodone in the academic literature include dihydrohydroxycodeinone 1 172 173 Eucodal 172 173 Eukodal 5 13 14 hydroxydihydrocodeinone 1 172 and Nucodan 172 173 In a UNESCO convention the translations of oxycodone are oxycodon Dutch oxycodone French oxicodona Spanish الأوكسيكودون Arabic 羟考酮 Chinese and oksikodon Russian 174 The word oxycodone should not be confused with oxandrolone oxazepam oxybutynin oxytocin or Roxanol 175 Other brand names include Longtec and Shortec 176 References edit a b c O Neil MJ ed 2006 The Merck index 14th ed Whitehouse Station NJ Merck amp Co ISBN 978 0 911910 00 1 Oxycodone Use During Pregnancy Drugs com 14 October 2019 Archived from the original on 19 June 2020 Retrieved 12 April 2020 Bonewit West K Hunt SA Applegate E 2012 Today s Medical Assistant Clinical and Administrative Procedures Elsevier Health Sciences p 571 ISBN 978 1 4557 0150 6 Archived from the original on 6 October 2022 Retrieved 20 August 2019 Bonewit West K Hunt SA Applegate E 2012 Today s Medical Assistant Clinical and Administrative Procedures Elsevier Health Sciences p 571 ISBN 9781455701506 Archived from the original on 10 January 2023 Retrieved 20 August 2019 a b c d Kalso E May 2005 Oxycodone Journal of Pain and Symptom Management 29 5 Suppl S47 S56 doi 10 1016 j 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