Oxycodone, sold under brand names such as Percocet and OxyContin among many others, is an opioid medication which is used for the relief of moderate to severe pain.[9] It is usually taken by mouth, and is available as a single-ingredient medication in immediate release and controlled release formulations. In the United Kingdom, it is available in 10 mg/mL and 50 mg/mL formulation for intramuscular or intravenous administration.[10] Combination products are also available as immediate-release formulations, with non-narcotic analgesic ingredients such as paracetamol (acetaminophen) and nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin and ibuprofen. Side effects of oxycodone include constipation, nausea, vomiting, somnolence, dizziness, itching, dry mouth, and sweating.[11][12] The medication can produce euphoria and can result in addiction, dependence, and withdrawal symptoms upon discontinuation. With overdose, oxycodone can cause respiratory depression, slowed heart rate, low blood pressure, circulatory collapse, respiratory arrest, and death.[13] Oxycodone is an opioid, and acts as a selective agonist of the μ-opioid receptor, the main biological target of the endogenous neuropeptide β-endorphin.[14] It is a moderately potent opioid pain medication (orally roughly 1.5 times more potent than morphine).[15] Oxycodone is a semisynthetic opioid derived from thebaine, an opioid alkaloid found in the Persian poppy and one of the many alkaloids found in the opium poppy. Oxycodone was developed in 1917 in Germany[16][17] as one of several semisynthetic opioids in an attempt to improve on the existing opioids.[1] As it has euphoric effects similar to other opioids, oxycodone is one of the drugs abused in the current opioid epidemic in the United States.[18][19] An abuse-deterrent combination with naloxone is available in managed-release tablets. If injected, the naloxone blocks the effect of the medication and precipitates opioid withdrawal symptoms. However, there have been concerns raised about the effectiveness of the abuse prevention measures.[19][20] Oxycodone has been in clinical use since 1916,[1] and it is used for managing moderate to moderately severe acute or chronic pain.[21] It has been found to improve quality of life for those with many types of pain.[22] Experts are divided regarding use for non-cancer-related chronic pain, as most opioids have great potential for dependence and have also been alleged to create paradoxical pain sensitivity. Oxycodone is available as controlled-release (OxyContin, Xtampza ER) tablet, intended to be taken every 12 hours.[23] A July 1996 study independent of Purdue Pharma and led by Abraham Sunshine, former chair of the medical board of NYU Tisch Hospital, found the controlled-release formulation actually had a variable duration of action ranging from 10–12 hours.[8] A 2006 review found that controlled-release oxycodone is comparable to instant-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.[24] In 2014, the European Association for Palliative Care recommended oral oxycodone as a second-line alternative to oral morphine for cancer pain.[25] In the U.S., extended-release oxycodone is approved for use in children as young as 11 years old. The approved indication is for relief of cancer pain, trauma pain, or pain due to major surgery, in children 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.[26] Oxycodone is available in a variety of formulations for oral or sublingual administration:[5][27][28][29] In the United States, oxycodone is only approved for oral use, available as tablets and oral solutions. Parenteral formulations of oxycodone (brand name Oxynorm) are also available in the world however, and are widely used in Europe.[34][35][36] 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.[1] Serious side effects of oxycodone include reduced sensitivity to pain (beyond the pain the drug is taken to reduce), euphoria, anxiolysis, feelings of relaxation, and respiratory depression.[11] Common side effects of oxycodone include constipation (23%), nausea (23%), vomiting (12%), somnolence (23%), dizziness (13%), itching (13%), dry mouth (6%), and sweating (5%).[11][12] Less common side effects (experienced by less than 5% of patients) include loss of appetite, nervousness, abdominal pain, diarrhea, urine retention, dyspnea, and hiccups.[13] Oxycodone in combination with naloxone in managed-release tablets, has been formulated to both deter abuse and reduce "opioid-induced constipation".[38] 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".[39] Withdrawal symptoms have also been reported in newborns whose mothers had been either injecting or orally taking oxycodone during pregnancy.[40] As with other opioids, chronic use of oxycodone (particularly with higher doses) often causes concurrent hypogonadism (low sex hormone levels).[41] 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.[13] 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.[42] Oxycodone is metabolized by the enzymes CYP3A4 and CYP2D6, and its clearance therefore can be altered by inhibitors and inducers of these enzymes.[35] (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.[35] Ritonavir or lopinavir/ritonavir greatly increase plasma concentrations of oxycodone in healthy human volunteers due to inhibition of CYP3A4 and CYP2D6.[43] Rifampicin greatly reduces plasma concentrations of oxycodone due to strong induction of CYP3A4.[44] There is also a case report of fosphenytoin, a CYP3A4 inducer, dramatically reducing the analgesic effects of oxycodone in a chronic pain patient.[45] Dosage or medication adjustments may be necessary in each case.[43][44][45] Oxycodone is a highly selective full agonist of the μ-opioid receptor (MOR).[34][35] This is the main biological target of the endogenous opioid neuropeptide β-endorphin.[14] Oxycodone has low affinity for the δ-opioid receptor (DOR) and the κ-opioid receptor (KOR), where it is an agonist similarly.[34][35] 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.[51] 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).[52] 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.[53][54] 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).[55] Taken orally, 20 mg of immediate release oxycodone is considered to be equivalent in analgesic effect to 30 mg of morphine,[56][57] while extended release oxycodone is considered to be twice as potent as oral morphine.[58] Similarly to most other opioids, oxycodone increases prolactin secretion, but its influence on testosterone levels is unknown.[34] 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.[34] 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.[59][60][61] Oxymorphone possesses 3- to 5-fold higher affinity for the MOR than does oxycodone,[4] while noroxycodone and noroxymorphone possess one-third of and 3-fold higher affinity for the MOR, respectively,[4][61] and MOR activation is 5- to 10-fold less with noroxycodone but 2-fold higher with noroxymorphone relative to oxycodone.[62] Noroxycodone, noroxymorphone, and oxymorphone also have longer biological half-lives than oxycodone.[59][63] 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.[60] 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.[60] 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.[60] 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.[59][62][60][61] 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.[64] Further research by this group indicated the drug appears to be a high-affinity κ2b-opioid receptor agonist.[65] However, this conclusion has been disputed, primarily on the basis that oxycodone produces effects that are typical of MOR agonists.[66] In 2006, research by a Japanese group suggested the effect of oxycodone is mediated by different receptors in different situations.[67] 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.[67][68] 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%.[69] After a dose of conventional (instant-release) oral oxycodone, the onset of action is 10 to 30 minutes,[4][5] and peak plasma levels of the drug are attained within roughly 30 to 60 minutes;[4][5][59] in contrast, after a dose of OxyContin (an oral controlled-release formulation), peak plasma levels of oxycodone occur in about three hours.[13] The duration of instant-release oxycodone is 3 to 6 hours, although this can be variable depending on the individual.[4] Oxycodone in the blood is distributed to skeletal muscle, liver, intestinal tract, lungs, spleen, and brain.[13] 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.[21] 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.[4][70] Around 10% (range 8–14%) of a dose of oxycodone is excreted essentially unchanged (unconjugated or conjugated) in the urine.[4] The major metabolites of oxycodone are noroxycodone (70%), noroxymorphone ("relatively high concentrations"),[11] and oxymorphone (5%).[59][62] The immediate metabolism of oxycodone in humans is as follows:[4][7][71] 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.[4][34] Several of the immediate metabolites of oxycodone are subsequently conjugated with glucuronic acid and excreted in the urine.[4] 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).[4][7] Oxymorphone is also further metabolized, as follows:[4][7][71] 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.[71] After N-demethylation of oxymorphone, noroxymorphone is further glucuronidated to noroxymorphone-3-glucuronide.[71] 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.[13] Some people are fast metabolizers of oxycodone, resulting in reduced effects, while others are slow metabolizers, resulting in increased effects and toxicity.[72][73] 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).[74] The dose of oxycodone must be reduced in patients with reduced liver function.[21] Oxycodone and its metabolites are mainly excreted in urine.[75] Therefore, oxycodone accumulates in patients with kidney impairment.[21] 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).[75][76] OxyContin currently is protected under patent and has no available generic. Its manufacturer Purdue Pharma claimed in their 1992 patent application that the duration of action of OxyContin, oxycodone's controlled-release preparation, 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." [77] 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 only taken twice a day.[77][78] Purdue strongly discouraged the practice: Purdue's medical director Robert Reder wrote to one doctor in 1995 that "OxyContin has been developed for q12h dosing...I request that you not use a q8h 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!!"[77] The journalists who covered the investigation argue that Purdue Pharma has insisted on a 12-hour duration of action for nearly all patients, despite evidence to the contrary, in order 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.[77] 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.[77] Oxycodone's chemical name is derived from codeine. The chemical structures are very similar, differing only in that It is also similar to hydrocodone, differing only in that it has a hydroxyl group at carbon-14.[21] Oxycodone is marketed as various salts, most commonly as the hydrochloride salt. The free base conversion ratios of different salts are: hydrochloride (0.896), bitartrate (0.667), tartrate (0.750), camphosulphonate (0.576), pectinate (0.588), phenylpriopionate (0.678), sulphate (0.887), phosphate (0.763), and terephthalate (0.792). The hydrochloride salt is the basis of most American oxycodone products whilst bitartrate, tartrate, pectinate, terephthalate and phosphate salts are also available in European products. Methyiodide and hydroiodide are mentioned in older European publications. 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.[79] Oxycodone and/or its major metabolites may be measured in blood or urine to monitor for clearance, abuse, 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.[80] Freund and Speyer of the University of Frankfurt in Germany first synthesized oxycodone from Thebaine in 1916,[17] a few years after the German pharmaceutical company Bayer had stopped the mass production of heroin due to hazardous use, harmful use, and dependence. It was hoped that a thebaine-derived drug would retain the analgesic effects of morphine and heroin with less dependence. Unfortunately, this was ultimately not found to be the case. The first clinical use of the drug was documented in 1917, the year after it was first developed.[17][81] It was first introduced to the US 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). This combination is essentially an oxycodone analogue of the morphine-based ´twilight sleep´, with ephedrine added to reduce circulatory and respiratory effects.[82] The personal notes of Adolf Hitler's physician, Dr. Theodor Morell, indicate Hitler received repeated injections of "eukodal" (oxycodone).[83] In the early 1970s, the United States government classified oxycodone as a schedule II drug. Purdue Pharma — a privately held company based in Stamford, Connecticut, developed the prescription painkiller OxyContin. Upon its release in 1995, OxyContin was hailed as a medical breakthrough, a long-lasting narcotic that could help patients suffering from moderate to severe pain. The drug became a blockbuster, and has reportedly generated some thirty-five billion dollars in revenue for Purdue.[84] Expanded expression for the compound oxycodone in the academic literature include "dihydrohydroxycodeinone",[2][85][86] "Eucodal",[85][86] "Eukodal",[1][81] "14-hydroxydihydrocodeinone",[2][85] and "Nucodan".[85][86] In a UNESCO convention, the translations of "oxycodone" are oxycodon (Dutch), oxycodone (French), oxicodona (Spanish), الأوكسيكودون (Arabic), 羟考酮 (Chinese), and оксикодон (Russian).[87] The word "oxycodone" should not be confused with "oxandrolone", "oxazepam", "oxybutynin", "oxytocin", or "Roxanol".[88] 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.[89] The 1961 Single Convention on Narcotic Drugs of the United Nations, which replaced the 1931 convention, categorized oxycodone in Schedule I.[90] 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".[90] Oxycodone is in Schedule I (derived from the Single Convention on Narcotic Drugs) of the Commonwealth's Narcotic Drugs Act 1967.[91] 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".[92] Oxycodone is a controlled substance under Schedule I of the Controlled Drugs and Substances Act (CDSA).[93] 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 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 February 29, 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.[94] 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 preventative 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.[95] This Act, introduced in 2010, commits to the establishment of a unified database to fulfil this intention.[96] 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.[97] 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.[98] 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. The drug is in Appendix III of the Narcotics Act (Betäubungsmittelgesetz or BtMG).[99] The law allows only physicians, dentists, and veterinarians to prescribe oxycodone and the federal government to regulate the prescriptions (e.g., by requiring reporting).[99] Oxycodone is regulated under Part I of Schedule 1 of Hong Kong's Chapter 134 Dangerous Drugs Ordinance.[100] Oxycodone is a restricted drug in Japan. Its import and export is strictly restricted to specially designated organizations having 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.[101][102] Oxycodone is listed as a Class A drug in the Misuse of Drugs Act of Singapore, which means offences in relation to 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.[103] 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.[104] Oxycodone is a Class A drug under the Misuse of Drugs Act.[105] 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.[106] Dealing of the drug illegally is punishable by up to life imprisonment, an unlimited fine, or both.[106] In addition, 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".[107] Under the Controlled Substances Act, signed into law in 1971 by President Richard Nixon,[108] oxycodone is a Schedule II controlled substance whether by itself or part of a multi-ingredient medication. 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.[109] Oxycodone, like other opioid analgesics, tends to induce feelings of euphoria, relaxation and reduced anxiety in those who are occasional users.[110] These effects make it one of the most commonly abused pharmaceutical drugs in the United States.[111] In August 2010, Purdue Pharma reformulated their long-acting oxycodone line, marketed as OxyContin, using a polymer, Intac,[112] to make the pills extremely difficult to crush or dissolve[113] in water to reduce OxyContin abuse.[114] The FDA approved relabeling the reformulated version as abuse-resistant in April 2013.[115] Pfizer manufactures a preparation of short-acting oxycodone, marketed as Oxecta, which contains inactive ingredients, referred to as tamper-resistant Aversion Technology.[116] It does not deter oral abuse. Approved by the FDA in the US in June 2011, the new formulation makes crushing, chewing, snorting, or injecting the opioid impractical because of a change in its chemical properties.[117] 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.[118] Opioid-related deaths in Ontario had increased by 242% from 1969 to 2014.[119] By 2009 in Ontario there were more deaths from oxycodone overdose than from cocaine overdose.[120] 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.[121] The abuse of oxycodone in Canada became a problem. Areas where oxycodone is most problematic are Atlantic Canada and Ontario, where its abuse is prevalent in rural towns, and in many smaller to medium-sized cities.[122] Oxycodone is also widely available across Western Canada, but methamphetamine and heroin are more serious problems in the larger cities, while oxycodone is more common in rural towns. Oxycodone is diverted through doctor shopping, prescription forgery, pharmacy theft, and overprescribing.[122][123] The recent formulations of oxycodone, particularly Purdue Pharma's crush-, chew-, injection- and dissolve-resistant OxyNEO[124] which replaced the banned OxyContin product in Canada in early 2012, have led to a decline in the abuse of this opiate but have increased the abuse of the more potent drug fentanyl.[125] 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.[126] 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[127] 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.[128] Province-wide, approximately 120 Albertans died from fentanyl-related overdoses in 2014.[127] Abuse and diversion of oxycodone in the UK commenced in the early- to mid-2000s.[129] The first known death due to overdose in the UK occurred in 2002.[130] However, recreational use remains relatively rare. In the United States, more than 12 million people use opioid drugs recreationally.[131] In 2010, 16,652 deaths were related to opioid overdose in combination with other drugs such as benzodiazepines and alcohol.[132] 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."[133] The updated labeling will not restrict physicians from prescribing opioids for moderate, as needed use.[131] Oxycodone is the most widely recreationally used opioid in America. The U.S. Department of Health and Human Services estimates that about 11 million people in the US consume oxycodone in a non-medical way annually.[134] In 2007, about 42,800 emergency room visits occurred due to "episodes" involving oxycodone.[135] Diverted oxycodone may be taken orally or ingested through insufflation; used intravenously, or the heated vapors inhaled. In 2008, recreational use of oxycodone and hydrocodone were involved in 14,800 deaths. Some of the cases were due to overdoses of the acetaminophen component, resulting in fatal liver damage.[136] Reformulated OxyContin is causing some recreational users to change to heroin, which is cheaper and easier to obtain.[137] The International Narcotics Control Board estimated 11.5 short tons (10.4 t) of oxycodone were manufactured worldwide in 1998;[138] by 2007 this figure had grown to 75.2 short tons (68.2 t).[138] 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.[138][139] 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.[140] 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.[141]

Source:Wikipedia.org