Oxycodone

{{drugbox | verifiedrevid = 408988121 | IUPAC_name = (5R,9R,13S,14S)-4,5α-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one | image = Oxycodone.svg | image2 = Oxycodone3.png | width = 155 | UNII_Ref = | UNII = CD35PMG570 | InChI = 1/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 | InChIKey = BRUQQQPBMZOVGD-XFKAJCMBBP | StdInChI_Ref = | StdInChI = 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 | StdInChIKey_Ref = | StdInChIKey = BRUQQQPBMZOVGD-XFKAJCMBSA-N | ChEMBL_Ref = | ChEMBL = 656 | CAS_number = 76-42-6 | CASNo_Ref = | synonyms = dihydrohydroxycodeinone, 14-hydroxydihydrocodeinone, 6-deoxy-7,8-dihydro-14-hydroxy-3-O-methyl-6-oxomorphine

Oxycodone oral medications are generally prescribed for the relief of moderate to severe pain. Currently it is formulated as single ingredient products or compounded products. Some common examples of compounding are oxycodone with acetaminophen/paracetamol or NSAIDs such as ibuprofen. The formulations are available as generics but are also made under various brand names. OxyContin is Purdue Pharma's brand for time-release oral oxycodone. The manufacturing rights to time-released generic oxycodone are under dispute.

Medical uses

Oxycodone is effective for managing moderate to moderately severe acute or chronic pain. It has been found to improve quality of life for those with many types of pain.

In 2001, the European Association for Palliative Care recommended that oral oxycodone be a second-line alternative to oral morphine for cancer pain. There is no evidence that any opioids are superior to morphine in relieving the pain of cancer, and no controlled trials have shown oxycodone to be superior to morphine.

Adverse effects

of oxycodone]] The most commonly reported effects include euphoria, memory loss, constipation, fatigue, dizziness, nausea, lightheadedness, headache, dry mouth, anxiety, pruritus, and diaphoresis. It has also been claimed to cause dimness in vision due to miosis. Some patients have also experienced loss of appetite, nervousness, abdominal pain, diarrhea, ischuria, dyspnea, and hiccups, As a result, it is generally better tolerated than morphine.

In high doses, overdoses, or in patients not tolerant to opiates, oxycodone can cause shallow breathing, bradycardia, cold, clammy skin, apnea, hypotension, miosis (pupil constriction), circulatory collapse, respiratory arrest, and death.

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

Detection in biological fluids

Oxycodone and/or its major metabolites may be quantitated in blood or urine to monitor for 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.

Pharmacology

Mechanism of action

A group of Australian researchers has proposed (based on a 1997 study in rats) that oxycodone, unlike morphine (the effect of which is mediated by μ-opioid receptors), acts on κ-opioid receptors. Further research by this group indicates the drug appears to be a κ_2b-opioid agonist. However, this has been disputed, primarily on the basis that oxycodone produces effects typical of μ-opioid agonists.

Research by a Japanese group suggests that the effect of oxycodone is mediated by different receptors in different situations. Specifically, in diabetic mice the κ-opioid receptor appears to be involved in the antinociceptive effects of oxycodone, while in non-diabetic mice the μ₁-opioid receptor seems to be primarily responsible for these effects.

Absorption

After a dose of conventional oral oxycodone, peak plasma levels of the drug are attained in approximately one hour; in contrast, after a dose of OxyContin (an oral continuous release formulation), peak plasma levels of oxycodone occur in about three hours.

Distribution

Oxycodone in the blood is distributed to skeletal muscle, liver, intestinal tract, lungs, spleen, and brain. As many as six metabolites for oxycodone (14-hydroxydihydromorphinone, 14-hydroxydihydrocodeine, 14-hydroxydihydrocodeinone N-oxide {oxycodone N-oxide}, 14-hydroxydihydroisocodeine, 14-hydroxydihydrocodeine N-oxide, and noroxycodone) have been found in rabbits, several of which are thought to be active metabolites to some extent, although a study using conventional oral oxycodone concluded that oxycodone itself, and not its metabolites, is predominantly responsible for the drug's opioid effects on the brain. The dose of OxyContin must be reduced in patients with reduced hepatic function.

Oxycodone is approximately 1.5–2 times as potent as morphine when administered orally. However, 10–15 mg of oxycodone produces an analgesic effect similar to 10 mg of morphine when administered intramuscularly. Therefore, as a parenteral dose, morphine is approximately up to 50% more potent than oxycodone.

There are no comparative trials showing that oxycodone is more effective than any other opioid. In palliative care, morphine remains the gold standard;

Expanded expression for the compound oxycodone in the academic literature include "dihydrohydroxycodeinone", "Eucodal", The word "oxycodone" should not be confused with "oxandrolone", "oxazepam", "oxybutynin", "oxytocin", or "Roxanol".

History

Freund and Speyer of the University of Frankfurt in Germany first synthesized oxycodone from thebaine in 1916, 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. To some extent this was achieved, as oxycodone does not have the same immediate effect as heroin or morphine nor does it last as long.

The first clinical use of the drug was documented in 1917. It was first introduced to the US market in May 1939.

The International Narcotics Control Board estimates that 11.5 tons of oxycodone were manufactured worldwide in 1998, which grew to 75.2 tons in 2007. Of all countries, the United States had the highest total consumption of oxycodone in 2007 (82% of the world total of 51.6 tons). It was approved by the U.S. Food and Drug Administration in 1995 and first introduced to the U.S. market in 1996. An analysis of data from the U.S. Drug Enforcement Administration found that retail sales of oxycodone "jumped nearly six-fold between 1997 and 2005." Mundipharma distributes OxyContin in Australia, China, and Europe.

In 2001, Purdue Pharma permanently suspended distribution of 160 mg tablets in the U.S. because of the "possibility of illicit use of tablets of such high strength." It is speculated that the DEA had requested Purdue to discontinue manufacturing the 160 mg Tablets, however the DEA has publicly denied asking Purdue to do so. Beginning in 2010, the brand name OxyContin by Purdue was reformulated to prevent the misuse and abuse of the tablets. Additional binders have been added to prevent the grinding of tablets for insufflation or injection, and to maintain OxyContin's extended release characteristics. These new tablets are more often prescribed by physicians than previous generic versions for this exact purpose and bear the stamp 'OP' instead of the previous 'OC.'

Lawsuits concerning generics

Purdue has multiple patents for OxyContin, but has been involved in a series of ongoing legal battles on the validity of these patents. On June 7, 2005, the United States Court of Appeals for the Federal Circuit upheld a decision from the previous year that some of Purdue’s patents for OxyContin could not be enforced. This decision allowed and led to the immediate announcement from Endo Pharmaceuticals that would begin launching a generic version of all four strengths of OxyContin. Purdue, however, had already made negotiations with another pharmaceutical company (IVAX Pharmaceuticals) to distribute their brand OxyContin in a generic form.

On February 1, 2006, the Federal Circuit Court of Appeals issued a decision revising its 2005, decision. This time the court vacated the lower court's "judgment that the patents-in-suit are unenforceable due to inequitable conduct," and the case was "remanded for further proceedings." Teva, IMPAX, and Mallinckrodt. Endo and Teva each agreed to cease selling generic forms of OxyContin. for "fail[ing] to adequately warn consumers of the risks" of OxyContin such as dependence; and for promoting the drug "aggressively" and by means such as "promotional beach hats, pedometers and swing-music CDs."

In May 2007 Purdue Pharma "agreed to pay $19.5 million" in fines relating to aggressive off-label marketing practices of OxyContin in 26 states and the District of Columbia. In specific, the company encouraged dosing more frequent than the recommended interval of 12 hours, and did not fully disclose the risk of hazardous or harmful use. The FDA had not approved these claims. The company and the executives were to pay $634 million in fines for felony and misdemeanor misbranding.

Other preparations

Oxy·IR immediate-release oxycodone tablets from Purdue Pharma in Canada are available in 5, 10, and 20 mg strengths. Effective August 10, 2009, Purdue discontinued manufacture and distribution of OxyIR Capsules.

OxyNorm is available in 5, 10, and 20 mg capsules, and also as a 5 mg/5 ml liquid in 250 ml bottles in Australia, New Zealand, the Netherlands and the UK. In addition, OxyNorm is available in a 10 mg/ml liquid concentrate for oral use in the Netherlands and the UK, and in 10 mg/ml solutions and 50 mg/ml solutions for injection or infusion in New Zealand, the Netherlands and the UK. It is also availablein Australia as Endone, a generic 5 mg tablet.

Percocet (oxycodone with paracetamol/acetaminophen) tablets are available in Canada and the U.S. with 2.5, 5, 7.5, and 10 mg of oxycodone and varying amounts of acetaminophen.

Depalgos (oxycodone with paracetamol) tablets are marketed in Italy, with 325 mg Paracetamol and 5, 10, and 20 mg oxycodone. Recent legislation in Italy has made it easier for physicians to prescribe this medication and other opioids to pain patients.

Percodan tablets available in the U.S. contain 4.8355 mg of oxycodone HCl and 325 mg of aspirin.

Proladone suppositories, available in Australia, contain 30 mg of oxycodone pectinate.

Roxicodone, a generic oxycodone product designed to have an immediate release effect for rapid pain relief, is available in 5 mg (white), 15 mg (green), and 30 mg (blue) tablets; in a 5 mg per 5 ml oral solution; and in a 20 mg per ml liquid concentrate. On March 31, 2009, the U.S. Food and Drug Administration directed Boehringer Ingelheim Roxane and Xanodyne Pharmaceuticals to cease manufacture and distribution of 5 mg Roxicodone tablets in the U.S. because they lacked proper approval. In the US Oxycodone Immediate Release tablets are also available in 10 mg (pink) and 20 mg (grey) tablets from KVK-Tech, a generic manufacturer. Targin is a tablet with a prolonged-release oxycodone/naloxone combination.

Recreational use

;General Info Although the effects, addiction, and chemical composition of oxycodone are extremely similar to heroin, oxycodone abuse often lacks the strong taboos and negative reputation of heroin. Heroin's reputation has been developed over years of observing the detrimental effects on heroin abusers' lives. Lacking the reputation of heroin, many youths and novice drug users engage in oxycodone abuse without understanding the consequences associated with its abuse, such as a heroin-like addiction potential and the threat of a fatal overdose. The appeal to youth and novice drug users is principally due to its ease of use (oral, intranasal) and its availability. Also, pharmaceutical drugs like oxycodone have a definite purity and known ingredients, unlike street-drugs like heroin, which have relatively unknown purity and ingredients.

;Australia The illegal use of OxyContin began in Australia in the early 2000s. By 2007, 51% of a national sample of injection drug users in Australia had reported using oxycodone, and 27% had injected it in the last six months.

;Canada Deaths from opioid pain relievers increased from 13.7 deaths per million residents in 1991 to 27.2 deaths per million residents in 2004, which may be related to the spread of OxyContin.

;United Kingdom Hazardous use, harmful use and diversion of OxyContin in the UK commenced in the early- to mid-2000s. The first known death due to OxyContin overdose in the UK occurred in 2002.

;United States Instances of recreational use and diversion of OxyContin have increased in the U.S. beginning in the late 1990s. The slang term hillbilly heroin (which originally referred to hydromorphone) for OxyContin refers to the occurrence of the "earliest reported cases of Oxycontin abuse" in the U.S. in rural areas such as Appalachia. Diversion of OxyContin in the U.S. may occur through "fraudulent prescriptions, doctor shopping, over-prescribing, and pharmacy theft." Purdue Pharma has attempted to reformulate the 10–40 mg strengths of OxyContin to prevent the release of a high percentage of the oxycodone by crushing; however, in 2008 a joint panel convened by the U.S. Food and Drug Administration was "concerned that abusers could find a way to manipulate the new formulation." In 2010, Purdue Pharma introduced 'Oxycontin OP', Purdue Pharma predicts that abuse of higher dose formulations such as 'OxyContin' will go down, but this change may cause heavy recreational users to resort to other drugs such as heroin or may increase the number of deaths caused by acetaminophen poisoning from users attempting to take similar doses of drugs like 'Percocet' or 'Vicodin' to get similar effects. Since 'Oxycontin OP' has now fully saturated the street markets, recreational users find it nearly impossible to find the original Oxycontin formulations).

One investigation in Boston found that OxyContin was a "gateway" drug for heroin, which addicts turned to as a cheaper alternative.

Legal status

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. The 1961 Single Convention on Narcotic Drugs of the United Nations, which replaced the 1931 convention, categorized oxycodone in Schedule I. 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." In addition, it is in Schedule 8 of the Australian Standard for the Uniform Scheduling of Drugs and Poisons ("Poisons Standard"), meaning that 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."

;Canada Oxycodone is a controlled substance under Schedule I of the Controlled Drugs and Substances Act (CDSA). Every person who seeks or obtains from a practitioner either the substance or an authorization to obtain the substance must disclose to that practitioner information on all controlled substances and authorizations for controlled substances obtained from any other practitioner within the preceding 30 days; otherwise, the person may be found "guilty of an indictable offence and liable to imprisonment for a term not exceeding seven years". The law states that only physicians, dentists and veterinarians ("Ärzte, Zahnärzte und Tierärzte") can prescribe oxycodone, and that the federal government can regulate the prescriptions (e.g., by requiring reporting). The penalty for trafficking (Section 4) or manufacturing (Section 6) the substance is a $5,000,000 HKD fine and/or life imprisonment. The minimum and maximum penalties for unauthorized trafficking in the drug are respectively five years' imprisonment and five strokes of the cane, and 20 years' imprisonment and 15 strokes of the cane.

;United Kingdom Oxycodone is a Class A drug under the Misuse of Drugs Act. 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. Dealing of the drug illegally is punishable by up to life imprisonment, an unlimited fine, or both.

;United States Under the Controlled Substances Act, oxycodone is a Schedule II drug because it "has a high potential for abuse," because it "has a currently accepted medical use in treatment in the United States or a currently accepted medical use with severe restrictions," and because use of the drug "may lead to severe psychological or physical dependence." According to Section 829 of the Act, Schedule II drugs must be dispensed only with the written prescription of a practitioner except in certain situations (e.g., "dispensed directly by a practitioner, other than a pharmacist," or "dispensed upon oral prescription (i.e. telephone)" in "emergency situations only"). The abuse resistant formulation is recognizable by a pill marking "OP" on one side and the milligrams of oxycodone contained within the pill on the other. The previous formulation has an "OC" marking replacing the "OP" of the new formulation.

See also

Illegal drug trade

List of drug-related deaths

Psychoactive drug

Recreational drug use

Notes

In WHO usage, the first two terms replace the term "abuse" and the third term replaces the term "addiction."

References

Further reading

External links

Coluzzi F, Mattia C. Oxycodone. Pharmacological profile and clinical data in chronic pain management. Minerva Anestesiol 2005 Jul–Aug;71(7–8):451-60.

Rosenberg T. When is a pain doctor a drug pusher? New York Times 2007 Jun 17.

Deadly combinations. St. Petersburg Times 2008 Feb 17 – May 19.

Watch Cottonland, a National Film Board of Canada documentary on OxyContin addiction

U.S. National Library of Medicine: Drug Information Portal – Oxycodone

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Category:Semisynthetic opioids Category:Morphinans Category:German inventions Category:Euphoriants Category:Ketones Category:Alcohols Category:Phenol ethers Category:Mu-opioid agonists