Oxycodone

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Not to be confused with oxandrolone, oxazepam, oxybutynin, or oxytocin.
"OxyContin" redirects here.
Oxycodone
Systematic (IUPAC) name
4,5α-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one
Identifiers
CAS number 76-42-6
ATC code N02AA05
N02AA55 (in combinations)
PubChem 5284603
DrugBank APRD00387
ChemSpider 4447649
Chemical data
Formula C18H21NO4 
Mol. mass 315.364 g/mol
SMILES eMolecules & PubChem
Synonyms dihydrohydroxycodeinone, 14-hydroxydihydrocodeinone, 6-deoxy-7,8-dihydro-14-hydroxy-3-O-methyl-6-oxomorphine[1]
Pharmacokinetic data
Bioavailability Up to 87%
Protein binding 45%
Metabolism Hepatic (CYP450: 2D6 substrate)
Half life 3 - 4.5 h
Excretion Urine (19% unchanged)
Therapeutic considerations
Pregnancy cat.

B/D (prolonged use or in high doses at term)
Legal status

Controlled (S8)(AU) Schedule I(CA) Class A(UK) Schedule II(US)
Dependence Liability Moderate - High
Routes oral, intramuscular, intravenous, intranasal, subcutaneous, transdermal, rectal, epidural[2]

Oxycodone is an opioid analgesic medication synthesized from opium-derived thebaine. It was developed in 1916 in Germany, as one of several new semi-synthetic opioids with several benefits over the older traditional opiates and opioids; morphine, diacetylmorphine (heroin) and codeine.

Currently it is best known as the main active ingredient in a number of oral medications commonly prescribed for the relief of moderate to severe pain. Oxycodone can be combined with inert binders (e.g., OxyContin); with paracetamol, also known as acetaminophen (e.g., Percocet, Endocet, Tylox, and Roxicet); with aspirin (e.g., Percodan, Endodan, Roxiprin); and with ibuprofen (Combunox). Of the oral medications containing oxycodone, OxyContin is notable for controversy concerning its patent status and for its potential for drug abuse.

Contents

[edit] Chemistry and nomenclature

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

  • Oxycodone has a hydroxyl group at carbon-14 (codeine has just a hydrogen in its place), hence oxycodone;
  • Oxycodone has a 7,8-dihydro feature, whereas 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, hence the "-one" suffix.

It is also similar to hydrocodone, differing only in that it has a hydroxyl group at carbon-14.[3]

The synonyms for oxycodone in the academic literature include "dihydrohydroxycodeinone,"[1][4][5] "Eucodal,"[4][5] "Eukodal,"[2][6] "14-hydroxydihydrocodeinone,"[1][4] and "Nucodan."[4][5] In a UNESCO convention, the translations of "oxycodone" are oxycodone (French), oxicodona (Spanish), والأوآسيكودون (Arabic), 羟考酮 (Chinese), and оксикодон (Russian).[7] The word "oxycodone" should not be confused with "oxandrolone," "oxazepam," "oxybutynin," "oxytocin," "Roxanol," or "Roxicet."[8]

[edit] History

Freund and Speyer of the University of Frankfurt in Germany first synthesized oxycodone from thebaine in 1916[9], a few years after the German pharmaceutical company Bayer had stopped the mass production of heroin due to addiction and abuse. It was hoped that a thebaine-derived drug would retain the analgesic effects of morphine and heroin with less addiction. 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.[6] 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.[10] Of all countries, the United States had the highest total consumption of oxycodone in 2007 (82% of the world total of 51.6 tons).[10] In addition, in 2007 the U.S. had the highest per capita consumption of oxycodone, followed by Canada, Denmark, Australia, and Norway.[10]

[edit] OxyContin

Oxycontin tablets of varying dosage

OxyContin is the brand name of a time-release formula of oxycodone produced by the pharmaceutical company Purdue Pharma.[11] It was approved by the U.S. Food and Drug Administration in 1995 and first introduced to the U.S. market in 1996.[11] By 2001, OxyContin was the best-selling non-generic narcotic pain reliever in the U.S.; in 2002, over 7.2 million prescriptions were written for it, for total sales of $1.5 billion.[11]

OxyContin is available in 5 mg (blue) tablets in Canada and the U.K.; 10 mg (white) in Canada, the U.S., and the U.K.; 15 mg (grey) in the U.S.; 20 mg (pink) in Canada, the U.S., and the U.K.; 30 mg (brown) in the U.S.; 40 mg (yellow) in Canada, the U.S., and the U.K.; 60 mg (red) in the U.S.; and 80 mg (green) in Canada, the U.S., and the U.K.[12][13][14] In 2001, Purdue Pharma suspended distribution of 160 mg tablets in the U.S. because of the "possibility of illicit use of tablets of such high strength."[11][15]

Slang terms for OxyContin include "Hillbilly Heroin," "Killers," "OC," "Oxy," and "Oxycotton."[16][17][18] The word "OxyContin" should not be confused with "morphine sulfate," "MS Contin," "Oxandrin," "oxybutynin," "oxytocin," or "Roxicodone."[8][19]

[edit] Lawsuits concerning generic OxyContin

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.[20] This decision allowed and led to the immediate announcement from Endo Pharmaceuticals that they would begin launching a generic version of all four strengths of OxyContin.[21] Purdue, however, had already made negotiations with another pharmaceutical company (IVAX Pharmaceuticals) to distribute their brand OxyContin in a generic form. This contract was severed, and currently Watson Pharmaceuticals is the exclusive U.S. distributor of Purdue-manufactured generic versions of OxyContin tablets in 10, 20, 30, 40, 60, and 80 milligram dosages in the United States.[22]

On February 1, 2006, the Federal Circuit Court of Appeals issued a revised decision varied their prior decision.[23] The court concluded that the patents-in-suit are unenforceable, and the case is remanded for further proceedings. Purdue Pharma has since announced resolution of its infringement suits with Endo,[24] Teva,[25] IMPAX,[26] and Mallinckrodt.[27]

Endo and Teva each agreed to cease selling generic forms of OxyContin. IMPAX negotiated a temporary, and potentially renewable, license. In 2008, Mallinckrodt Pharmaceuticals reintroduced generic OxyContin in the strengths of 10 mg, 20 mg, 40 mg and 80 mg.[27] This was made possible by a temporary royalties-bearing license with Purdue Pharma that expires in 2009.[27]

[edit] Misbranding and fraud

Critics have accused Purdue of putting profits ahead of public interest by understating or ignoring the addictive potential of the drug.[28][29][30]

Purdue Pharma and its top executives pleaded guilty to felony charges that they misbranded and misled physicians and the public by claiming OxyContin was less likely to be abused, less addictive, and less likely to cause withdrawal symptoms than other opiate drugs.[31] The company also paid millions in fines relating to aggressive off-label marketing practices in several states.[32]

[edit] Other preparations

Formulations containing oxycodone and other analgesics.

Oxy·IR immediate-release oxycodone tablets from Purdue Pharma in Canada are available in 5, 10, and 20 mg strengths.[13]

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, and the U.K.[33][34][35] In addition, in the U.K. OxyNorm is available in a 10 mg/ml liquid concentrate for oral use and a 10 mg/ml solution for injection or infusion.[35]

Percocet (oxycodone with paracetamol/acetaminophen) tablets are available in the U.S. with 2.5, 5, 7.5, and 10 mg of oxycodone and varying amounts of acetaminophen.[36]

Percodan tablets available in the U.S. contain 4.8355 mg of oxycodone HCl and 325 mg of aspirin.[37]

Available in Europe and other areas outside the United States, Proladone suppositories contain 15 mg of oxycodone pectinate. Other suppository strengths under this and other trade names are less frequently encountered.

Injectable oxycodone hydrochloride or tartrate is available in ampoules and multi-dose vials in many European countries and to a lesser extent various places in the Pacific Rim. For this purpose, the most common trade names are Eukodol and Eucodol.

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.[38][39] 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.[40]

[edit] Clinical use

In a 2008 review written by authors who "are members of advisory boards and speaker panels for Mundipharma," prolonged-release oxycodone (i.e., OxyContin) was found to be superior to placebo in randomized controlled trials concerning diabetic neuropathy, post-herpetic neuralgia, osteoarthritis, ambulatory laparoscopic tubal ligation surgery, unilateral total knee arthroplasty, and abdominal/gynaecological surgery.[41]

In 2001, the European Association for Palliative Care recommended that oral hydromorphone or oxycodone, "if available in both normal release and modified release formulations for oral administration," be second-line alternatives to oral morphine for cancer pain.[42] 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.[43] However, switching to an alternative opioid can be useful if adverse effects are troublesome, although the switch can be in either direction, i.e. some patients have fewer adverse effects on switching from morphine to oxycodone and vice versa.

[edit] Pharmacokinetics and pharmacodynamics

[edit] Absorption

After a dose of conventional oral oxycodone, peak plasma levels of the drug are attained in approximately one hour[44]; in contrast, after a dose of OxyContin, peak plasma levels of oxycodone occur in about three hours.[12]

[edit] Distribution

Oxycodone in the blood is distributed to "skeletal muscle, liver, intestinal tract, lungs, spleen, and brain."[12] Conventional oral preparations of oxycodone start to reduce pain within 10-15 minutes; in contrast, OxyContin starts to reduce pain within 1 hour.[3]

[edit] Metabolism

Oxycodone is metabolized to α and β oxycodol; oxymorphone, then α and β oxymorphol and noroxymorphone; and noroxycodone, then α and β noroxycodol and noroxymorphone.[44] A study using conventional oral oxycodone concluded that oxycodone itself, and not its metabolites, is responsible for the drug's opioid effects on the brain.[44]

Unlike morphine and hydromorphone, oxycodone is metabolized by the cytochrome P450 enzyme system in the liver, making it vulnerable to drug interactions.[12] Some people are fast metabolizers resulting in reduced analgesic effect but increased adverse effects, while others are slow metabolisers resulting in increased toxicity without improved analgesia.[45][46] The dose of OxyContin must be reduced in patients with reduced hepatic function.[3]

[edit] Elimination

Oxycodone and its metabolites are mainly excreted in the urine; therefore, it accumulates in patients with renal impairment.[3]

[edit] Dosage and administration

Oxycodone can be administered orally, intranasally, via intravenous/intramuscular/subcutaneous injection or rectally. The bioavailability of oral administration averages 60–87%, with rectal administration yielding the same results.

Oxycodone is approximately 1.5–2 times as potent as morphine when administered orally.[47][48] However, 10–15 mg of oxycodone produces an analgesic effect similar to 10 mg of morphine when administered intramuscularly.[49] 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;[43] however, oxycodone can be useful as an alternative opioid if a patient has troublesome adverse effects with morphine.

[edit] Side effects

Main side effects of oxycodone. Red color denotes more serious effects, requiring immediate contact with health provider.[50]

The most commonly reported effects include constipation, fatigue, dizziness, nausea, lightheadedness, headache, dry mouth, anxiety, pruritus, euphoria, and diaphoresis.[51] 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, dyspnea, and hiccups,[12] although these symptoms appear in less than 5% of patients taking oxycodone. Rarely, the drug can cause impotence, enlarged prostate gland, and decreased testosterone secretion.[52]

In high doses, overdoses, or in patients not tolerant to opiates, oxycodone can cause shallow breathing, bradycardia, cold, clammy skin, apnea, hypotension, pupil constriction, circulatory collapse, respiratory arrest, and death.[12]

[edit] Withdrawal related side effects

There is a high risk of experiencing severe withdrawal symptoms if a patient discontinues oxycodone abruptly. Therefore therapy should be gradually discontinued rather than abruptly discontinued. Drug abusers are at even higher risk of severe withdrawal symptoms as they tend to use higher than prescribed doses. The symptoms of oxycodone withdrawal are the same as for other opiate based painkillers and may include "anxiety, nausea, insomnia, muscle pain, fevers, and other flu like symptoms."[16]

Withdrawal symptoms have also been reported in a newborn whose mother had been injecting OxyContin during pregnancy.[53]

[edit] Abuse and pharmaceutical diversion

Well-known people who have become addicted to oxycodone include:

  • William S. Burroughs, writer, who wrote to Allen Ginsberg in 1954 that he was injecting "Eukodol" (apparently meaning "Eukodal" or oxycodone) every two hours.[54]
  • Adam Gontier, lead singer for Three Days Grace, who was "taking 10 to 20 80-milligrams of OxyContin a day" before undergoing rehabilitation in 2005.[55]
  • Patrick J. Kennedy, politician, who said that he was at the Mayo Clinic on Christmas Day 2005 for addiction to OxyContin.[56]
  • Heath Ledger, actor, who died in 2008 as a result of "acute intoxication" from a combination of drugs that included oxycodone; the overdose was ruled an accident "resulting from the abuse of prescription medications."[57]
  • Rush Limbaugh, radio personality, who admitted to an addiction to painkillers in 2003; it was reported that these painkillers included OxyContin.[58]
  • Lindsay Lohan, actress; her father claimed in 2007 that she was addicted to OxyContin and other substances.[59]
  • Courtney Love, musician, who reportedly "admitted to overdosing on the prescription painkiller OxyContin" in 2003.[60]

Instances of abuse and pharmaceutical diversion of OxyContin have increased in the U.S. beginning in the late 1990s[61] and in Australia beginning in the early 2000s.[18][62] Diversion of OxyContin in the U.S. may occur through "fraudulent prescriptions, doctor shopping, over-prescribing, and pharmacy theft."[61]

A 2003 study by the Government Accountability Office found four factors that may have contributed to abuse and diversion of OxyContin in the U.S.:[11]

  • Oxycodone is "twice as potent as morphine," and OxyContin contains a large amount of oxycodone compared with other types of pills.
  • OxyContin's warning label said to not crush the controlled-release tablets because of the potential for rapid release of oxycodone, which led to many people crushing the tablets and injecting or snorting the drug.
  • By 2001, sales of OxyContin in the U.S. exceeded $1 billion per year, which made it widely available.
  • People who received prescriptions for OxyContin and lived in poor areas of Appalachia may have perceived a "profit potential" in selling the pills to drug dealers (e.g., 20 mg of OxyContin could be bought for $2 but sold for $25).

A study published in 2005 examined the prevalence of abuse of opiate analgesics among "recreational drug users and street addicts" as perceived by "key informants" throughout the U.S.; the authors found that opiate abuse was increasing in general, but that of the drugs studied abuse of OxyContin "was mentioned most frequently."[63]

Research has shown that the brains of adolescent mice, which were exposed to OxyContin, can sustain lifelong and permanent changes in their reward system.[64][65] It is notable that the vast majority of OxyContin related deaths are attributed to ingesting substantial quantities of oxycodone in combination with another depressant of the central nervous system such as alcohol, barbiturates and related drugs.[66]

[edit] Conventions and national laws

 This section needs additional citations for verification. Please help improve this article by adding reliable references (ideally, using inline citations). Unsourced material may be challenged and removed. (March 2009)

Oxycodone is subject to international conventions on narcotic drugs. In addition, oxycodone is subject to national laws that differ by country.

[edit] International

The 1931 Convention for Limiting the Manufacture and Regulating the Distribution of Narcotic Drugs of the League of Nations included oxycodone (but incorrectly called it "dihydrohydrooxycodeinone" instead of "dihydrohydroxycodeinone").[67] The 1961 Single Convention on Narcotic Drugs of the United Nations, which replaced the 1931 convention, categorized oxycodone in Schedule I.[68] 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."[68]

[edit] Australia

A General Practitioner can prescribe for short term treatment without consulting another practitioner or government body. Prescriptions for chronic pain or cancer patients require the prescriber to have referred the patient to another medical practitioner to confirm the need for ongoing treatment with narcotic analgesics. Pharmacists must record all incoming purchases of oxycodone products, and maintain a register of all prescription sales for inspection by their state Health Department on request. In addition, details of all Pharmaceutical Benefits Scheme prescriptions for oxycodone are sent to Medicare Australia. This data allows Medicare Australia to assist prescribers to identify Doctor-shoppers via a telephone hotline.

[edit] Canada

Oxycodone is a controlled substance under Schedule I of the Controlled Drugs and Substances Act (CDSA).[69] 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".[69] Anyone possessing the substance for the purpose of trafficking "is guilty of an indictable offence and liable to imprisonment for life".[69]

[edit] Germany

Only physicians (Ärzte) can prescribe oxycodone. Prescribing physicians need to have a special BtM number (controlled substance number). BtM prescriptions are handled very cautiously and the central Federal Opium Bureau (Bundesopiumstelle) records all traffic.

[edit] Hong Kong

Oxycodone is regulated under Schedule 1 of Hong Kong's Chapter 134 Dangerous Drugs Ordinance. It can only be used legally by health professionals and for university research purposes. The substance can be given by pharmacists under a prescription. Anyone who supplies the substance without a prescription can be fined $10,000 (HKD). The penalty for trafficking or manufacturing the substance is a $5,000,000 HKD fine and/or life imprisonment. Possession of the substance for consumption without license from the Department of Health is illegal with a $1,000,000 HKD fine and/or 7 years of jail time.

[edit] United Kingdom

Oxycodone is a Class A drug under the Misuse of Drugs Act.[70] It is available by prescription from a GP on the NHS for short-term severe pain and long-term for cancer patients. 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.[71]

[edit] United States

Oxycodone is a schedule II drug in the United States. Except when dispensed directly by a practitioner, other than a pharmacist, to an ultimate user, no controlled substance in schedule II, which is a prescription drug as determined under the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 301 et seq.), may be dispensed without the written prescription of a practitioner, except that in emergency situations, such drug may be dispensed upon oral prescription (i.e. telephone) in accordance with section 503(b) of that Act (21 U.S.C. 353(b). Prescriptions shall be retained in conformity with the requirements of section 827 of this title. No prescription for a controlled substance in schedule II may be refilled.[72] Some states may have more strict laws pertaining to the prescribing and dispensing of Schedule II medications.

[edit] See also

[edit] References

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[edit] Further reading

  • Meier, Barry (2003). Pain killer: a "wonder" drug's trail of addiction and death. Emmaus, PA: Rodale. ISBN 1579546382. 
  • Pinsky, Drew (2004). When painkillers become dangerous: what everyone needs to know about OxyContin and other prescription drugs. Center City, MN: Hazelden. ISBN 159285107X. 
  • Lockwood, Brad (2006). Oxycontin: from pain relief to addiction. New York: Rosen Pub. Group, Inc. ISBN 9781404209138. 

[edit] External links

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Analgesic products (N02A, N02B)
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See also: Opioids template
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