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Wikipedia - Oxycodone
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Oxycodone
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| Systematic (IUPAC) name | |
| 4, 5-epoxy-14-hydroxy-3- methoxy-17-methylmorphinan-6-one | |
| Identifiers | |
| CAS number | |
| ATC code | N02 |
| PubChem | |
| DrugBank | |
| Chemical data | |
| Formula | C18H21NO4 |
| Mol. mass | 315.364 g/mol |
| SMILES | & |
| Pharmacokinetic data | |
| Bioavailability | Up to 87% |
| Protein binding | 45% |
| Metabolism | Hepatic (CYP450: 2D6 substrate) |
| Half life | 3 - 4.5 hours |
| 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, intranasally, subcutaneous, transdermal, rectal |
Oxycodone is an opioid analgesic medication synthesized from 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 and codeine. It was introduced to the pharmaceutical market as Eukodal or Eucodal and Dinarkon. Its chemical name is derived from codeine - the chemical structures are very similar, differing only in that the hydroxyl group of codeine has been oxidized to a carbonyl group (as in ketones), hence the "-one" suffix, the 7,8-dihydro-feature (codeine has a double-bond between those two carbons), and the hydroxyl group at carbon-14 (codeine has just a hydrogen in its place), hence oxycodone.
In the United States, oxycodone is a Schedule II controlled substance both as a single agent and in combination with products containing paracetamol (aka acetaminophen), ibuprofen or aspirin. It was first introduced to the US market in May 1939 and is the active ingredient in a number of pain medications commonly prescribed for the relief of moderate to heavy pain, either with inert binders (oxycodone, OxyContin) or supplemental analgesics such as acetaminophen (Percocet, Endocet, Tylox, Roxicet) and aspirin (Percodan, Endodan, Roxiprin ). It is also sold in a sustained-release form by Mundipharma in Germany (Oxygesic), and in the United States by Purdue Pharma under the trade name OxyContin (Oxycodone Continuous release) as well as generic equivalents, and instant-release forms Endone, OxyIR, OxyNorm, Percolone, OxyFAST, Supeudol, and Roxicodone. More recently, ibuprofen has been added to oxycodone (Combunox).
Oxycodone is a drug subject to abuse.[1][2] The drug is included in the sections for the most strongly controlled substances that have a commonly accepted medical use, including the German Betäubungsmittelgesetz III (narcotics law), the Swiss law of the same title, UK Misuse of Drugs Act (Class A), Canadian Controlled Drugs and Substances Act (CDSA), Dutch Opium Law (List 1), Austrian Suchtmittelgesetz (Addictives Act), and others. It is also subject to international treaties controlling psychoactive drugs subject to abuse or dependence.
The abuse of OxyContin and its generic equivalents has greatly increased since the introduction of the sustained-release form of oxycodone. Illegal distribution of OxyContin occurs through pharmacy diversion, physicians, "doctor shopping," faked prescriptions, and robbery, all of which divert the pharmaceutical onto the illicit market. In Australia alone during 1999 and 2000, more than 260,000 prescriptions for narcotics and codeine-based medications were written to almost 9,000 known abusers at a cost of more than $750,000 AUD.[2] 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.[3] The company also paid millions in fines relating to aggressive off-label marketing practices in several states.[4]
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[edit] Chemistry
Oxycodone is commercially made from thebaine, an opiate alkaloid and minor component of opium.[5] The 14' hydroxy group increases potency by about 50% over hydrocodone.[citation needed]
The chemical structure of oxycodone is the methylether of oxymorphone: 3-methyl-oxymorphone. It could also be described as 14-hydroxy-7,8-dihydro-codeinone. It is principally supplied as its hydrochloride salt: oxycodone hydrochloride. The terephtalate salt of oxycodone is present in some formulations such as Percodan as 7.6 per cent of the weight of the oxycodone salts content of the product, viz. 5 mg of oxycodone in Percodan is 4.62 mg hydrochloride and 0.38 mg terephtlalate. There does not appear to be a significant difference in the action of the salts. The hydrochloride-terephtalate mixture appears to be part of the original formulation of Percodan by its German manufacturers from more than 75 years ago.[citation needed]
Other oxycodone salts used around the world include the phosphate, sulfate, pectinate, tartrate, bitartrate, citrate and iodide.
[edit] Side effects
The most commonly reported effects include constipation, fatigue, dizziness, nausea, lightheadedness, headache, dry mouth, pruritus, and diaphoresis. Some patients have also experienced loss of appetite, nervousness, euphoria, anxiety, abdominal pain, diarrhea, dyspnea, and hiccups,[6] 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.[5]
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.[6]
[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. Injecting oxycodone will result in a stronger effect and quicker onset.
Percocet tablets, oxycodone with acetaminophen (paracetamol), are routinely prescribed for post-operative pain control. Tablets are available with 2.5, 5, 7.5, 10 or 15 mg of oxycodone and varying amounts of acetaminophen. Oxycodone is also used in treatment of moderate to severe chronic pain. Both immediate-release and sustained-release oxycodone are now available (OxyNorm and OxyContin in the UK). There are no comparative trials showing that oxycodone is more effective than any other opioid. In palliative care, morphine remains the gold standard.[7] However, it can be useful as an alternative opioid if a patient has troublesome adverse effects with morphine.
OxyNorm is available in 5, 10, and 20 mg capsules and tablets; also as a 1 mg/1 ml liquid in 250 ml bottles and as a 10 mg/1 ml concentrated liquid in 100 ml bottles. Available in Europe and other areas outside the United States, Proladone suppositories contain 15 mg of oxycodone pectinate and 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 is a generically made oxycodone product designed to have an immediate release effect for rapid pain relief, and is available in 5 (white), 15 (green), and 30 (light blue) mg tablets. Generic versions of Roxicodone may differ in color from the brand name tablets.
OxyContin is available in 10 mg (white), 20 mg (pink), 40 mg (yellow), and 80 mg (green) in the U.S. and Canada, and 160 mg (blue) in Canada only. Because of its sustained-release mechanism, the medication is typically effective for eight to twelve hours.[6] The 160 mg tablets were removed from sale due to problems with overdose, but have been re-introduced for limited use under strict medical supervision. On October 18, 2006, the FDA gave approval for four new dosage strengths, to wit, 15, 30, 45, and 60 mg. Oxycontin is made of pure oxycodone hydrochloride. Nevertheless, an 80 mg Oxycontin has a mass of approximately 260 mg (not including the navy-colored coating) due to other compounds.
Generic OxyContin was introduced in 2005 (80 mg) and 2006 (10, 20, and 40 mg). However, because of numerous law suits related to the addictive and abuse potential of the medicine, generic manufacture (alternatively reported as "except by Dava") ceased on December 31, 2007. Because of stockpiled inventory, generic OxyContin is still available, albeit infrequently, as of May 2008.
The controlled (sustained)-release preparations are essential to provide a background plasma level of analgesia in anyone with persistent pain. The immediate release preparations are useful for breakthrough pain, which can break through the controlled-release baseline medication. There are no trials to show that one manufacturer produces a more effective oxycodone product than any other.
[edit] History
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This section needs additional citations for verification. Please help improve this article by adding reliable references. Unsourced material may be challenged and removed. (August 2007) |
Oxycodone is an opiate analgesic, and as such is a variation on an ancient theme beginning with the simple consumption or smoking of the alkaloid-bearing parts of Papaver somniferum, the opium poppy, first cultivated circa 3400 BC in lower Mesopotamia. Ancient Persians, Sumerians, Assyrians, Babylonians, and Egyptians found that smoking the extract derived from the seed pods yielded a pleasurable, peaceful feeling throughout the body. The Sumerians called the poppy plant "Hul Gil" or "joy plant". Cultivation and use spread quickly to the rest of the Persian Gulf, Levant and the Arabian Peninsula, eventually reaching India and China.
Oxycodone was first synthesized in a German laboratory in 1916, a few years after the German pharmaceutical company Bayer had stopped the mass production of heroin due to addiction and abuse by both patients and physicians. It was hoped that a thebaine-derived drug would retain the analgesic effects of morphine and heroin with less of the euphoric effect which led to addiction and over use. To some extent this was achieved, as oxycodone does not "hit" the central nervous system with the same immediate punch as heroin or morphine and it does not last as long. The subjective experience of a "high" was still reported for oxycodone, however, and it made its way into medical usage in small increments in most Western countries until the introduction of high strength preparations with inert (inactive) binders radically boosted oxycodone use.[citation needed]
The introduction of these higher strength preparations in 1995 resulted in increasing patterns of abuse.[1] Unlike Percocet, whose potential for abuse is somewhat limited by the presence of paracetamol (acetaminophen), OxyContin and other extended release preparations, contains only oxycodone and inert filler. Abusers simply crush the tablets, then either ingest the resulting powder orally, intranasally, via intravenous, intramuscular, or subcutaneous injection (by dissolving the powder), or rectally to achieve rapid absorption into the bloodstream. The tablets' coatings are removed, and they are crushed or chopped up by abusers to disable the time-release properties of the tablet, which allows the entire dose to "hit" the abuser at once. This rapid onset of the entire dose, or "hit", is referred to as "the rush" by drug abusers. This "rush" delivers a feeling of, what is described by abusers as, a "blissful apathy" and state of well-being, accompanied by a powerful and alluring euphoria. Injection of oxycodone directly into the bloodstream produces the most intense effects. Injection of OxyContin is also particularly dangerous since it contains binders which enable the time release of the drug. 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 or benzodiazepines.[8]
Oxycodone is a highly publicized and known drug to the general public. However, it is also widely misunderstood, and many people lack factual knowledge about the drug. The discovery of its recreational benefits has led to an illicit underground market. Due to acts such as pharmacy diversion and "doctor shopping", the drug is widely available to those without a prescription in some areas.[2] The increased misuse of the drug has led to a higher number of emergency department mentions and deaths associated with oxycodone. Between 1994 and 2001, there was a reported 352% increase in ER visits related to all forms of oxycodone usage.[9]
The increase of these illegal methods of obtainment coincides with the increase in the illegal use of this drug. The oxycodone contained in OxyContin produces typical opiate effects, and is, by some, considered a "reasonable substitute" for heroin, so much so that OxyContin is sometimes referred to as "hillbilly heroin". The most commonly diverted dosages are the 40mg and 80mg strengths.
[edit] Clinical use
In palliative care, oxycodone is viewed as a second line opioid to morphine, like hydromorphone and fentanyl. 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.[7] However, switching to an alternative opioid can be useful if adverse effects are troublesome, although the switch can be in either direction, ie. some patients have fewer adverse effects on switching from morphine to oxycodone (or hydromorphone or fentanyl), while others do better on switching to morphine.
Oxycodone has the disadvantage of accumulating in patients with renal and hepatic impairment. In addition, and unlike morphine and hydromorphone, it is metabolised by the cytochrome P450 enzyme system in the liver, making it vulnerable to drug interactions.[6] It is metabolised to the very active (but non-analgesic) oxymorphone,[10] and some people are fast metabolisers resulting in reduced analgesic effect but increased adverse effects, while others are slow metabolisers resulting in increased toxicity without improved analgesia.[11][12] These factors make the effects of oxycodone less predictable than opioids such as morphine or hydromorphone.
[edit] Manufacture and patents
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This section needs additional citations for verification. Please help improve this article by adding reliable references. Unsourced material may be challenged and removed. (August 2007) |
An extended-release formulation of oxycodone, OxyContin, was first introduced to the US market by Purdue upheld a decision from the previous year that some of Purdue’s patents for OxyContin could not be enforced.[13] This decision allowed and led to the immediate announcement from Endo Pharmaceutical Holdings, Inc. that they would begin launching a generic version of all four strengths of OxyContin.[14] 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 the generic versions of OxyContin tablets. The agreement stipulates that "Purdue will manufacture and supply oxycodone HCI controlled-release tablets to Watson, which will market, sell, and distribute the authorized generic product in 10, 20, 40, and 80 milligram dosages in the United States".[15]
On February 1, 2006, the Federal Circuit Court of Appeals issued a revised decision that affirmed-in-part, vacated-in-part, and remanded-in-part their prior decision.[16] The court concluded, "The trial court's judgment that the patents-in-suit are unenforceable due to inequitable conduct is vacated, and the case is remanded for further proceedings consistent with this opinion. The trial court's judgment of infringement is affirmed." Purdue Pharma has since announced resolution of its infringement suits with Endo,[17] Teva,[18] and IMPAX.[19] Endo and Teva each agreed to cease selling generic forms of OxyContin, while IMPAX negotiated a temporary, and potentially renewable, license.
Since the drug is a controlled substance, a prescription is required to obtain it, and is shown to be most frequently prescribed in the eastern United States. Purdue Pharma also exports OxyContin to wholesale distributors in Mexico and Canada. However, they have experienced increasing levels of illicit drug trafficking with the distribution outside of the U.S. that has led to certain responsive actions. The pill exported to Mexico is stamped with the letters "EX" instead of the customary "OC," and similarly the pills to Canada read "CDN" Purdue stopped exporting to Canada in 2001, and instead Canada imports the drug from a manufacturer in England. Despite these problems, OxyContin is one of the leading opioid painkillers on the market. In 2001, OxyContin was the highest sold drug of its kind, and in 2000, over 6.5 million prescriptions were written.[20]
[edit] Regulation
Regulation of oxycodone (and opioids in general) differs according to country, with different places focusing on different parts of the "supply chain".
In Australia, a General Practitioner can prescribe for short term treatment without consulting another practitioner or government body. Ongoing treatment requires approval from their state Health Department. Only twenty tablets are normally available per prescription on the Pharmaceutical Benefits Scheme, Australia's government-funded pharmaceutical insurance system, but a patient can potentially get up to sixty tablets for as little as $4.90AUD. Prescriptions for larger quantities require prior approval from Medicare Australia. These prescriptions (i.e. 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.
In Cana