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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 | 76-42-6 |
| ATC code | N02AA05 |
| PubChem | 5284603 |
| DrugBank | APRD00387 |
| Chemical data | |
| Formula | C18H21NO4 |
| Mol. weight | 315.364 g/mol |
| Pharmacokinetic data | |
| Bioavailability | Up to 87% |
| Protein binding | 45% |
| Metabolism | Hepatic |
| Half life | 3 - 4.5 hours |
| Excretion | Urine |
| Therapeutic considerations | |
| Pregnancy cat. | B/D(prolonged use or in high doses at term) |
| Legal status | Schedule I(CA) Class A(UK) Schedule II(US) |
| Dependence Liability | Moderate - High |
| Routes | Oral, intramuscular, intravenous, intranasally, subcutaneous, transdermal, rectal |
Oxycodone is a potent and addictive opioid analgesic medication synthesized from thebaine. Its name is derived from codeine - the chemical structures are very similar, differing only in that the hydrogen on the codeine is oxidised to a hydroxyl group, hence 'oxy' and the hydroxyl group from the codeine becomes a ketone group, hence 'oxycodone.'
It is effective orally and is marketed in combination with acetylsalicylic acid (Percodan, Endodan, Roxiprin) or paracetamol/acetaminophen (Percocet, Endocet, Roxicet, Tylox) for the relief of pain. More recently, ibuprofen has been added to oxycodone (Combunox). It is also sold in a sustained-release form by Purdue Pharma under the trade name OxyContin as well as generic equivalents, and instant-release forms Endone, OxyIR, OxyNorm, Percolone, OxyFAST, and Roxicodone. Roxicodone is available in 5, 15, and 30 mg tablets. OxyContin is available in 10, 20, 40, 80, and 160 mg tablets, and, due to its sustained-release mechanism, is effective for eight to twelve hours. Outside the U.S. OxyContin is also available in a 5 mg tablet. (The 160 mg formulation was discontinued in May 2001.) OxyNorm is available in 5, 10, and 20 mg capsules and tablets; also as a 1 mg/1 ml liquid in 250 mg bottles and as a 10 mg/1 ml concentrated liquid in 100 mg bottles.
In the United States, oxycodone is a Schedule II controlled substance both as a single agent and in combination products containing paracetamol, ibuprofen or aspirin.
Contents |
Chemical structure
The chemical structure of oxycodone is the methylether of oxymorphone: 3-Methyl-oxymorphone. It could also be described as 14-Hydroxy-Codeinone. It is principally supplied as its hydrochloride salt: oxycodone hydrochloride
Bioavailability
Oxycodone can be administered orally, intranasally, via intravenous/intramuscular/subcutaneous injection, or rectally. The bioavailability of intranasal administration averages between 46-47%, but can be as much as 75%. Oral oxycodone is the most efficient means of administration, having an absorbtion of 60-87%. Rectal administration yields the same results. Injecting oxycodone will result in a stronger effect, and quicker onset, with a bioavailability slightly higher than oral administration.[1]
Medical use
Oxycodone is one of the most powerful medications for pain control that can be taken orally. Percocet tablets (Oxycodone with acetaminophen) are routinely prescribed for post-operative pain control. Oxycodone is also used in treatment of moderate to severe chronic pain. When used at recommended doses for relatively short periods (several weeks), it provides effective pain control with manageable side effects. Both immediate release oxycodone and sustained-release OxyContin are prescribed for pain due to cancer more than for any other condition. Due to an increase in cranial pressure, though clinically negligible, oxycodone is rarely recommended as a first-line treatment for medical issues of the head, including accidents involving brain trauma or spinal meningitis infections.
Nausea, constipation, lightheadedness, rash or itchiness, dizziness, and emotional mood disorders are the most frequently reported side effects. Other side-effects can also include slightly decreased testosterone levels in men. Misuse or long-term medical use of the drug can cause temporary impotence as well as a significant prostate enlargement in men.
Tolerance and physical dependence occurs after several days to weeks of treatment, with larger doses being required to achieve the same degree of analgesia.
According to the DEA and the companies that manufacture the drug, psychological addiction as a result of medical use is uncommon. Despite this statement, there are several lawsuits underway brought by plaintiffs who claim to have developed addiction as a result of medical use.
Several companies such as Elite Pharmaceuticals, Inc. and Pain Therapeutics, Inc are currently developing an anti-abuse version of oxycodone. Elite's ELI-216 has completed Phase I clinical trials and Pain Therapeutics' new drug called Remoxy is in Phase III clinical trials.
History
Oxycodone is an agonist opioid, 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 Sumerians, Assyrians, Babylonians, and Egyptians found that smoking the extract derived from the seedpods 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 Levant and the Arabian Peninsula, eventually reaching India and China.
Oxycodone is a semi-synthetic opioid derived from the alkaloid thebaine, unlike most early opium-derived drugs which instead used the morphine or codeine alkaloids also found in the plant. 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 do 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 the OxyContin preparation radically boosted oxycodone use.
Abuse
The introduction of OxyContin in 1995 resulted in increasing patterns of abuse. Unlike Percocet, whose potential for abuse is limited by the presence of paracetamol, OxyContin contains only oxycodone and inert filler. Abusers wash off the coating and crush the tablets to defeat the time-release mechanism, then either ingest the resulting powder orally, intranasally, via intravenous/intramuscular/subcutaneous injection, or rectally to achieve rapid absorption into the bloodstream. Injection of OxyContin is particularly dangerous since it contains binders which enable the time release of the drug. Often mistaken as the time release, the outside coating of the pill is merely used as a color code for different dosage amounts. 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. While high doses of oxycodone can be fatal to an opiate-naïve individual in and of itself, this is (comparatively) rarely the case. It was once felt that "combination" opioids (those that contain one or more additional, non-narcotic ingredients) would be less subject to abuse, since, for example, the amount of paracetamol present in large overdoses of Percocet would cause stomach upset and liver damage. However, it has been demonstrated that abusers seeking the euphoric "high" are not deterred by these potential side effects or toxicities. Abusers soon discovered that extremely simple methods to separate the ingredients exist, particularly due to the widely disparate solubility of the alkaloids and analgesics in water ("cold water extraction").
Oxycodone has similar effects to morphine and heroin, and appeals to the same abuse community. Armed robberies of pharmacies where the robber demanded only OxyContin, not cash, have occurred. In some areas, particularly the eastern U.S., OxyContin has been the drug of greatest concern to enforcement authorities, although trustworthy data on the actual incidence of "Oxy abuse" have been difficult to establish.
Because oxycodone is highly regulated, when acquired illegally it is quite expensive. Black market prices in Washington, DC, and Portland, Maine, for example, have been reported to reach upwards of one dollar per milligram. In parts of Kentucky, particularly in Appalachia, nearly $1.25/mg. Legally acquired OxyContin is however rather expensive, costing as much as 400 US dollars for a normal month supply. Again, in mid-2006, brand-name or similar-quality generic (e.g., Watson, Purdue) eighty-milligram tablets sold for approximately twelve dollars whereas low-end generics (e.g., the above-referenced "footballs") scarcely pushed three dollars.
In Australia OxyContin is covered by the PBS, and a patient can get 3 boxes (60 tablets) for $4.70AUD in total. This has led to Federal tightening of restrictions from May 2006 (see Regulation below). The 20mg tablet can fetch $30AUD-$50AUD on the Gold Coast black market. As such there are professional "Doctor shoppers" making a tidy profit each week from OxyContin.
Like other opioids, oxycodone can be fatal at high doses or when combined with depressants such as alcohol. Several documented fatalities from OxyContin abuse have been made public; however, these have done little to deter the combined use of the drug with depressants on account of the intense euphoria it produces.
In early 2006 on the East Coast there were multiple antectodal reports of "fake" OxyContin 80mg tablets, especially in Philadelphia and New York City. These fake OxyContin consistly mainly of sugar and were of poor quality, noting the distinct green color which differs from commercially made tablets. There have also been multiple reports of fake OxyContin 80mg tablets that contained Fentanyl.[2]
Conservative radio host Rush Limbaugh is a famous admitted former OxyContin addict and abuser[3]. Jason Mewes was also addicted to OxyContin whilst also abusing heroin until he became clean.
Illegal distribution of OxyContin occurs through pharmacy diversion, dishonest physicians, "doctor shopping," fake prescriptions, and robbery, all of which divert the pharmaceutical onto the illicit market. The increase of this situation coincides with the increase in the illegal use and abuse of this drug. The oxycodone contained in OxyContin produces opiate-like effects, and is considered a "reasonable substitute" for heroin[4]. The most commonly diverted dosages are the 40mg and 80mg strengths[4].
Manufacturer and Patents
OxyContin was first introduced onto the market by Purdue Pharma L.P. in 1995. This pharmaceutical company was founded in 1892 in New York City, and is currently a privately owned company that operates solely within the United States. The different branches within this company include, Purdue Pharma L.P., The Purdue Frederick Company, Purdue Pharmaceutical Products L.P., and Purdue Products L.P. (www.pharma.com). It has multiple patents for their drug OxyContin, but has recently been involved in a series of on going legal battles deciding on whether or not these patents are valid. On June 7th, 2005, the United States Court of Appeals 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 Pharmaceutical Holdings, Inc. that they would begin launching a generic version of all four strengths of OxyContin[5]. 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"[6].
Purdue Pharma L.P. is based out of Stamford, Connecticut, and is the site of the company’s headquarters. Manufacturing takes place at three different sites, which include: Purdue Pharmaceuticals L.P., a plant located in Wilson, North Carolina, The P.F. Laboratories Inc. in Totowa, New Jersey, and Rhodes Technologies L.P. located in Coventry, Rhode Island. Purdue Pharma L.P. also has research labs located in Cranbury, New Jersey. OxyContin is currently legally and illegally distributed throughout the U.S., Canada, and Mexico. Legal distribution takes place from the P.F. Laboratories Inc. in Totowa. 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 U.S.[4]. Purdue 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[7].
Chemistry
Oxycodone is made, commercially, from thebaine, a minor component of opium. The 14 hydroxy group increases potency by about 50% over hydrocodone. The 14 cinnamyl ester is 114x morphine in potency.
Regulation
Regulation of oxycodone (and opioids in general) differs according to country, with different places focusing on different parts of the "supply chain".
Regulation in the USA
Regulation of prescription drugs comes from many different areas. The Food and Drug Administration (FDA) approves drugs for medical use, as well as sets regulations for the marketing of drugs, including controlled substances. The Drug Enforcement Administration (DEA) on the other hand, receives its regulatory authority from the Controlled Substances Act (CSA) [21 U.S.C. §§ 801-971], which "mandates that DEA prevent, detect and investigate the diversion of legally manufactured controlled substances while, at the same time, ensuring that there are adequate supplies to meet the legitimate medical needs in the United States"[8].
Part of the regulation of prescription drugs is connected to their marketing and advertising. The FDA has authority over this sector under the Food, Drug, and Cosmetic (FD&C) Act and its implementing regulations. The Division of Drug Marketing, Advertising, and Communications (DDMAC) is "responsible for regulating prescription drug advertising and promotion," and has a "mission is to protect the public health by ensuring that prescription drug information is truthful, balanced, and accurately communicated"[9].
Regulation in Australia
In contrast, in Australia a General Practitioner can prescribe up to a 10 day supply of OxyContin, provided that they gain authority from Canberra for each prescription written. Prescriptions for a 30 day supply require two doctors, and must be cleared by Canberra. Additional prescriptions (i.e. for chronic pain or cancer patients) require two doctors for the first prescription, one of whom is a Pain Specialist, the treatment must have started within a hospital, and at least one of the prescribing doctors must be a designated as primary prescriber by a Pain Specialist, and each prescription must be cleared by Canberra. Pharmacists must report the issuing of all oxycodone to the same authority in Canberra - mismatches found between prescribers, patients and Pharmacists result in investigation.
Advertising
Purdue Pharma L.P. does not use direct-to-consumer advertising, but instead focuses their marketing tactics towards health care professionals exclusively. They do this through the use of paper advertisements in medical journals and other publications of this nature, as well as promotion and sale directly to physicians, pharmacies, and hospitals. In January of 1996, Purdue signed a co-promotion agreement with Abbott in regards to their OxyContin Tablets. Abbott is now involved in the promotion of the drug to anesthesiologists and surgeons in hospitals throughout the U.S. (www.pharma.com). Although Purdue does not use direct-to-consumer advertising, OxyContin is becoming an increasingly more publicized and known drug to the general public. The discovery of its recreational benefits has led to an illicit underground market. As discussed earlier, due to acts such as pharmacy diversion and "doctor shopping" the drug is widely available to those without a prescription. The increased misuse of the drug has led to a higher number of emergency department mentions and deaths associated with oxycodone[4]. Despite the increased efforts by the FDA, DEA, and state/local authorities, along with this negative publicity of the drug is not stopping its illicit use, but instead seems to be fueling the underground market.
References
- ^ That's Poppycock! - Oxycodone: Pharmacology and Pharmacokinetics
- ^ [1]
- ^ http://www.cnn.com/2003/SHOWBIZ/10/10/rush.limbaugh/
- ^ a b c d http://police.byu.edu/community%20education/drugalert/oxycontinfacts.htm
- ^ http://www.pharma.com/pressroom/news/20050608.htm
- ^ http://www.pharma.com/pressroom/news/20051028.htm
- ^ http://www.drugpolicy.org/drugbydrug/oxycontin/
- ^ http://www.deadiversion.usdoj.gov/drugs concern/oxycodone/oxycontin faq.htm
- ^ http://www.fda.gov/ola/2002/oxycontin0212.html
External links
- Kaufman, Gil. Courtney Love Turns Herself In On Felony Drug Charges vh1.com. Tue. October 28, 2003 7:51 p.m. EST.
- Limbaugh admits addiction to pain medication CNN.com. Friday, October 10, 2003 Posted: 10:52 p.m. EDT (0252 GMT).
- Oxycontin Doesn't Cause Addiction. Its Abusers are Already Addicts. Forbes.com. September 6, 2004
- Oxycodone: Pharmacological profile and clinical data in chronic pain management minervamedica.it. Minerva Anestesiologica, 2005;71:451-60. [pdf file]
- Percocet Drug Information from Thomson Healthcare database
