Oxycodone

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Oxycodone
Oxycodone.svg
Oxycodone3DanBS.gif
Systematic (IUPAC) name
(5R,9R,13S,14S)-4,5α-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one
Clinical data
Trade names Roxicodone, OxyContin, Oxecta, OxyIR, Endone, Oxynorm
AHFS/Drugs.com monograph
MedlinePlus a682132
Pregnancy cat.
  • AU: C
  • B US
Legal status
High[medical citation needed]
Routes oral, intramuscular, intravenous, intranasal, subcutaneous, transdermal, rectal, epidural[1]
Pharmacokinetic data
Bioavailability 60–87%[2]
Protein binding 45%[2]
Metabolism Hepatic: primarily CYP3A and to a lesser extent, CYP2D6 to oxymorphone[2]
Half-life 2–4 hours.[2]
Excretion Urine (83%)[2]
Identifiers
CAS number 76-42-6 YesY
ATC code N02AA05
N02AA55 (in combinations)
PubChem CID 5284603
DrugBank DB00497
ChemSpider 4447649 YesY
UNII CD35PMG570 YesY
KEGG D05312 YesY
ChEBI CHEBI:7852 YesY
ChEMBL CHEMBL656 YesY
Synonyms dihydrohydroxycodeinone, 14-hydroxydihydrocodeinone, 6-deoxy-7,8-dihydro-14-hydroxy-3-O-methyl-6-oxomorphine[3]
Chemical data
Formula C18H21NO4 
Mol. mass 315.364 g/mol
Physical data
Solubility in water HCl: 166 mg/mL (20 °C)
 YesY (what is this?)  (verify)

Oxycodone is a semi-synthetic opioid synthesized from poppy-derived thebaine. It is a narcotic analgesic generally indicated for relief of moderate to severe pain. It was developed in 1916 in Germany[4][5] as one of several new semi-synthetic opioids in an attempt to improve on the existing opioids.[1]

Oxycodone is available as single-ingredient medication in immediate release and controlled release. Parenteral formulations of 10 mg/mL and 50mg/mL are available in the U.K. for IV/IM administration.[6] Combination products formulated with non-narcotic ingredients such as NSAIDs and paracetamol (acetaminophen) are also available as immediate release formulations; a combination with naloxone is available in managed-release tablets, naloxone reduces opioid-induced euphoria, as well as side-effects such as constipation.

Medical uses[edit]

Oxycodone has been in clinical use since 1917,[1] and it is used for managing moderate to moderately severe acute or chronic pain.[7] It has been found to improve quality of life for those with many types of pain.[8]

Controlled-release oral tablet form is intended to be taken every 12 hours.[9] As is the case with other opioids, oxycodone is clearly useful for acute pain and in some instances of chronic cancer pain. Experts are divided in regards to the efficacy of all opioids in non-malignant chronic pain. While the opioids induce acute pain relief, all of them have the potential for dependence, withdrawal and the induction of pain sensitivity and hyperalgesia, thereby causing the symptom (pain) that they are being used to treat.

An Italian study concluded from investigating multiple studies that controlled-release oxycodone is comparable to instant-release oxycodone, morphine and hydromorphone in management of moderate to severe cancer pain. It indicated that side effects appear to be less than those associated with morphine and that it is a valid alternative to morphine and a first-line treatment for cancer pain.[10]

In 2001, the European Association for Palliative Care recommended that oral oxycodone could be taken as a second-line alternative to oral morphine for cancer pain.[11]

Administration[edit]

Oxycodone can be administered by parenteral or oral route.[1]

Side effects[edit]

Main side effects of oxycodone[12]

Common side effects include euphoria, constipation, fatigue, dizziness, nausea, vomiting, dry mouth, anxiety, itching, and sweating.[13] Less common side effects (experienced by less than 5% of patients) include loss of appetite, nervousness, abdominal pain, diarrhea, urine retention, dyspnea, and hiccups.[14]

In high doses, overdoses, or in patients not tolerant to opiates, oxycodone can cause shallow breathing, bradycardia, cold-clammy skin, apnea, hypotension, miosis, circulatory collapse, respiratory arrest, and death.[14]

Oxycodone in combination with naloxone in managed-release tablets, has been formulated to reduce side effects.[15]

Dependence, addiction and withdrawal[edit]

Main article: Opioid dependence

The risk of experiencing severe withdrawal symptoms is high if a patient has become physically dependent or addicted and discontinues oxycodone abruptly. Therefore, particularly in cases where the drug has been taken regularly over an extended period of time, use should be discontinued gradually rather than abruptly. People who use oxycodone in a recreational, hazardous, or harmful fashion (not as intended by the prescribing physician) 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, panic attack, nausea, insomnia, muscle pain, muscle weakness, fevers, and other flu-like symptoms".[16]

Withdrawal symptoms have also been reported in newborns whose mothers had been either injecting or orally taking oxycodone during pregnancy.[17]

Hormone imbalance[edit]

As with other opioids, oxycodone (particularly during chronic heavy use) often causes temporary hypogonadism or hormone imbalance.[18]

Detection in biological fluids[edit]

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.[19]

Pharmacology[edit]

Mechanism of action[edit]

In 1997, a group of Australian researchers proposed (based on a study in rats) that oxycodone acts on κ-opioid receptors, unlike morphine, which acts upon μ-opioid receptors.[20] Further research by this group indicated the drug appears to be a κ2b-opioid agonist.[21] However, this conclusion has been disputed, primarily on the basis that oxycodone produces effects that are typical of μ-opioid agonists, mainly because oxycodone is metabolized in the liver to oxymorphone as a metabolite, which is a more potent opioid agonist with stronger/higher binding affinity to μ-opioid receptors compared to oxycodone.[22]

In 2006, research by a Japanese group suggested 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,[23] while in nondiabetic mice, the μ1-opioid receptor seems to be primarily responsible for these effects.[24]

After oxycodone binds to the opioid receptor, a G-protein complex is released, which inhibits the release of neurotransmitters by the cell by reducing the amount of cAMP produced, closing the Ca++ channels, and opening the K channels.[25]

Absorption[edit]

After a dose of conventional oral oxycodone, peak plasma levels of the drug are attained in about one hour;[26] in contrast, after a dose of OxyContin (an oral controlled-release formulation), peak plasma levels of oxycodone occur in about three hours.[14]

Distribution[edit]

Oxycodone in the blood is distributed to skeletal muscle, liver, intestinal tract, lungs, spleen, and brain.[14] Conventional oral preparations start to reduce pain within 10–15 minutes on an empty stomach; in contrast, OxyContin starts to reduce pain within one hour.[7]

Metabolism[edit]

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 (N-desmethyloxycodone).[26] (14-Hydroxydihydrocodeine that in turn becomes 14-Hydroxydihydromorphine) These metabolites are true only for humans.[27] 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,[28] several of which are thought to be active metabolites to some extent, although a study using conventional oral oxycodone concluded oxycodone itself, and not its metabolites, is predominantly responsible for the drug's opioid effects on the brain.[26]

Oxycodone is metabolized by the cytochrome P450 enzyme system in the liver, making it vulnerable to drug interactions.[14] 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.[29][30] The dose of OxyContin must be reduced in patients with reduced hepatic function.[7]

Elimination[edit]

Oxycodone and its metabolites are mainly excreted in the urine and sweat; therefore, it accumulates in patients with renal impairment.[7]

Dosage and administration[edit]

Oxycodone can be administered orally, intranasally, via intravenous, intramuscular, or subcutaneous injection, or rectally. The bioavailability of oral administration of oxycodone averages 60–87%, with rectal administration yielding the same results; intranasal varies between individuals with a mean of 46%.[31]

Equivalency[edit]

Taken orally, the conversion ratio between morphine to extended release oxycodone is reported as 2:1.[32]

Chemistry[edit]

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)
  • Oxycodone has a 7,8-dihydro feature. 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.

It is also similar to hydrocodone, differing only in that it has a hydroxyl group at carbon-14.[7]

Expanded expression for the compound oxycodone in the academic literature include "dihydrohydroxycodeinone",[3][33][34] "Eucodal",[33][34] "Eukodal",[1][35] "14-hydroxydihydrocodeinone",[3][33] and "Nucodan".[33][34] In a UNESCO convention, the translations of "oxycodone" are oxycodon (Dutch), oxycodone (French), oxicodona (Spanish), الأوكسيكودون (Arabic), 羟考酮 (Chinese), and оксикодон (Russian).[36] The word "oxycodone" should not be confused with "oxandrolone", "oxazepam", "oxybutynin", "oxytocin", or "Roxanol".[37]

History[edit]

Freund and Speyer of the University of Frankfurt in Germany first synthesized oxycodone from thebaine in 1916,[5] 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.[citation needed]

The first clinical use of the drug was documented in 1917, the year after it was first developed.[5][35] 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.

In the early 1960s the United States government classified Oxycodone as a schedule II drug. In 1995 the FDA approved OxyContin.[38]

As of May 2013 an extended release version in the United States is only available as OxyContin brand.[39]

Statistics[edit]

The International Narcotics Control Board estimated 11.5 tons (23,000 lbs) of oxycodone were manufactured worldwide in 1998;[40] by 2007 this figure had grown to 75.2 tons (150,400 lbs).[40] United States accounted for 82% of consumption in 2007 at 51.6 tons. Canada, Germany, Australia and France combined accounted for 13% of consumption in 2007.[40][41] In 2010, 122.5 tons of oxycodone were manufactured, according to the International Narcotics Control Board. This number had decreased slightly from the all time high in 2009 of 135.9 tons.[42]

Recreational use[edit]

Effects[edit]

Oxycodone, like other opioid analgesics, tends to induce feelings of euphoria, relaxation and reduced anxiety in its users.[43] These effects, along with its addictive qualities and legal prohibition, make it one of the most commonly abused pharmaceutical drugs in the United States.[44]

Preventive measures[edit]

In August 2010, Purdue Pharma reformulated their long-acting oxycodone line, marketed as OxyContin, to use a misuse-resistant polymer designed to decrease abuse potential by defeating the release mechanism.[45] The FDA approved relabeling the reformulated version as abuse-resistant in April 2013.[46]

Pfizer manufactures a preparation of short-acting oxycodone, marketed as Oxecta, which contains inactive ingredients designed to induce nasal irritation if the tablet is crushed and snorted.[47]

Australia[edit]

The non-medical 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.[48]

Canada[edit]

Deaths from opioid pain relievers increased from 13.7 deaths per million residents in 1991 to 27.2 deaths per million residents in 2004.[49] 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.[50] 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.[50][51]

United Kingdom[edit]

Abuse and diversion of oxycodone in the UK commenced in the early- to mid-2000s.[52] The first known death due to overdose in the UK occurred in 2002.[53] However, recreational use remains relatively rare.

United States[edit]

As a street drug, Oxycodone is also called oxycotton. In the United States, more than 12 million people abuse opioid drugs.[54] In 2010, 16,652 deaths were related to opioid overdose.[55] 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 usage, instead stating the drug is for "pain severe enough to require daily, around-the-clock, long term opioid treatment."[56] The updated labeling will not restrict physicians from prescribing opioids for moderate, as needed usage.[54]

Based on statistical estimates by the US Department of Health and Human Services, about 11 million people in the US will consume at least one of dose of this opioid in a non-medical way. About 100,000 men or women per year are admitted to US hospitals due to misuse of this drug, making it the most widely abused opioid drug in America. Diverted oxycodone is taken orally or ingested through insufflation, it can also be prepared for injection and administered intravenously, while some abusers will heat the pills on aluminum foil and inhale the smoke as a means of ingesting oxycodone. Other ways of abuse include intravenous injection of oral dosage forms, which are not designed for parenteral use. In 2008, oxycodone and hydrocodone misuse caused 14,800 deaths. Some of the cases, however, were due to the hepatotoxic effect of acetaminophen.[57]

Legal status[edit]

General[edit]

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.[58] The 1961 Single Convention on Narcotic Drugs of the United Nations, which replaced the 1931 convention, categorized oxycodone in Schedule I.[59] 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".[59]

Australia[edit]

Oxycodone is in Schedule I (derived from the Single Convention on Narcotic Drugs) of the Commonwealth's Narcotic Drugs Act 1967.[60] 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".[61]

Canada[edit]

Oxycodone is a controlled substance under Schedule I of the Controlled Drugs and Substances Act (CDSA).[62]

Legislative changes regulating oxycodone in Canada[edit]

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.[63]

Much of the legislative activity has stemmed from Purdue Pharma’s decision in 2011 to begin a modification of oxycodone’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 pain killer. 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.[64] This Act, introduced in 2010, commits to the establishment of a unified database to fulfill this intention.[65] 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.[66]

Lawsuits in Canada[edit]

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 $650 million in settling litigation or facing criminal fines.[67]

Germany[edit]

The drug is in Appendix III of the Narcotics Act (Betäubungsmittelgesetz or BtMG).[68] The law allows only physicians, dentists, and veterinarians (Ärzte, Zahnärzte und Tierärzte) to prescribe oxycodone and the federal government to regulate the prescriptions (e.g., by requiring reporting).[68]

Hong Kong[edit]

Oxycodone is regulated under Part I of Schedule 1 of Hong Kong's Chapter 134 Dangerous Drugs Ordinance.[69]

Singapore[edit]

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 five strokes of the cane, and a maximum sentence of life imprisonment or 30 years of imprisonment and 15 strokes of the cane.[70] The minimum and maximum penalties for unauthorized trafficking in the drug are respectively five years of imprisonment and five strokes of the cane, and 20 years of imprisonment and 15 strokes of the cane.[71]

United Kingdom[edit]

Oxycodone is a Class A drug under the Misuse of Drugs Act.[72] 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.[73] Dealing of the drug illegally is punishable by up to life imprisonment, an unlimited fine, or both.[73] 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".[74]

United States[edit]

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.[75] The salts in use are the hydrochloride (free base conversion ratio .896), bitartrate (.667), tartrate (.750), camphosulphonate (.576), pectinate (.588), phenylpriopionate (.678), sulphate, (.887), phosphate (.763), and terephthalate (.792); the first and last are found together in Percodan and the hydrochloride by itself is the basis of most American oxycodone products whilst the bitartrate, tartrate, pectinate, and phosphate are also used alongside the other two in Europe. The methyiodide and hydroiodide are mentioned in older European publications.

See also[edit]

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