Codeine

Codeine
noframe The skeletal formula of Codeine.
Dosage (oral)
Threshold	~30mg
Light	<100mg
Common	100-250mg
Strong	300mg
Heavy	>400mg
Duration (oral)
Total Duration	~3 hours
Onset	~20 minutes
Peak	~1 hour
After effects	~2 hours

Codeine or 3-methylmorphine (a naturally occurring methylated morphine) is an opiate used for its analgesic, antitussive, antidiarrheal, antihypertensive, anxiolytic, antidepressant, sedative and hypnotic properties. It is also used to suppress premature labor contractions, myocardial infarction, and has many other potential and indicated uses. It is often sold as a salt in the form of either codeine sulfate or codeine phosphate.

Codeine is the second-most predominant alkaloid in opium, at up to three percent. Although codeine can be extracted from natural sources, a semi-synthetic process is the primary source of codeine for pharmaceutical use. It is considered the prototype of the weak to midrange opioids (tramadol, dextropropoxyphene, dihydrocodeine, hydrocodone, oxycodone).

Codeine is currently the most widely used opiate in the world, and is one of the most commonly used drugs overall according to numerous reports by organizations including the World Health Organization and its League of Nations predecessor agency. It is one of the most effective orally administered opioid analgesics and has a wide safety margin.

Pharmacology

Codeine is not itself centrally active, and must first be converted via first pass metabolism into morphine by the cytochrome P450 enzyme CYP2D6. Codeine is also metabolised into the inactive norcodeine via the CYP3A4 enzyme system. Both resultant forms are conjugated by UGT2B7 into their corresponding 3-glucuronide.

Some percentage of the population produce less CYP2D6 and so experience a reduction of effects from codeine. Others produce it in higher quantities which can exhibit hypersensitivity to the drug.

There is a limit to the amount of codeine which can be converted by enzymatic metabolism in an individual each session. This limit is commonly referred to as the "ceiling dose", which appears to be around ~400mg. Consuming higher doses will lead to higher peripheral effects such as itchyness, but will not necessarily increase the euphoria experienced.

Some methods of potentiating opioids, such as using grape fruit juice throughout the day before consumption, rely on disrupting the cytochrome P450 enzymes' ability to metabolise the chemical. Since codeine is a prodrug and relies on enzymatic conversion for activation, these methods will actually inhibit codeine's effectiveness. Other methods of potentiation such as coadministration of DXM or, very carefully, benzodiazepines will still increase effects.

The active metabolites of codeine, notably morphine, exert their effects by binding to and activating the μ-opioid receptor.

Subjective effects

The subjective effects of opioids are extremely similar across individual substances with very little variation. These usually only differ in terms of their potency, intensity and duration. In comparison to other opiods, this particular substance can be considered as less intense in its physical and cognitive euhoria when compared with that of morphine or diacetylmorphine (heroin) due to the upper limit of how much can be converted into its active form through metabolism . It also presents greater amounts of itchyness due to higher amounts of histamine release and is considerably more sedating than that of Oxycontin and Hydrocodone.

Toxicity and harm potential

Codeine has not been shown to be toxic and is physically benign at reasonable dosages. As with all opiates, longer-term effects can vary but can include diminished libido, apathy and memory loss. Some people may also have an allergic reaction to codeine, such as the swelling of skin and rashes.

Tolerance and addiction potential

Tolerance to many of the effects of codeine develops with prolonged use, including therapeutic effects. The rate at which this occurs develops at different rates for different effects, with tolerance to the constipation-inducing effects developing particularly slowly for instance.

As with other opiate-based pain killers, chronic use of codeine can be considered as highly addictive and is capable of causing both physical and psychological dependence. When physical dependence has developed, withdrawal symptoms may occur if a person suddenly stops their usage.

Legality

• Australia: In Australia, codeine preparations must be sold only at a pharmacy. Preparations will often be a combination of paracetamol (500 mg), ibuprofen (200 mg) and doxylamine succinate (5 mg), and the codeine content may range from 5 mg to 15 mg; preparations with in excess of 30 mg per tablet are S4 (schedule 4, or Prescription Only) medications. Preparations containing pure codeine (e.g., codeine phosphate tablets or codeine phosphate linctus) are available on prescription and are considered S8 (schedule 8, or Controlled Drug (Possession without authority illegal)). Schedule 8 preparations are subject to the strictest regulation of all medications available to consumers.
• Denmark: In Denmark, codeine is sold over the counter with max 9.6 mg in mixture. The item is given over the counter, no prescriptions. The strongest available over the counter preparation containing codeine has 9.6 mg (with aspirin, brand name Kodimagnyl); anything stronger requires a prescription for legal possession.
• France: In France, most preparations containing codeine do not require a doctor's prescription. Example products containing codeine include Néocodion (cough pills, and syrup), Codoliprane (codeine with paracetamol), Prontalgine and Migralgine (codeine, paracetamol and caffeine).
• Greece: Codeine is classed as an illegal drug in Greece, and individuals possessing it could conceivably be arrested, even if they were legitimately prescribed it in another country. It is sold only with a doctor's prescription.
• Hong Kong: In Hong Kong, codeine is regulated under Laws of Hong Kong, Dangerous Drugs Ordinance, Chapter 134, Schedule 1. It can be used legally only by health professionals and for university research purposes. The substance can be given by pharmacists under a prescription. However, codeine is available without prescription from licensed pharmacists in doses up to 0.1%
• Iceland: Preparations of paracetamol and codeine require a prescription in Iceland.
• India: Codeine preparations require a prescription in India. A preparation of paracetamol and codeine is available in India. Codeine is also present in various cough syrups as codeine phosphate
• Iran: Preparations of codeine in Iran normally comes with paracetamol, but can be purchased over-the-counter. Iran's deputy health minister reported that codeine is Iran's best selling OTC medication. The recreational use of codeine has also become widespread throughout Iran but authorities continue to let codeine be purchased without permission from a doctor, although the pharmacist may ask for the identification of the purchaser to verify they are 18 years or older to buy.
• Ireland: Codeine remains a semi non-prescriptive, over-the-counter drug up to a limit of 12.8 mg per pill, but codeine products must be out of the view of the public. Products containing more than 12.8 mg codeine are available on prescription only.
• Italy: Codeine tablets or preparations require a prescription in Italy. Preparations of paracetamol and codeine are available in Italy as Co-Efferalgan and Tachidol.
• Japan: Codeine and similar mid-level centrally acting agents in combination with non-opioid analgesics, antihistamines, vitamins, inert GI agents like kaolin & pectin, mild laxatives, antacids, and herbal preparations, can be purchased over the counter, with 10 mg being the ceiling for OTC dispensing.
• Russia: According to ITAR-Tass and Austria Presse-Agentur, OTC availability of codeine products was rescinded nationwide in 2012 because of the discovery of the Krokodil method of underground desomorphine synthesis.
• Sri Lanka: Codeine preparations are available as over the counter pharmacy medicines in Sri Lanka. The most common preparation is Panadeine, which contains 500 mg of Paracetamol and 8 mg of Codeine.
• Maldives: The Maldives takes an infamously strict line on medicines, with many common drugs, anything containing codeine is banned unless you have a notarized and authenticated doctor's prescription. Visitors breaking the rules, even inadvertently, have been deported or imprisoned.
• United States: In the United States, codeine is regulated by the Controlled Substances Act. Federal law dictates that codeine be a Schedule II controlled substance when used in products for pain-relief that contain codeine alone or more than 90 mg per dosage unit. Tablets of codeine in combination with aspirin or acetaminophen (paracetamol/Tylenol) made for pain relief are listed as Schedule III; and cough syrups are Schedule III or V, depending on formula.
• Spain: Codeine tablets or preparations require a prescription in Spain, although this is often not enforced and many pharmacies will sell codeine products without the requirement of a prescription.
• United Arabian Emirates: The UAE takes an exceptionally strict line on medicines, with many common drugs, notably anything with containing codeine being banned unless you have a notarized and authenticated doctor's prescription. Visitors breaking the rules, even inadvertently, have been deported or imprisoned. The US Embassy to the UAE maintains an unofficial list of what may not be imported.
• Romania: Codeine is not allowed without a medical prescription.
• United Kingdom: Under the Misuse of Drugs Act 1971 codeine is a Class B controlled substance or a Class A drug when prepared for injection. The possession of controlled substances without a prescription is a criminal offence.<ref>http://www.legislation.gov.uk/ukpga/1971/38/contents</erf> However, certain preparations of codeine are exempt from this restriction under Schedule 5 of the Misuse of Drugs Regulations 2001. It is thus legal to possess codeine without a prescription, provided that it is compounded with at least one other active or inactive ingredient and that the dosage of each tablet, capsule, etc does not exceed 100 mg or 2.5% concentration in the case of liquid preparations.

See also

• Extraction of opioids from painkiller products