codeine

This article is about the drug. For the band, see Codeine (band).

Codeine
Systematic (IUPAC) name
7,8-didehydro-4,5-epoxy- 3-methoxy-17-methylmorphinan-6-ol
Identifiers
CAS number	76-57-3
ATC code	R05DA04 N02AA59
PubChem	5284371
DrugBank	APRD00120
Chemical data
Formula	C18H21NO3
Mol. mass	299.364 g/mol
Pharmacokinetic data
Bioavailability	~90% Oral
Metabolism	?
Half life	2.5 - 3 hours
Excretion	?
Therapeutic considerations
Pregnancy cat.	?
Legal status	Controlled (S8)(AU) Schedule I(CA) Class B(UK) Schedule II(US)
Routes	oral, intra-rectally, SC, IM

Codeine (INN) or methylmorphine is an opiate used for its analgesic, antitussive and antidiarrheal properties. It is marketed as the salts codeine sulfate and codeine phosphate. Codeine hydrochloride is more commonly marketed in continental Europe and other regions.

Codeine is an alkaloid found in opium in concentrations ranging from 0.3 to 3.0 percent. While codeine can be extracted from opium, most codeine is synthesized from morphine through the process of O-methylation.

Indications

Approved indications for codeine include:

• Cough, though its efficacy in low dose over the counter formulations has been disputed.^[1]
• Diarrhea
• Moderate to severe pain
• Irritable bowel syndrome

Codeine is sometimes marketed in combination preparations with paracetamol (acetaminophen) as co-codamol or paracod (best known in North America as Tylenol 3), with aspirin as co-codaprin or with ibuprofen. These combinations provide greater pain relief than either agent alone (drug synergy; see synergy). Codeine is also commonly compounded with other pain killers or muscle relaxers such as Fioricet with Codeine, Soma Compound/Codeine, etc. Codeine-only products can be obtained with a prescription as a time release tablet (eg. Codeine Contin(r) 100mg).

Controlled substance

In Australia, New Zealand, Canada and many other countries, codeine is regulated. In some countries it is available without prescription in combination preparations from licensed pharmacists in doses up to 8 mg/tablet in Canada, and 15 mg/tablet in Australia and New Zealand, 10mg/t in Israel.^{[citation needed]}

In Canada, codeine can be sold over the counter only in combination with two or more ingredients, which has resulted in the prevalence of AC&C (aspirin, codeine, and caffeine), and similar combinations using acetaminophen (paracetamol) rather than aspirin. Caffeine, being a stimulant, tends to offset the sedative effects of codeine. It also can increase the effectiveness and absorption rate of analgesics in some circumstances.^[2]

Codeine is listed under the Betäubungsmittelgesetz in Germany and the similarly-named narcotics & controlled substances law in Switzerland and the Suchtmittelgesetz in Austria in categories corresponding to their classification under the Single Convention on Narcotic Drugs. Dispensing of products containing codeine and similar drugs (dihydrocodeine, nicocodeine, benzylmorphine, ethylmorphine &c.) generally require a prescription order from a doctor or the discretion of the pharmacist. Municipal and provincial regulations may impact the range of products which can be dispensed in the latter case.

In Hong Kong, codeine is regulated under Schedule 1 of Hong Kong's Chapter 134 Dangerous Drugs Ordinance. It can be used legally only by health professionals and for university research purposes. The substance can be given by pharmacists under a prescription. Anyone who supplies the substance without prescription can be fined $10000(HKD). The penalty for trafficking or manufacturing the substance is a $5,000,000 (HKD) fine and 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.

However, codeine is available without prescription from licensed pharmacists in doses up to 0.1%(5mg/5ml) according to Hong Kong "Dangerous Drugs Ordinance"^[3]

In the United Kingdom, codeine is regulated by the Misuse of Drugs Act 1971; it is a Class B drug, except for concentrations of less than 12.8 mg when combined with paracetamol or ibuprofen, which are available in many over the counter preparations.

In the United States, codeine is regulated by the Controlled Substances Act. It is a Schedule II controlled substance for pain-relief products containing codeine alone or more than 90 mg per dosage unit. In combination with aspirin or acetaminophen (paracetamol/Tylenol) it is listed as Schedule III or V, depending on formula. Preparations for cough or diarrhoea containing small amounts of codeine in combination with two or more other active ingredients are Schedule V in the US, and may be dispensed in amounts up to 4 fl. oz. per 48 hours without a prescription. Schedule V specifically consigns the product to state and local regulation beyond certain required record-keeping requirements (a dispensary log must be maintained for two years in a ledger from which pages cannot easily be removed and/or a pre-numbered and the pharmacist must ask for a picture ID such as a driving licence) and also which maintain controlled substances in the closed system at the root of the régime intended by the Controlled Substances Act of 1970 -- e.g. the codeine in these products was a Schedule II substance when the company making the Schedule V product acquired it for mixing up the end product. In locales where dilute codeine preparations are non-prescription, anywhere from very few to perhaps a moderate percentage of pharmacists will sell these preparations without a prescription. However, many states have their own laws that do require a prescription for Schedule V drugs.

Codeine is also available outside the United States as an over-the-counter drug in liquid cough-relief formulations. Internationally, codeine is a Schedule II drug under the Single Convention on Narcotic Drugs.^[4]

Pharmacokinetics

Codeine is considered a prodrug, since it is metabolised in vivo to the primary active compounds morphine and codeine-6-glucuronide^{[5] [6]}. Roughly 5-10% of codeine will be converted to morphine, with the remainder either free or conjugated to codeine-6-glucuronide(~70%) or converted to norcodeine(~10%) and hydromorphone(~1%). It is less potent than morphine and has a correspondingly lower dependence-liability than morphine. ^[7] Like all opiates, codeine is addictive unless used infrequently. However, the withdrawal symptoms are relatively mild and as a consequence codeine is considerably less addictive than the other opiates.

Theoretically, a dose of approximately 200 mg (oral) of codeine must be administered to give equivalent analgesia to 30 mg (oral) of morphine (Rossi, 2004). However, codeine is generally not used in single doses of greater than 60 mg (and no more than 240 mg in 24 hours). When analgesia beyond this is required, stronger opioids such as hydrocodone or oxycodone are favored. Because codeine needs to be metabolized to an active form, there is a ceiling effect around 400-450 mg. This low ceiling further contributes to codeine being less addictive than the other opiates.

The conversion of codeine to morphine occurs in the liver and is catalysed by the cytochrome P450 enzyme CYP2D6. CYP3A4 produces norcodeine and UGT2B7 conjugates codeine, norcodeine and morphine to the corresponding 3- and 6- glucuronides. Approximately 6–10% of the Caucasian population, 2% of Asians, and 1% of Arabs^[8] have poorly functional CYP2D6 and codeine should be virtually ineffective for analgesia in these patients (Rossi, 2004), although it is speculated that codeine-6-glucuronide is responsible for a large percentage of the analgesia of codeine and thus these patients should experience some analgesia.^[9] Conversely, 0.5-2% of the population has multiple copies of the 2D6 gene and will metabolise 2D6 dependent drugs more efficiently than others. Many of the adverse effects will still be experienced in poor 2D6 metabolisers.

Also, some medications are CYP2D6 inhibitors and reduce or even completely eliminate the efficacy of codeine. The most well-known of these are the selective serotonin reuptake inhibitors, such as fluoxetine (Prozac) and citalopram (Celexa). Others induce expression of CYP450 isozymes and thus increase the rate of metabolism, for example rifampicin and dexamethasone.

It is important to note that whereas usually an EM (extensive metaboliser) will need a higher drug dose for a sufficient therapeutic effect and a PM (poor metaboliser) may suffer from drug toxicity due to accummulation with normal dose, with Codeine, the opposite is true. This being because it is a pro-drug. Thus, an EM may have an adverse toxicity effect and PM will have little or no pain relief.

Pharmacology

Main article: Opioid receptor

Codeine is a prodrug, itself inactive, but demethylated to the active morphine by the liver enzyme CYP2D6. Because of the wide variability in CYP2D6 activity among humans, the effect of codeine can vary between individuals. In persons with little or no CYP2D6 function, codeine has little or no effect.

Adverse effects

Common adverse drug reactions associated with the use of codeine include itching, nausea, vomiting, drowsiness, dry mouth, miosis, orthostatic hypotension, urinary retention and constipation.^[10]

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.

A potentially serious adverse drug reaction, as with other opioids, is respiratory depression. This depression is dose-related and is the mechanism for the potentially fatal consequences of overdose.

Another side effect commonly noticed is the lack of sexual drive.^[11]

Codeine has also been known to interact negatively with some psychiatric medications such as reboxetine and venlafaxine.^{[citation needed]}

Some people may also have an allergic reaction to codeine, which may cause severe allergic reactions such as the swelling of skin and rashes. ^[12]

Recreational use

Codeine can be used as a recreational drug, however has much less abuse potential than some other opiates or opioids such as oxycodone and hydrocodone. In some countries it has easy availability over the counter or on prescription in combination products (which, in certain countries, are scheduled lower than codeine as a single-agent). People use it in order to obtain the euphoric effects associated with use of opioids. Codeine-containing cough syrups are often taken whole by drinking the syrup; combination pills may be taken whole or crushed and mixed with water for faster absorption into the body, or the codeine may be extracted using methods like cold water extraction.

Therapeutic use of codeine falls in the category of 10-60 mg at once. The recreational dose of codeine is between 60 mg and 400 mg; a dose over 400 mg will be wasted, because the liver cannot metabolise any more than that amount at once. Since codeine is an inhibitor of its own cyp2d6 pathway, it is preferred to take the dose at one time instead of gradually over a period of time, with respect to cold water extracted codeine.^{[citation needed]}. Codeine can be administered orally, rectally and by intramuscular injection. Codeine should never be insufflated (snorted), smoked, or injected intravenously.

In some countries, cough syrups and tablets containing codeine are available without prescription; some potential recreational users are reported to buy the aforementioned from multiple pharmacies as to not incur any suspicion. It is reported that in France, 95% of the consumption of Néo-codion cough preparation, containing codeine, can be attributed to non-medical use. A heroin addict may use codeine to ward off the effects of a withdrawal.^[13]

Codeine, in the form of codeine-based cough syrup, is the primary active ingredient in the recreational drink known as purple drank or lean, popular in the hip-hop communities of eastern Texas and the southern United States.^[14].

In the United Kingdom, Ireland, Australia, New Zealand, and Canada tablets which combine codeine and paracetamol (acetaminophen) are widely available, and these can be consumed at higher-than-recommended doses for recreational effect. In doing so, users run the serious risk of hepatotoxicity associated with large doses of paracetamol, so some try to extract the codeine from the paracetamol through various methods, the most common and simplest being cold water extraction. While the combination of codeine with paracetamol at higher-than-recommended doses can possibly cause hepatotoxicity (liver damage), combination with ibuprofen can result in kidney problems/failure and additional stomach pain and nausea, and combination with aspirin can lead to internal hemorrhaging, particularly gastrointestinal hemorrhage.

Codeine is also demethylated by reaction with pyridine to illicitly synthesize morphine. Pyridine is toxic and carcinogenic, so morphine produced in this manner may be particularly harmful.^[15]

References

External links

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