Codeine

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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
PubChem	5284371
DrugBank	APRD00120
Chemical data
Formula	C18H21NO3
Mol. mass	299.364 g/mol
Pharmacokinetic data
Bioavailability	well absorbed
Metabolism	Hepatic
Half life	2–4 hours
Excretion	renal
Therapeutic considerations
Pregnancy cat.	A(AU)
Legal status	Controlled (S8)(AU) Schedule I(CA) Class B(UK) Schedule II(US)
Routes	oral, intra-nasally, 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.

Contents 1 Indications 2 Controlled substance 3 Pharmacokinetics 4 Pharmacology 5 Adverse effects 6 Recreational use 7 Footnotes 8 External links

[edit] 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 (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 (drug synergy; see synergy).

[edit] Controlled substance

In Australia, New Zealand and Canada, codeine is regulated; however, it is available without prescription in combination preparations from licensed pharmacists in doses up to 8 mg/tablet in Canada, 13.8 mg/tablet in Australia and 15 mg/tablet in New Zealand.

In Canada, codeine can only be sold over the counter in combination with 2 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]

In Hong Kong, codeine is regulated under Schedule 1 of Hong Kong's Chapter 134 Dangerous Drugs Ordinance. It can only be used legally 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.

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. In combination with aspirin or acetaminophen (paracetamol/Tylenol) it is listed as Schedule III or V, depending on formula. Preparations containing small amounts of codeine are Schedule V in the US, and may be dispensed without a prescription; however, very few pharmacists will sell these preparations without a prescription.

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.^[3]

[edit] Pharmacokinetics

Codeine is considered a prodrug, since it is metabolised in vivo to the primary active compounds morphine and codeine-6-glucuronide^{[4] [5]}. 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. ^[6]

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). It is not used, however, in single doses of greater than 60mg (and no more than 240 mg in 24 hours) because there is a ceiling effect.

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 Arabic^[7] 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^[8]. Conversely, 0.5-2% of the population has multipe copies of the 2D6 gene and will metabolise 2D6 dependent drugs more effiently 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.

[edit] Pharmacology

Main article: opioid receptor

Codeine itself has weak affinity for the μ-opioid receptor. Its principal analgesic actions are mediated by the affinity of morphine for the μ-opioid receptor, though other therapeutic and adverse effects are produced by activation of other opioid receptors.

[edit] 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.^[9]

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.

Codeine has also been known to interact negatively with some psychiatric medications such as reboxetine and venlafaxine.

Some people may also have an allergic reaction to codeine, which may cause severe illness or even death.

[edit] Recreational use

Codeine is often used as a recreational drug. This is mainly due to its 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. The recreational dose of codeine is between 120 mg and 400 mg; anything over 400 mg will be wasted because the liver can not metabolise any more^{[citation needed]}. Therapeutic use of codeine falls in the category of 10-60 mg at once, and above 60 mg is used recreationally. Codeine can be administered orally, rectally and by intramuscular injection. Codeine should never be insufflated (snorted), smoked, or injected intravenously.

• In certain areas of the United States, such as Texas, codeine in syrup form is called Lean. It is commonly mixed with a soft drink such as Sprite (to make a drink called purple drank).

• When prepared with promethazine, codeine is a Schedule V ("behind-the-counter"—sold over the counter at the pharmacist's discretion) controlled substance in the United States. The syrup, sometimes known as Phenergan With Codeine, contains 6.25 mg of promethazine and 10 mg of codeine per teaspoonful.

• In some countries, cough syrups and tablets containing codeine are available without prescription; people will frequently purchase it from multiple pharmacies so as not to incur suspicion. It is reported that in France, 95% of the consumption of Néo-codion cough preparation, containing codeine, cannot be attributed to medical use, but is rather used as a substitute for heroin. A heroin addict may use codeine to ward off the effects of a withdrawal.^[10]

• 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. Codeine linctus is also available from pharmacies OTC (over the counter) without prescription, however, pharmacists are obliged to use professional judgement and refuse sales if requests are not judged appropriate.

• 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.

• In South Asian countries codeine has become a multi-million-dollar market in the form of codeine-phosphate-containing cough syrups which are easily available at chemist shops without a prescription, notable among them being Corex and Phensydyl. Although it is nominally mandatory to have a prescription, it is a highly neglected rule, especially in smaller cities where prescriptions are ignored on a regular basis. Codeine phosphate tablets are also available over the counter, despite being prescription-only as well. They are among the most abused over-the-counter drugs in South Asia (across all sections of its society), and continue to be freely available despite legislations by States to curb their availability to buyers without prescriptions.^{[citation needed]}

• Certain codeine products are encountered on the illicit market, frequently in combination with carisoprodol. Combinations of codeine and glutethimide (Doriden) used to be fairly commonplace, but are almost unheard of today, due to the withdrawal of glutethimide products from the marketplace in the US and almost all other countries.

• 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.^[11]

[edit] Footnotes

1. ^ Schroeder K, Fahey T (2001). "Over-the-counter medications for acute cough in children and adults in ambulatory settings.". Cochrane Database Syst Rev: CD001831. DOI:10.1002/14651858.CD001831. PMID 15495019. 
2. ^ Headache Triggers: Caffeine. WebMD (June 2004). Retrieved on 2007-03-23.
3. ^ International Narcotics Control Board. List of Narcotic Drugs under International Control (PDF). Retrieved on 2006-05-24.
4. ^ http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11092114&dopt=Abstract
5. ^ http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15102399&dopt=Abstract
6. ^ http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11092114&dopt=Abstract
7. ^ http://codeine.50g.com/info/codeine.html
8. ^ http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15102399&dopt=Abstract
9. ^ Australian Medicines Handbook (2004). in Rossi S: Australian Medicines Handbook. Adelaide: Australian Medicines Handbook. ISBN 0-9578521-4-2. 
10. ^ Boekhout van Solinge, Tim [1996]. "7. La politique de soins des années quatre-vingt-dix", L'héroïne, la cocaïne et le crack en France. Trafic, usage et politique (in French). Amsterdam: CEDRO Centrum voor Drugsonderzoek, Universiteit van Amsterdam, 247-262. 
11. ^ Hogshire, Jim (June 1999). Pills-A-Go-Go: A Fiendish Investigation into Pill Marketing, Art, History & Consumption. Los Angeles: Feral House, 216-223. ISBN 0-922915-53-9. 

[edit] External links

• Codeine Addiction Help Forum
• Links to external chemical sources

v • d • e Analgesics (N02A, N02B)
Opioids	Bezitramide, Buprenorphine, Butorphanol, Dextromoramide, Dextropropoxyphene, Diamorphine, Dihydrocodeine, Fentanyl, Hydromorphone, Ketobemidone, Methadone, Morphine, Nalbufine, Nicomorphine, Opium, Oxycodone, Papaveretum, Pethidine, Piritramide, Tramadol (see also longer list)
Salicylic acid and derivatives	Aspirin (Acetylsalicylic Acid), Diflunisal, Ethenzamide -- See also: NSAIDs
Pyrazolones	Aminophenazone, Metamizole, Phenazone
Anilides	Paracetamol (acetaminophen), Phenacetin
Others	Ziconotide, Tetrahydrocannabinol, Ibuprofen, Ketoprofen, Mefenamic Acid, Naproxen, Diclofenac, Flurbiprofen, Diflunisal, Fenoprofen, Indomethacin, Ketorolac, Meclofenamate, Meloxicam, Piroxicam, Tolmetin