History
Codeine is an alkaloid found in opium and other poppy saps like Papaver bracteatum, the Iranian poppy, 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. It was first isolated in 1830 in France by Jean-Pierre Robiquet.

The effects of the Nixon War On Drugs by 1972 or so had caused across-the-board shortages of illicit and licit opiates because of a scarcity of natural opium, poppy straw and other sources of opium alkaloids, and the geopolitical situation was getting less helpful for the United States. After a large percentage of the opium and morphine in the US National Stockpile of Strategic & Critical Materials had to be tapped in order to ease severe shortages of medicinal opiates -- the codeine-based antitussives in particular -- in late 1973, researchers were tasked with and quickly succeeded in finding a way to synthesize codeine and its derivatives and precursors from scratch from petroleum or coal tar using a process developed at the United States' National Institutes of Health.

Numerous codeine salts have been prepared since the drug was discovered. The most commonly used are the hydrochloride (freebase conversion ratio 0.805), phosphate (0.736), sulphate (0.859) and citrate (0.842). Others include a salicylate NSAID, codeine salicylate (0.686), and at least four codeine-based barbiturates, the cyclohexenylethylbarbiturate (0.559), cyclopentenylallylbarbiturate (0.561), diallylbarbiturate (0.561), and diethylbarbiturate (0.619).

Pharmacology
Codeine is considered a prodrug, since it is metabolised in vivo to the primary active compounds morphine and codeine-6-glucuronide.[2][3] Roughly 5-10% of codeine will be converted to morphine, with the remainder either free, conjugated to form 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.[4] Like all opioids, continued use of codeine induces physical dependence and can be psychologically addictive. However, the withdrawal symptoms are relatively mild and as a consequence codeine is considerably less addictive than the other opiates.

A dose of approximately 200 mg (oral) of codeine must be administered to give analgesia approximately equivalent 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)[5]. 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 ceiling dose can be more accurately calculated by using 7 mg per 1 kg of bodyweight for males and 6 mg per 1 kg of bodyweight for females, taking into consideration an 18.5-25 BMI bodyweight to not over or under calculate in cases of obese or underweight people (this rule does not take into consideration the usage of other CYP2D6 inhibiting drugs, alcohol or naturally low or high enzyme presence though a 25% enzyme occupancy reduction can prove more accurate results). Example: A 85kg male, bearing a height of 180cm is 5kg overweight, therefore the ceiling dose can be calculated by 7mg x (85-5)kg = 560mg and for a female of the same height and weight, 6mg x (85-5)kg = 480mg. 25% reduction to consider momentary enzyme occupancy, (560x0.75) putting the ceiling limit at 420mg. Total CYP2D6 saturation or exceeding the ceiling dose often results in excessive histamine release to combat the yet to be processed codeine which results in swelling of bodily areas such as the genitals, cheeks, hands and feet often mimicking an adverse or allergic reaction despite subsidence with time.

Indications

Approved indications for codeine include:
Cough, though its efficacy in low dose over the counter formulations has been disputed.[8]
Diarrhea
Mild to severe pain
Irritable bowel syndrome
Codeine is sometimes marketed in combination preparations with the analgesic acetaminophen (paracetamol), as co-codamol, paracod, panadeine, or Tylenol 3; with the analgesic acetylsalicylic acid (aspirin), as co-codaprin; or with the NSAID (non-steroidal anti-inflammatory drug) ibuprofen, as Nurofen Plus. These combinations provide greater pain relief than either agent alone (drug 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 (e.g. Codeine Contin(r) 100 mg and Perduretas 50 mg).

The narcotic content number in the US names of codeine tablets and combination products like Tylenol With Codeine No. 3, Emprin With Codeine No. 4 are as follows: No. 1 - 7½ or 8 mg (1/8 grain), No. 2 - 15 or 16 mg (1/4 grain), No. 3 - 30 or 32 mg (1/2 grain), No. 4 - 60 or 64 mg (1 grain). The Canadian 222 series is identical to the above list 222=1/8 grain, 292=1/4 grain, 293=1/2 grain, and 294=1 grain of codeine.

Injectable codeine is available for subcutaneous or intramuscular injection; intravenous injection can cause a serious reaction which can progress to anaphylaxis. Codeine suppositories are also marketed in some countries.

Availability
Codeine phosphate and sulphate are marketed in the United States and Canada. Codeine hydrochloride is more commonly marketed in continental Europe and other regions, and codeine hydroiodide and codeine citrate round out the top five most-used codeine salts worldwide. Codeine is usually present in raw opium as free alkaloid in addition to codeine meconate, codeine pectinate, and possibly other naturally-occurring codeine salts. Codeine bitartrate, tartrate, nitrate, picrate, acetate, hydrobromide and others are occasionally encountered on the pharmaceutical market and in research.

In certain jurisdictions, codeine is available over-the-counter in combination with guaifenesin or promethazine to be sold at the pharmacist's discretion, though many pharmacists decline to do so[citation needed].

Relation to other opiates
Codeine is the starting material and prototype of a large class of mainly mild to moderately strong opioids such as hydrocodone, dihydrocodeine and its derivatives such as nicocodeine. Other series of codeine derivatives include isocodeine and its derivatives, which were developed in Germany starting around 1920. Related to codeine in other ways are Codeine-N-Oxide (Genocodeine), related to the nitrogen morphine derivatives as is codeine methobromide, and heterocodeine which is a drug six times stronger than morphine and 72 times stronger than codeine due to a small re-arrangement of the molecule, viz. moving the methyl group from the 3 to the 6 position on the morphine carbon skeleton. Drugs bearing resemblance to codeine in effects due to close structural relationship are variations on the methyl groups at the 3 position including ethylmorphine a.k.a. codethyline (Dionine) and benzylmorphine (Peronine). While having no narcotic effects of its own, the important opioid precursor thebaine differs from codeine only slightly in structure. Pseudocodeine and some other similar alkaloids not currently used in medicine are found in trace amounts in opium as well.

Adverse effects
Common effects other than analgesia associated with the use of codeine include euphoria, itching, nausea, vomiting, drowsiness, dry mouth, miosis, orthostatic hypotension, urinary retention, depression and constipation.[9] Another side effect commonly noticed is the lack of sexual drive and increased complications in erectile dysfunction.[10] Some people may also have an allergic reaction to codeine, such as the swelling of skin and rashes.[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. As codeine is metabolized to morphine, morphine can be passed through breast milk in potentially lethal amounts, fatally depressing the respiration of a breastfed baby.[11]

Withdrawal effects
As with other opiate-based pain killers, chronic use of codeine can cause physical dependence. When physical dependence has developed, withdrawal symptoms may occur if a person suddenly stops the medication. Withdrawal symptoms include: drug craving, runny nose, yawning, sweating, insomnia, weakness, stomach cramps, nausea, vomiting, diarrhea, muscle spasms, chills, irritability and pain. To minimize withdrawal symptoms, long-term users should gradually reduce their codeine medication under the supervision of a healthcare professional.[12] A support group called CodeineFree exists to help people who have found themselves dependent on codeine.

Recreational use
Codeine can be used as a recreational drug. However, it has much less abuse potential than some other opiates or opioids, such as oxycodone and hydrocodone.

In some countries, cough syrups and tablets containing codeine are available without prescription; some potential recreational users are reported to buy codeine from multiple pharmacies so as not to arouse suspicion. A heroin addict may use codeine to ward off the effects of a withdrawal.[13]

Codeine is also available in conjunction with the anti-nausea medication promethazine in the form of a syrup. Brand named as Phenergan with Codeine or generically as promethazine with codeine this medication is quickly becoming one of the most highly abused codeine preparations.[14]

Codeine is also demethylated by reaction with pyridine to illicitly synthesize morphine. Pyridine is toxic and possibly carcinogenic, so morphine illicitly produced in this manner (and potentially contaminated with pyridine) may be particularly harmful.[15] Codeine can also be turned into α-chlorodide which is used in the clandestine synthesis of desomorphine (Permonid®). Codeine can also be turned directly into stronger derivatives of the dihydrocodeine and hydrocodone families and a few others with various chemicals and equipment.

Controlled substance
In Australia, New Zealand, The United Kingdom, Romania, 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 15 mg/tablet in Australia, New Zealand, Poland (Thiocodin) and Costa Rica, 12.8 mg/tablet in the United Kingdom, 10 mg/tablet in Israel and 8 mg/tablet in Canada and Estonia.[citation needed]
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