CAS NO.:76-57-3 Codeine;3-Methylmorphine C18H21NO3 Recreational Club Clinical General anesthetics;Strong painkiller；Analgesic；Elixir

Detail:

        Codeine is an opiate used to treat pain, as a cough medicine, and for diarrhea. It is typically used to treat mild to moderate degrees of pain. Greater benefit may occur when combined with paracetamol (acetaminophen) or a nonsteroidal anti-inflammatory drug (NSAID) such as aspirin or ibuprofen. Evidence does not support its use for acute cough suppression in children or adults. In Europe it is not recommended as a cough medicine in those under twelve years of age. It is generally taken by mouth. It typically starts working after half an hour with maximum effect at two hours. The total duration of its effects last for about four to six hours.

        Common side effects include vomiting, constipation, itchiness, lightheadedness, and drowsiness. Serious side effects may include breathing difficulties and addiction. It is unclear if its use in pregnancy is safe. Care should be used during breastfeeding as it may result in opiate toxicity in the baby. Its use as of 2016 is not recommended in children. Codeine works following being broken down by the liver into morphine. How quickly this occurs depends on a person's genetics.

        Codeine was discovered in 1832 by Pierre Jean Robiquet. In 2013 about 361,000 kilograms of codeine were produced while 249,000 kilograms were used. This makes it the most commonly taken opiate. It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system. The wholesale cost in the developing world is between 0.04 and 0.29 USD per dose as of 2014. In the United States it costs about one dollar a dose. Codeine occurs naturally and makes up about 2% of opium.

Medical uses:

        Codeine is used to treat mild to moderate pain and to relieve cough. Codeine is also used to treat diarrhea and diarrhea-predominant irritable bowel syndrome, although loperamide (which is available without a prescription for milder diarrhea), diphenoxylate, paregoric or even laudanum are more frequently used to treat severe diarrhea.

There is weak evidence that it is useful in cancer pain but it is associated with increased side effects. The American Academy of Pediatrics does not recommend its use in children due to side effects. The FDA lists age under 12 years old as a contraindication to use.

        Furthermore, codeine has been found as an endogenous compound, along with morphine, in the brains of non human primates with depolarized neurons, indicating that codeine may function as a neurotransmitter or neuromodulator in the central nervous system.

Cough:

        Evidence does not support its use for acute cough suppression in children or adults. In Europe it is not recommended as a cough medicine in those under twelve years of age. There is some tentative evidence it can reduce a chronic cough in adults.

Formulations:

       Codeine is marketed as both a single-ingredient drug and in combination preparations with paracetamol (as co-codamol: e.g., brands Paracod, Panadeine, and the Tylenol-with-codeine series, including Tylenol 3 and 1,2,4); with aspirin (as co-codaprin); or with ibuprofen (as Nurofen Plus). These combinations provide greater pain relief than either agent alone (drug synergy).

        Codeine is also commonly marketed in products containing codeine with other pain killers or muscle relaxers, as well as codeine mixed with phenacetin (Emprazil with codeine No. 1, 2, 3, 4 and 5), naproxen, indomethacin, diclofenac, and others, as well as more complex mixtures, including such mixtures as aspirin + paracetamol + codeine ± caffeine ± antihistamines and other agents, such as those mentioned above.

        Codeine-only products can be obtained with a prescription as a time release tablet. Codeine is also marketed in cough syrups with zero to a half-dozen other active ingredients, and a linctus (e.g., Paveral) for all of the uses for which codeine is indicated.

        Injectable codeine is available for subcutaneous or intramuscular injection only; intravenous injection is contraindicated as this can result in non-immune mast-cell degranulation and resulting anaphylactoid reaction. Codeine suppositories are also marketed in some countries.

Adverse effects:

        Common adverse effects associated with the use of codeine include drowsiness and constipation. Less common are itching, nausea, vomiting, dry mouth, miosis, orthostatic hypotension, urinary retention, euphoria, dysphoria, and coughing. Rare adverse effects include anaphylaxis, seizure, acute pancreatitis, and respiratory depression. As with all opiates, longer-term effects can vary, but can include diminished libido, apathy, and memory loss. Some people may have allergic reactions to codeine, such as the swelling of skin and rashes.

        Tolerance to many of the effects of codeine, including its therapeutic effects, develops with prolonged use. This occurs 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 a 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. In August 2012, the United States Federal Drug Administration issued a warning about deaths in pediatric patients < 6 years old after ingesting "normal" doses of paracetamol with codeine after tonsillectomy; this warning was upgraded to a black box warning in February 2013.

        Some patients are very effective converters of codeine to its active form, morphine, resulting in lethal blood levels. The FDA is presently recommending very cautious use of codeine in young tonsillectomy patients: use the drug in the lowest amount that can control the pain, use "as needed" and not "around the clock", and seek immediate medical attention if a child on codeine exhibits excessive sedation or abnormally noisy breathing.

Withdrawal and dependence:

        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.

        There is also no evidence that CYP2D6 inhibition is useful in treating codeine dependence, though the metabolism of codeine to morphine (and hence further metabolism to glucuronide morphine conjugates) does have an effect on the abuse potential of codeine.However, CYP2D6 has been implicated in the toxicity and death of neonates when codeine is administered to lactating mothers, particularly those with increased 2D6 activity ("ultra-rapid" metabolizers).

Pharmacokinetics:

        The conversion of codeine to morphine occurs in the liver and is catalyzed by the cytochrome P450 enzyme CYP2D6. CYP3A4 produces norcodeine and UGT2B7 conjugates codeine, norcodeine, and morphine to the corresponding 3- and 6- glucuronides. Srinivasan, Wielbo and Tebbett speculate that codeine-6-glucuronide is responsible for a large percentage of the analgesia of codeine, and, thus, these patients should experience some analgesia. Many of the adverse effects will still be experienced in poor metabolizers. Conversely, 0.5-2% of the population are "extensive metabolizers"; multiple copies of the gene for 2D6 produce high levels of CYP2D6 and will metabolize drugs through that pathway more quickly than others.

        Some medications are CYP2D6 inhibitors and reduce or even completely block the conversion of codeine to morphine. The most well-known of these are two of the selective serotonin reuptake inhibitors, paroxetine (Paxil) and fluoxetine (Prozac) as well as the antihistamine diphenhydramine (Benadryl) and the antidepressant, bupropion (Wellbutrin, also known as Zyban). Other drugs, such as rifampicin and dexamethasone, induce CYP450 isozymes and thus increase the conversion rate.

        CYP2D6 converts codeine into morphine, which then undergoes glucuronidation. Life-threatening intoxication, including respiratory depression requiring intubation, can develop over a matter of days in patients who have multiple functional alleles of CYP2D6, resulting in ultra-rapid metabolism of opioids such as codeine into morphine.

        Studies on codeine's analgesic effect are consistent with the idea that metabolism by CYP2D6 to morphine is important, but some studies show no major differences between those who are poor metabolizers and extensive metabolizers. Evidence supporting the hypothesis that ultrarapid metabolizers may get greater analgesia from codeine due to increased morphine formation is limited to case reports.

        Due to increased metabolism of codeine to morphine, ultrarapid metabolizers (those possessing more than 2 functional copies of the CYP2D6 allele) are at increased risk of adverse drug effects related to morphine toxicity. Guidelines released by the Clinical Pharmacogenomics Implementation Consortium (CPIC) advise against administering codeine to ultrarapid metabolizers, where this genetic information is available. The CPIC also suggests that codeine use be avoided in poor metabolizers, due to its lack of efficacy in this group.

        Codeine and its salts are readily absorbed from the gastrointestinal tract and ingestion of codeine phosphate produces peak plasma concentrations in about one hour. Plasma half life is between 3 and 4 hours and oral/intramuscular analgesic potency ratio is approximately equal to 1:1.5. The most common conversion ratio, given on equianalgesia charts used in the United States, Canada, the UK, Republic of Ireland, the European Union, Russia and elsewhere as 130 mg IM equals 200 mg PO—both of which are equivalent to 10 mg of morphine sulphate IV and 60 mg of morphine sulphate PO. The salt:freebase ratio of the salts of both drugs in use are roughly equivalent, and do not generally make a clinical difference.

        Codeine is metabolised by O- and N-demethylation in the liver to morphine and norcodeine. Codeine and its metabolites are excreted almost entirely by the kidney, mainly as conjugates with glucuronic acid.

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

Relation to other opioids:

        Codeine has been used in the past as the starting material and prototype of a large class of mainly mild to moderately strong opioids; such as hydrocodone (1920 in Germany), oxycodone (1916 in Germany), dihydrocodeine (1908 in Germany), and its derivatives such as nicocodeine (1956 in Austria).[citation needed] However, these opioids are no longer synthesized from codeine and are usually synthesized from other opium alkaloids; specifically thebaine.[citation needed] Other series of codeine derivatives include isocodeine and its derivatives, which were developed in Germany starting around 1920. In general, the various classes of morphine derivatives such as ketones, semisynthetics like dihydromorphine, halogeno-morphides, esters, ethers, and others have codeine, dihydrocodeine, and isocodeine analogues. The codeine ester acetylcodeine is a common active impurity in street heroin as some codeine tends to dissolve with the morphine when it is extracted from opium in underground heroin and morphine base labs.

        As an analgesic, codeine compares weakly to other opiates. Related to codeine in other ways are codoxime, thebacon, 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.

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