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 OTC for milder diarrhea), diphenoxylate, paregoric or even laudanum (also known as Tincture of Opium ) are more frequently used to treat severe diarrhea.
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.
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.
Codeine has been used in the past as the starting material and prototype of a large class of mainly mild to moderay 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). However, these opiates are no longer synthesized from codeine and are usually synthesized from other opioid alkaloids; specifically thebaine. Other series of codeine derivatives include isocodeine and its derivatives, which were developed in Germany starting around 1920.
The active metabolites of codeine, notably morphine, exert their effects by binding to and activating the μ-opioid receptor.
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 is found in concentrations of 1.0 to 3.0 per cent in opium prepared by the latex method from unripe pods of Papaver somniferum. The name codeine is derived from the Greek word kodeia (κώδεια) for "poppy head". The relative proportion of codeine to morphine, the most common opium alkaloid at 4 to 23 per cent, tends to be somewhat higher in the poppy straw method of preparing opium alkaloids.
The progressive isolation of opium's several active components opened the path to improved selectivity and safety of the opiates-based pharmacopeia.
Codeine-only products can be obtained with a prescription as a time release tablet ( e.g., Codeine Contin 100 mg and Perduretas 50 mg). 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.
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).
It is useful in cancer pain.
Codeine and/or its major metabolites may be quantitative in blood, plasma or urine to monitor therapy, confirm a diagnosis of poisoning or assist in a medico-legal death investigation. Drug abuse screening programs generally test urine, hair, sweat or saliva. Many commercial opiate screening tests directed at morphine cross-react appreciably with codeine and its metabolites, but chromatographic techniques can easily distinguish codeine from other opiates and opioids. It is important to note that codeine usage results in significant amounts of morphine as an excretion product. Furthermore, heroin contains codeine (or acetyl codeine) as an impurity and its use will result in excretion of small amounts of codeine. Poppy seed foods represent yet another source of low levels of codeine in one's biofluids. Blood or plasma codeine concentrations are typically in the 50–300 µg/L range in persons taking the drug therapeutically, 700–7000 µg/L in chronic users and 1000–10,000 µg/L in cases of acute fatal over dosage.
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 in the United States and Canada; codeine hydrochloride is more common worldwide and the citrate, hydroiodide, hydrobromide, tartrate, and other salts are also seen.
As an analgesic, codeine compares moderay 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.
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 to 4 hours and oral/intramuscular analgesic potency ratio is approximay equal to 1:1.5. It 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.
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.
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.
Morphine had already been isolated in Germany by German pharmacist Friedrich Sertürner in 1804. Codeine was first isolated decades later in 1832 in France by Pierre Robiquet, a French chemist and pharmacist already famous for the discovery of alizarin, the most widespread red dye, while working on refined morphine extraction processes. This paved the way for the elaboration of a new generation of safer, codeine-based specific antitussive and antidiarrheal formulations.
Codeine is also demethylated by reaction with pyridine to synthesize morphine, which can then be acetylated to make heroin (diacetylmorphine). Pyridine is toxic and possibly carcinogenic, so morphine produced in this manner (and potentially contaminated with pyridine) may be particularly harmful. Codeine can also be turned into α-chlorocodide, which is used in the clandestine synthesis of desomorphine (Permonid) (desomorphine attracted attention in 2010 in Russia due to an upsurge in clandestine production, presumably due to its relatively simple synthesis from codeine. The drug is easily made from codeine, iodine and red phosphorus, in a similar process to the manufacture of methamphetamine from pseudoephedrine, but desomorphine made this way is highly impure and contaminated with various toxic and corrosive byproducts.).
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).
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 15 mg per tablet are S4 (Schedule 4, or "Prescription Only") medications. The item is given over the counter, no prescriptions, at the discretion of the pharmacist. Most preparations are considered S3 (schedule 3, or "Pharmacist Only") medications, meaning that they must be sold with the direct involvement of a pharmacist. It must be labelled and usage history monitored by the pharmacist to help deter misuse and dependence. The exception to this rule is cold and flu preparations such as "Codral". These preparations contain phenylephrine (5 mg), paracetamol (500 mg) and codeine (9.5 mg).
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 ).
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.
Whilst all sedating antihistamines will potentiate the effects of codeine, enzyme induction leading to greater hepatic conversion of codeine to morphine is the reason for both the clinical and recreational use of promethazine with codeine. This was the case all the more with another drug, Doriden (glutethemide) (q.v.) Codeine and glutethidmide were taken in combination known as Loads, Dors & Fours, and Six Packs (two Doriden tablets or 1000 mg of glutethimide and four tablets of a codeine combination totalling 240 mg of codeine) as a substitute for heroin or a primary opioid drug of choice; first mentioned in medical journals in the late 1960s, then reappearing along with Ts & Blues (pentazocine and tripelennamine) during the late 1970s. Glutethimide was off the market by the end of 1988 around the world, but the use of this combination is apparently a major driver for the small amount of illicit glutethimide synthesis uncovered since that time. Taking the combination on an empty stomach was particularly favoured for partially approximating the rush and bang of injecting heroin or morphine.
Codeine and morphine as well as opium were used for control of diabetes until relatively recently, and still are in rare cases in some countries, and the hypoglycemic effect of codeine, although usually weaker than that of morphine, diamorphine, or hydromorphone, can lead to cravings for sugar.
Codeine can be used as a recreational drug.
By 1972, the effects of the War On Drugs 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 growing difficult for the United States. After a large percentage of the opium and morphine in the US National Stockpile of Strategic & Critical Materials was tapped in order to ease severe shortages of medicinal opiates — the codeine-based antitussives in particular — in late 1973, researchers were tasked with finding a way to synthesize codeine and its derivatives. They quickly succeeded using petroleum or coal tar and a process developed at the United States' National Institutes of Health.
Some medications are CYP2D6 inhibitors and reduce or even compley 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.
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 in generic form as promethazine with codeine. Called 'syrup', 'lean', or ' purple drank ', this medication is quickly becoming one of the most commonly misused codeine preparations. Rapper Pimp C, from the group UGK, died from an overdose of this combination. This mixture is, owing to promethazine being a prescription-only antihistamine, available only on prescription in all 50 USA states.
Some patients are very effective converters of codeine to its active form, morphine, resulting in lethal blood levels. The FDA presently is 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.
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, depression, 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 also have an allergic reaction to codeine, such as the swelling of skin and rashes.
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.
Until the beginning of the 19th century, raw opium was used in diverse preparations known as laudanum (see Thomas de Quincey 's " Confessions of an English Opium-Eater ", 1821) and paregoric elixirs, a number of which were popular in England since the beginning of the 18th century; the original preparation seems to have been elaborated in Leiden, the Netherlands around 1715 by a chemist named Lemort; in 1721 the London Pharmocopeia mentions an Elixir Asthmaticum, replaced by the term Elixir Paregoricum ("pain soother") in 1746.
Codeine, or 3-methylmorphine, is an alkaloid found in the opium poppy, Papaver somniferum var. album, a plant in the papaveraceae family. Opium poppy has been cultivated and utilized throughout human history for a variety of medicinal (analgesic, anti-tussive and anti-diarrheal) and hypnotic properties linked to the diversity of its active components, which include morphine, codeine and papaverine.
Codeine is metabolized to codeine-6-glucuronide (C6G) by uridine diphosphate glucuronosyl transferase UGT2B7, and, since only about 5% of codeine is metabolized by cytochrome P450 CYP2D6, the current evidence is that C6G is the primary active compound. Claims about the supposed "ceiling effect" of codeine doses are based on the assumption that high doses of codeine saturate CYP2D6, preventing further conversion of codeine to morphine, however it is now known that C6G is the main metabolite responsible for codeine's analgesia.
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.
While codeine can be directly extracted from opium, its original source, most codeine is synthesized from the much more abundant morphine through the process of O- methylation.
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. Its strength ranges from 8 to 12 percent of morphine in most people; differences in metabolism can change this figure as can other medications, depending on its route of administration.
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.
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 Federal Drug Administration issued a warning about deaths in pediatric patients < 6 years old after ingesting "normal" doses of acetaminophen with codeine after tonsillectomy.
In Australia, Canada, New Zealand, Sweden, the United Kingdom, the United States and many other countries, codeine is regulated under various narcotic control laws. In some countries it is available without a medical prescription in combination preparations from licensed pharmacists in doses up to 15 mg.
It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.
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 ).
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. In some countries, in an effort to reduce recreational use, all OTC purchases of codeine are electronically recorded, and any pharmacy can access these records if desired. A heroin addict may use codeine to ward off the effects of a withdrawal.