Introduction

Codeine is a natural alkaloid and opiate derived from the opium poppy plant (Papaver somniferum). It is a commonly used medication for pain relief and is also known for its antitussive properties, making it useful in the treatment of coughs. Codeine has been used for centuries and remains an important component in various pharmaceutical products. This article delves into the general information, physico-chemical properties, synthesis, pharmacology, effects, applications, and legal status of codeine.

General information about Codeine

Codeine, chemically known as methylmorphine, falls under the class of opioids found in extracts of the poppy, particularly Papaver bracteatum. It was first isolated in 1832 by Pierre Robiquet, a French chemist, and is closely related to other opioids such as morphine and heroin. As an opiate, codeine acts on the opioid receptors in the brain, spinal cord, and other parts of the body to reduce pain and suppress cough reflexes.

Codeine, comprising up to three percent of opium’s alkaloids, holds the position of the second most prevalent alkaloid. While codeine can be derived from natural origins, its primary source for pharmaceutical purposes is a semi-synthetic process. This process involves modifying certain elements to create codeine, establishing it as the prototype for weak to midrange opioids, which includes tramadol, dextropropoxyphene, dihydrocodeine, and hydrocodone.

Presently, codeine stands as the most widely utilized opiate worldwide and ranks high among the most frequently employed drugs, as confirmed by various reports from reputable organizations like the World Health Organization and its League of Nations precursor agency. As an orally administered opioid analgesic, codeine is highly effective and possesses a broad safety margin.

In recreational settings, codeine is often procured over-the-counter within painkillers that combine it with other more hazardous substances. However, it is possible to isolate codeine from these mixtures using a cold water extraction method.

The use of codeine dates back to ancient civilizations, where opium was employed for its analgesic effects. Over time, advancements in chemistry and pharmaceuticals led to the isolation and purification of codeine, making it easier to use in medical treatments.

Codeine: A Fairly Pointless Drug

Physico-chemical Properties of Codeine

Codeine is a white, odorless crystalline powder with a bitter taste. Its molecular formula is C18H21NO3, and it has a molecular weight of 299.36 g/mol. The chemical structure of codeine includes a benzene ring and a dihydrocodeine ring, both of which contribute to its pharmacological properties.

Its melting point ranges from 154 to 156°C, and it is stable under normal conditions. Boiling point is 250°C. These physico-chemical properties play a crucial role in formulating various codeine-containing pharmaceutical products.

Codeine is sparingly soluble in water (0.577 g/L) but dissolves well in alcohol and chloroform. Soluble in alcohol 1:9.5. Poorly soluble in diethyl ether 1:50. It is best dissolved in chloroform (1:0.5, according to other sources 1:1), which is often used to extract from codeine—containing substrates. Solubility in benzene is 1:10. Almost insoluble in petroleum ether and alkali solutions, except for ammonia. Aqueous and alcoholic solutions have an alkaline pH.

Names: (5α,6α)-7,8-didehydro-4,5-epoxy-3-methoxy-17-methylmorphinan-6-ol; Methylmorphine; Morphine 3-methyl ether; Morphine monomethyl ether; (-)-Codeine; Coducept; l-Codeine; O3-Methylmorphine; Codecept; Mytussin; Kodelak fito; 3-Methylmorphine;

CAS Number: 76-57-3

Codeine Synthesis

The primary source of codeine is the opium poppy plant. It is present in the plant’s latex in small quantities, along with other alkaloids like morphine and thebaine. To obtain codeine, opium latex is first collected from the unripe seed pods of the poppy plant. The latex is then processed through various chemical and extraction methods to isolate and purify the codeine.

Apart from the natural source, codeine can also be synthesized chemically. The process involves a straightforward methylation of the phenolic –OH group, while leaving the –OH group in the other ring untouched. This method was first introduced by the Russian chemist V. M. Rodionov (1878-1954). However, creating it from the beginning would be excessively inefficient. However, due to the availability of codeine from natural sources, chemical synthesis is not commonly practiced for its production.

Pharmacology of Codeine

Codeine does not exhibit central activity on its own and necessitates conversion through first-pass metabolism into morphine, achieved by the cytochrome P450 enzyme CYP2D6. As a result, codeine functions as a prodrug for morphine. The CYP3A4 enzyme system further metabolizes codeine into the inactive norcodeine. Both resulting forms are conjugated by UGT2B7 into their respective 3-glucuronide forms.

Certain individuals possess lower levels of CYP2D6 enzymes, leading to a significant reduction in codeine’s effects compared to the average person. On the other hand, some individuals produce higher quantities of CYP2D6 enzymes, making them hypersensitive to the drug. Methods of potentiating opioids, such as consuming grapefruit juice before codeine intake, inhibit the CYP3A4 enzyme, resulting in less conversion of codeine into norcodeine and leaving more available to be metabolized into morphine. Conversely, antihistamines like diphenhydramine can impair the metabolism of codeine into morphine when taken prior to codeine ingestion.

An upper limit, often referred to as the “ceiling dose,” exists for the amount of codeine that can be converted into morphine through enzymatic metabolism during a single session. This limit, which is commonly considered to be around 400mg, means that consuming higher doses will not increase euphoria but may lead to greater side effects like itchiness and nausea.

The active metabolites of codeine, especially morphine, exert their effects by binding to and activating opioid receptors, primarily the μ-opioid receptor. Opioids structurally mimic naturally occurring endorphins within the body, leading to euphoria, pain relief, muscle relaxation, and anxiolytic effects. Endorphins are responsible for reducing pain, inducing sleepiness, and creating feelings of pleasure in response to pain, exercise, orgasm, or excitement.

Although codeine itself acts as a weak ligand for opioid receptors, its primary active metabolite, morphine, exhibits much stronger agonistic effects.

Codeine Effects

Physical effects

• Numerous individuals characterize the overall mental state induced by codeine as a sense of euphoria, calmness, alleviation of anxiety, and relief from pain.
• Pain relief
• Physical euphoria – Comparatively, this substance can be seen as producing milder physical euphoria in contrast to morphine or diacetylmorphine (heroin) because of the maximum limit on its conversion into an active form through metabolism. The experience can be described as profound feelings of immense physical comfort, warmth, and bliss that permeate the entire body.
• Itchiness – This substance induces more pronounced itchiness as a result of elevated histamine release in comparison to other opioids.
• Respiratory depression – At lower to moderate dosages, this effect leads to a perception of mild to moderate slowing of breath, without causing evident impairment. However, at higher doses and in cases of overdosing, opioid-induced respiratory depression may lead to breathlessness, abnormal breathing patterns, partial consciousness, or loss of consciousness. In severe overdose situations, immediate medical attention becomes crucial, as it can result in a coma or even fatalities.
• Sedation – At elevated doses, this substance can induce sensations of sedation and is notably more sedative than both oxycodone and hydrocodone.
• Appetite suppression
• Constipation
• Cough suppression
• Decreased libido
• Difficulty urinating
• Nausea – This effect is more prone to manifest at higher dosages and/or when the user fails to pace themselves properly.
• Orgasm suppression
• Pupil constriction

Cognitive effects

• Cognitive euphoria – This specific compound is perceived as generating less pronounced cognitive euphoria when compared to morphine or diacetylmorphine (heroin) because of the maximum limit on its conversion into an active form through metabolism. Nevertheless, at higher doses with low tolerance, it can still produce intense and overpowering bliss. The experience itself can be described as a potent and overwhelming feeling of emotional bliss, contentment, and happiness.
• Anxiety suppression
• Thought deceleration
• Compulsive redosing – It is important to mention that taking additional doses of codeine will not increase the intensity of its effects.
• Dream potentiation
• Sleepiness

Visual effects

• Suppressions
• Double vision – At elevated doses, the eyes experience involuntary unfocusing and refocusing. This leads to a blurred effect and double vision that persists regardless of where one directs their gaze. The intensity of this effect can be so profound that reading or driving becomes impractical.

Applications of Codeine

Codeine finds a wide range of applications in the field of medicine due to its potent analgesic and antitussive properties. Some of the notable applications include:

1. Pain Management: Codeine is commonly prescribed for mild to moderate pain relief. It is particularly effective in alleviating pain associated with dental procedures, post-operative recovery, and headaches. In cases where non-opioid pain relievers prove insufficient, codeine-based medications offer a valuable alternative.
2. Cough Suppression: As an effective antitussive agent, codeine is a key component in numerous over-the-counter and prescription cough syrups. It helps suppress the cough reflex, providing relief for persistent and irritating coughs caused by various respiratory conditions.
3. Diarrhea Treatment: Codeine exhibits antidiarrheal properties by slowing down bowel movements. This makes it useful in managing acute diarrhea and easing discomfort caused by gastrointestinal disturbances.
4. Chronic Pain Conditions: In some chronic pain conditions, where other treatments may not offer adequate relief, codeine may be prescribed to manage pain and improve the patient’s quality of life.
5. Combination Products: Codeine is frequently combined with other medications, such as acetaminophen or ibuprofen, to create combination products that enhance its analgesic effects. These combinations provide more comprehensive pain relief and reduce the need for higher doses of codeine.
6. Pre- and Post-operative Pain: In surgical settings, codeine is sometimes used to manage pain before and after procedures. It can effectively control pain during recovery, promoting a smoother healing process for patients.
7. Terminal Illness Care: For patients with terminal illnesses or palliative care needs, codeine may be utilized to alleviate severe pain, providing comfort and enhancing their end-of-life experience.

It is crucial to note that while codeine has various medical applications, its use should be closely monitored due to the potential for abuse and dependence. Healthcare professionals carefully consider the risks and benefits before prescribing codeine-containing medications, ensuring responsible and safe use to optimize patient outcomes.

Codeine Legal Status

• Australia: In Australia, codeine preparations are Schedule 4 (Prescription Only) medications when combined with other substances. Preparations containing pure codeine (e.g., codeine phosphate tablets or codeine phosphate linctus) are available on prescription and are considered Schedule 8 (Controlled Drug (Possession without authority illegal)). Schedule 8 drugs are drugs that are available to be prescribed but are heavily restricted to prevent abuse and dependence. Possessing Schedule 8 drugs without authority is a criminal offense and can have varying punishments depending on the state of prosecution.
• Austria: Codeine is legal for medical use under the AMG (Arzneimittelgesetz Österreich) and illegal when sold or possessed without a prescription under the SMG (Suchtmittelgesetz Österreich).
• Canada: In Canada, codeine is available over the counter in combination tablets with the following restrictions: no more than 8 mg per dosage unit and it must be combined with at least two other active ingredients. It is kept behind the counter, to be sold on request– generally to those 18 and over– after a brief consultation and at the pharmacist’s discretion. The other active ingredients most commonly consist of another non-opioid analgesic (300 mg acetaminophen, as in Tylenol No. 1; or 325 mg aspirin, as in 222s) and 15 mg caffeine. OTC tablets containing ibuprofen are generally unavailable. Preparations with a codeine content higher than 8 mg per dosage unit, or fewer than two other active ingredients, are available on prescription.
• Denmark: In Denmark, codeine is sold over the counter with max 9.6 mg in the mixture. The item is given over the counter, with no prescriptions. The strongest available over the counter preparation containing codeine has 9.6 mg (with aspirin, brand name Kodimagnyl); anything stronger requires a prescription for legal possession.
• Finland: In Finland, codeine cough syrups with a maximum strength of 1mg/ml is sold in pharmacies over the counter. Codeine isn’t available in pill form without a prescription. Any stronger cough syrup and combination painkillers (codeine with paracetamol or ibuprofen such as Panacod, Co-codamol, and Ardinex) require a prescription.
• France: In France, most preparations containing codeine do not require a doctor’s prescription. Example products containing codeine include Néocodion (cough pills, and syrup), Codoliprane (codeine with paracetamol), Prontalgine and Migralgine (codeine, paracetamol, and caffeine). Codeine is regulated/controlled substance (schedule 2) since 2017 after a decision of the “Minister of Health” Agnès Buzyn, it is therefore now under prescription only and raw pure codeine is not being available altogether anymore. The most common prescribed codeine brands are Klipal and Codoliprane, both mixed with paracetamol heavily. Klipal being the strongest ratio, 50mg codeine for 600mg paracetamol.
• Germany: Codeine is a controlled substance under Anlage III of the BtMG. It can only be prescribed on a narcotic prescription form. There is an exception for preparations, containing up to 2,5% or 100mg codeine per unit, which can be prescribed on a regular prescription if not prescripted to an alcohol or drug dependent person.
• Greece: Codeine is classed as an illegal drug in Greece, and individuals possessing it could conceivably be arrested, even if they were legitimately prescribed it in another country. It is sold only with a doctor’s prescription.
• Hong Kong: In Hong Kong, codeine is regulated under Laws of Hong Kong, Dangerous Drugs Ordinance, Chapter 134, Schedule 1. It can be used legally only by health professionals and for university research purposes. The substance can be given by pharmacists under a prescription. However, codeine is available without prescription from licensed pharmacists in doses up to 0.1%
• Iceland: Preparations of paracetamol and codeine require a prescription in Iceland.
• India: Codeine preparations require a prescription in India. Preparation of paracetamol and codeine is available in India. Codeine is also present in various cough syrups as codeine phosphate.
• Iran: Preparations of codeine in Iran normally comes with paracetamol, but can be purchased over-the-counter. Iran’s deputy health minister reported that codeine is Iran’s best selling OTC medication. The recreational use of codeine has also become widespread throughout Iran but authorities continue to let codeine be purchased without permission from a doctor, although the pharmacist may ask for the identification of the purchaser to verify they are 18 years or older to buy.
• Ireland: Codeine remains a semi non-prescriptive, over-the-counter drug up to a limit of 12.8 mg per pill, but codeine products must be out of the view of the public. Products containing more than 12.8 mg codeine are available on prescription only.
• Italy: Codeine tablets or preparations require a prescription in Italy. Preparations of paracetamol and codeine are available in Italy as Co-Efferalgan and Tachidol.
• Japan: Codeine and similar mid-level centrally acting agents in combination with non-opioid analgesics, antihistamines, vitamins, inert GI agents like kaolin & pectin, mild laxatives, antacids, and herbal preparations, can be purchased over the counter, with 10 mg being the ceiling for OTC dispensing.
• Maldives: The Maldives takes an infamously strict line on medicines, with many common drugs, anything containing codeine is banned unless you have a notarized and authenticated doctor’s prescription. Visitors breaking the rules, even inadvertently, have been deported or imprisoned.
• Poland: Codeine is listed in “Wykaz środków odurzających i substancji psychotropowych” group ” II-N” which means it’s legal to use in scientific and medical pruposes, and is available over the counter in doses of 15mg in combination with 500mg paracetamol (Antidol) or 300mg sulfogaiacol (Thiocodin). However a pharmacy worker can refuse to sell it if they believe the client is a minor or wants to use it for drug abuse purposes.
• Romania: Codeine is sold OTC (when combined with another active ingredient), the limit being 12.8mg of codeine per pill, which is seen in Nurofen Plus. Any amount above 12.8mg/unit requires a prescription, whether it has another ingredient or not.
• Russia: According to ITAR-Tass and Austria Presse-Agentur, OTC availability of codeine products was rescinded nationwide in 2012 because of the discovery of the Krokodil method of underground desomorphine synthesis.
• Spain: Codeine tablets or preparations require a prescription in Spain, although this is often not enforced and many pharmacies will sell codeine products without the requirement of a prescription.
• Sri Lanka: Codeine preparations are available as over the counter pharmacy medicines in Sri Lanka. The most common preparation is Panadeine, which contains 500 mg of Paracetamol and 8 mg of Codeine.
• Sweden: Codeine is Schedule III under Swedish law, which means it is heavily regulated and sold only to those who have a prescription.
• Switzerland: Codeine is a controlled substance specifically named under Verzeichnis A. Medicinal use is permitted. Some preparations containing codeine are included in Verzechnis C, while certain ones are excluded.
• Turkey: Codeine is a ‘red prescription’ only substance and illegal when sold or possessed without a prescription.
• United Arabian Emirates: The UAE takes an exceptionally strict line on medicines, with many common drugs, notably anything with containing codeine being banned unless you have a notarized and authenticated doctor’s prescription. Visitors breaking the rules, even inadvertently, have been deported or imprisoned. The US Embassy to the UAE maintains an unofficial list of what may not be imported.
• United Kingdom: Under the Misuse of Drugs Act 1971 codeine is a Class B controlled substance or a Class A drug when prepared for injection. The possession of controlled substances without a prescription is a criminal offense. However, certain preparations of codeine are exempt from this restriction under Schedule 5 of the Misuse of Drugs Regulations 2001. It is thus legal to possess codeine without a prescription, provided that it is compounded with at least one other active or inactive ingredient and that the dosage of each tablet, capsule, etc does not exceed 100 mg or 2.5% concentration in the case of liquid preparations.
• United States: In the United States, codeine is regulated by the Controlled Substances Act. Federal law dictates that codeine be a Schedule II controlled substance when used in products for pain-relief that contain codeine alone or more than 90 mg per dosage unit. Tablets of codeine in combination with aspirin or acetaminophen (paracetamol/Tylenol) made for pain relief are listed as Schedule III; and cough syrups are Schedule III or V, depending on the formula.

Conclusion

Codeine is a valuable medication with potent analgesic and antitussive properties. Its historical significance as an ancient remedy for pain and cough relief underscores its importance in the field of medicine. However, codeine’s potential for abuse and addiction necessitates responsible use and strict regulation.

As pharmaceutical research continues, there may be advancements in pain management and antitussive medications that reduce the reliance on opioids like codeine. Nevertheless, codeine’s role in healthcare remains significant, and with appropriate use, it continues to provide relief to millions of patients worldwide.

Bibliography

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• Sindrup, Soren H., and Kim Brøsen. “The pharmacogenetics of codeine hypoalgesia.” Pharmacogenetics 5.6 (1995): 335-346. https://europepmc.org/article/med/8845855
• https://en.wikipedia.org/wiki/Codeine
• https://go.drugbank.com/drugs/DB00318
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