Codeine is a weak opioid analgesic which is derived from opium alkaloids.
Codeine is markedly less active than morphine, has predictable effects when given orally and is effective against mild to moderate pain.
Activity depends on the conversion to morphine by the cytochrome P-450 isoenzyme 2D6 (CYP2D6).
After conversion to morphine the latter is metabolized to the active morphine-6-to glucuronide by means of UDP-glucuronosyltransferase 2B7.
Has no analgesic effect as a parent compound, and must be metabolized to morphine.
A prodrug.
Variations in the genes encoding CYP26 has genetic variations that affect the conversion of codeine to its active form resulting in variable effects.
Patients with normal range of CYP2D6 activity represents 75-92% of the population.
Patients with normal range of CYP2D6 activityare called extensive metabolizers.
Approximately 5-10% of the population are poor metabolizers who have no functional alleles and receive little or no morphine or analgesia from taking codeine.
Ultra high CYP2D6 metabolizes have two or more functional alleles and can convert codeine into large amounts of morphine.
Ultra rapid metabolizers of codeine may have toxic effects, and this has been reported among children undergoing adenotonsillectomy.
Controlled Schedule II drug opiate with moderate dependence liability.
Can be administered orally, rectally, SC or IM.
Has a oral bioavailability of about 90%.
Its metabolism is hepatic via the CYP2D6 system.
Has a half-life of 2.5–3 h
Codeine or 3-methylmorphine is a natural isomer of methylated morphine.
An opiate used for its analgesic, antitussive, antidiarrheal, antihypertensive, anxiolytic, antidepressant, sedative and hypnotic properties, and can suppress premature labor contractions.
Codeine is extracted from natural sources.
Considered a weak to midrange opioid like tramadol, dextropropoxyphene, dihydrocodeine, hydrocodone, and oxycodone.
Used to treat mild to moderate pain and to relieve cough.
Can be used to treat diarrhea and diarrhea predominant irritable bowel syndrome.
Available as a single-ingredient drug and in combination preparations with paracetamol, aspirin, phenacetin, naproxen, indomethacon, diclofenac, or with ibuprofen.
Combinations provide greater pain relief than either agent alone
Can be obtained as a time release tablet.
Also marketed in cough syrups.
Available for subcutaneous or intramuscular injection.
Adverse effects include drowsiness and constipation as the most common problems, with euphoria, itching, nausea, vomiting, dry mouth, miosis, orthostatic hypotension, urinary retention, depression, and, paradoxical coughing occurring less commonly.
Rarely adverse anaphylaxis, seizure, and respiratory depression may occur.
May be associated with diminished libido, apathy and memory loss.
Allergic reactions include rashes.
Has hypoglycemic effects.
With prolonged use tolerance to therapeutic effects occur.
Tolerance to constipation induced effects develops slowly.
Respiratory depression is dose-related and is a potentially fatal consequence.
Because it is metabolized morphine, and the latter can be passed through breast milk and depress respirations of a breast-fed baby.
Deaths have occurred in pediatric patients less than six years old after ingesting acetaminophen with codeine after tonsillectomy.
Chronic use of codeine can cause physical dependence.
Physical dependence may cause withdrawal symptoms if a patient 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.
Codeine is metabolized to codeine-6-glucuronide (C6G) by uridine diphosphate glucuronosyl transferase UGT2B7.
About 5% of codeine is metabolized by cytochrome P450 CYP2D6
Codeine-6-glucuronide (C6G) is the primary active compound.
CYP2D6 has been implicated in the toxicity and death of neonates when codeine is administered to lactating mothers, particularly those with increased 2D6 activity.
The conversion of codeine to morphine occurs in the liver and is catalyzed by the cytochrome P450 enzyme CYP2D6.
Some medications are CYP2D6 inhibitors and reduce or completely block the conversion of codeine to morphine.
Common medications that reduce conversion of codeine to morphine are two of the selective serotonin reuptake inhibitors, paroxetine (Paxil) and fluoxetine (Prozac).
The antihistamine diphenhydramine and the antidepressant, bupropion (Wellbutrin) are also drugs that also known to reduce conversion of codeine to morphine.
The drugs rifampicin and dexamethasone, induce CYP450 isozymes and increase the conversion rate.
CYP2D6 converts codeine into morphine, which then undergoes glucuronidation.
Life-threatening toxicity including respiratory depression 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 studies suggest metabolism of codeine by CYP2D6 to morphine is important.
Yet some studies show no major differences between those who are poor metabolizers and extensive metabolizers.
The active metabolites of codeine, particularly morphine, exert their effects by binding to and activating the μ-opioid receptor.
Codeine is the prototype of a large class of mild to moderately strong opioids; such as hydrocodone, oxycodone, dihydrocodeine, and its derivatives.
The most widely-used opiate in the world, and is one of the most commonly used drugs overall..
One of the most effective orally administered opioid analgesics
Has a wide safety margin.
Its strength ranges from 8 to 12 percent of morphine in most people.
Can be directly extracted from opium.
Most codeine is synthesized from the much more abundant morphine through the process of O-methylation.
Codeine is also available in conjunction with the anti-nausea medication promethazine.
Codeine and/or its major metabolites may be quantitated in blood, plasma or urine to monitor therapy, confirm a diagnosis of poisoning or assist in a medicolegal death investigation.
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
Codeine usage results in significant amounts of morphine as an excretion product.
Heroin contains 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.
Blood or plasma codeine concentrations are typically in the 50–300 µg/L range therapeutically, 700–7000 µg/L in chronic users and 1000–10,000 µg/L in cases of acute fatal overdosage.
Narcotic content number in the US names of codeine tablets and combination products like Tylenol With Codeine No. 3, Emprin With Codeine No. 4, and pure codeine tablets 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).