Codeine was once considered to be a morphine prodrug, since it was thought that its analgesia was due in large part to its O-demethylation to the much more powerful opiate, morphine. However, more recent research shows that 80% of codeine is conjugated with glucuronic acid to Codeine-6-glucuronide (C6G), which is the metabolite that is most responsible for codeine's analgesia, although the relative contributions of codeine-6-glucuronide and morphine to analgesia are unclear and highly debated. Only 5% of the dose is O-demethylated to morphine, which in turn is immediately glucuronidated at the 3- and 6-position and excreted renally.[9][10] A portion (~ 15% ) of the codeine is N-demethylized to norcodeine.[11] It is less potent than morphine and has a correspondingly lower dependence-liability than morphine.[12] Like all opioids, continued use of codeine induces physical dependence and can be psychologically addictive. However, due to its low potency, the withdrawal symptoms are relatively mild compared to closely related opioids such as hydrocodone and oxycodone. As such, codeine has a lower physical dependence liability than most other opioids.[13]
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 in general isn't used in single doses greater than 60 mg (and no more than 240 mg in 24 hours).[14][15] When analgesia beyond 60 mg of codeine is required, stronger opioids such as hydrocodone or oxycodone are utilized.[16] When used to relieve dry coughs, codeine is used in doses ranging from 5-15 mg and is usually mixed as a syrup with other drugs such as promethazine[17] which is an antihistamine with strong sedative activity (some formulations come with different types of antihistamines),[18] guaifenesin which is an expectorant,[19] and other drugs. When codeine isn't effective in relieving stronger dry coughs, then the opioid hydrocodone is used instead.
Codeine is metabolized to 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 codeine-6-glucuronide (C6G) is the primary active compound.[20] Claims about the supposed "ceiling effect" of codeine doses seemed to rest on the assumption that high doses of codeine saturated CYP2D6, which prevented further conversion of codeine to morphine, which is simply incorrect since we now know that codeine-6-glucuronide (C6G) is the main metabolite responsible for codeine's analgesia.[9] There is also no evidence that CYP2D6 inhibition is useful in treating codeine dependence,[21] 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.[22] 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" metabolisers).[23][24]
[edit] Pharmacokinetics
The conversion of codeine to morphine occurs in the liver and is catalysed by the cytochrome P450 enzyme CYP2D6. CYP3A4 produces norcodeine and UGT2B7 conjugates codeine, norcodeine, and morphine to the corresponding 3- and 6- glucuronides. Approximately 6–10% of the Caucasians, 2% of Asians, and 1% of Arabs[25] are "poor metabolizers"; they have little CYP2D6, and codeine is less effective for analgesia in these patients (Rossi, 2004). 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.[10] 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 and the antidepressant, buproprion (Wellbutrin, also known as Zyban). Other drugs, such as rifampicin and dexamethasone, induce CYP450 isozymes and thus increase the conversion rate.
Since codeine is a prodrug, metabolism differences have the opposite effect. Thus an extensive metabolizer may have adverse effects from a rapid buildup of codeine metabolites while a poor metabolizer may get little or no pain relief. CYP2D6 is dysfunctional in 7% of white and black Americans, resulting in reduced metabolism of codeine. Other individuals may have two or more copies of the CYP2D6 gene, resulting in rapid metabolism of the target drug. CYP2D6 metabolizes and activates 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.[26][27][28]
The active metabolites of codeine, notably morphine, exert their effects by binding to and activating the μ-opioid receptor.
