Codeine Pharmacokinetics

Codeine is considered a prodrug, since it is metabolised in vivo to the primary active compounds morphine and codeine-6-glucuronide[5] [6]. Roughly 5-10% of codeine will be converted to morphine, with the remainder either free or conjugated to codeine-6-glucuronide(~70%) or converted to norcodeine(~10%) and hydromorphone(~1%). It is less potent than morphine and has a correspondingly lower dependence-liability than morphine. [7] Like all opiates, codeine is addictive unless used infrequently. However, the withdrawal symptoms are relatively mild and as a consequence codeine is considerably less addictive than the other opiates.

Theoretically, a dose of approximately 200 mg (oral) of codeine must be administered to give equivalent analgesia to 30 mg (oral) of morphine (Rossi, 2004). However, codeine is generally not used in single doses of greater than 60 mg (and no more than 240 mg in 24 hours). When analgesia beyond this is required, stronger opioids such as hydrocodone or oxycodone are favored. Because codeine needs to be metabolized to an active form, there is a ceiling effect around 400-450 mg. This low ceiling further contributes to codeine being less addictive than the other opiates.

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 Caucasian population, 2% of Asians, and 1% of Arabs[8] have poorly functional CYP2D6 and codeine should be virtually ineffective for analgesia in these patients (Rossi, 2004), although it is speculated that codeine-6-glucuronide is responsible for a large percentage of the analgesia of codeine and thus these patients should experience some analgesia.[9] Conversely, 0.5-2% of the population has multiple copies of the 2D6 gene and will metabolise 2D6 dependent drugs more efficiently than others. Many of the adverse effects will still be experienced in poor 2D6 metabolisers.

Also, some medications are CYP2D6 inhibitors and reduce or even completely eliminate the efficacy of codeine. The most well-known of these are the selective serotonin reuptake inhibitors, such as fluoxetine (Prozac) and citalopram (Celexa). Others induce expression of CYP450 isozymes and thus increase the rate of metabolism, for example rifampicin and dexamethasone.

It is important to note that whereas usually an EM (extensive metaboliser) will need a higher drug dose for a sufficient therapeutic effect and a PM (poor metaboliser) may suffer from drug toxicity due to accummulation with normal dose, with Codeine, the opposite is true. This being because it is a pro-drug. Thus, an EM may have an adverse toxicity effect and PM will have little or no pain relief.