Codeine is an opiate, and a natural constituent of opium where it is found ranging in concentrations from 0.7% to 2.5% by weight; however, most pharmaceutical-grade codeine is produced from morphine via O-methylation. Approved medical uses for codeine include moderate to severe pain, diarrhea, cough suppression, and IBS (irritable bowel syndrome). Most of the time codeine is found in combination with acetaminophen, resulting in a synergism that allows for greater pain relief than either drug alone.
The major effects of codeine are exerted on the central nervous system and the bowel. Like other opiates, its primary effects are a result of binding to opioid receptors in the brain, gut, and other parts of the body. While codeine itself has a weak binding affinity to mu-opioid receptors, 5% to 10% of codeine is converted into morphine, which has a high binding affinity to mu-opioid receptors. The primary metabolites of codeine are morphine and codeine-6-glucuronide. In addition to codeine being converted into morphine in the body, it is also converted into several other active compounds. The approximate distribution of those active compounds is as follows: codeine-6-glucuronide (~70%), norcodeine (~10%), and hydromorphone (~1%).
Conversion of codeine to morphine occurs in the liver via 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 Arabic 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."1
Some drugs may interfere with the effectiveness of codeine. Certain SSRIs (selective serotonin reuptake inhibitors) are CYP2D6 inhibitors, which consequently reduces the efficacy of codeine. Combining codeine with gluthethimide, a sleeping agent, is said to act as an enzyme-inducer, allowing the body to convert up to 10% of codeine into morphine.2 Other drugs that may increase the effectiveness of codeine include rifampicin, a bactericidal antibiotic, and dexamethasone, a steroid hormone.
Under United States law, codeine can appear as both a Schedule II or Schedule III substance depending on the formulation. Here are the differences between the two:
In the United States, this drug is sometimes considered a Schedule II substance, making it illegal to use or possess without a prescription. Schedule II substances, such as dextroamphetamine, morphine, oxycodone, and cocaine, meet the following criteria according to the Controlled Substances Act:
In the United States, this drug is sometimes considered a Schedule III substance, making it illegal to use or possess without a prescription. Schedule III substances, such as codeine, hydrocodone (when combined with a non-narcotic active ingredient), and Marinol (synthetic THC), meet the following criteria according to the Controlled Substances Act:
Codeine withdrawal typically starts within 12-24 hours after the last dose. The time it takes for codeine withdrawal to begin varies due to factors such as frequency of use, dosage, and body chemistry. Acute withdrawal symptoms peak between 48 and 72 hours and are generally gone within a week; however, post-acute withdrawal syndrome (PAWS) can affect a person for weeks or months after the initial withdrawal phase. Withdrawal from codeine is rarely fatal, though complications can arise which are largely dependent upon the person's health. Withdrawal from other drugs, such as alcohol or benzodiazepines, can easily result in death.