General Information

Codeine is an opiate, and a natural constituent of opium, where it is found in concentrations ranging 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, 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.

Chemical Names. (5alpha,6alpha)-7,8-Didehydro-4,5-epoxy-3-methoxy-17-methylmorphinan-6-ol.
Classification. Opiate.
Primary Uses. Analgesia, cough, diarrhea, irritable bowel syndrome.
Other Names. Tylenol #3, Codate, Codephos.

Pharmacology and Pharmacokinetics

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 and other parts of the body. Codeine has a weak binding affinity for the mu-opioid receptors; however, roughly 5% to 10% of codeine is converted into morphine, which has a high binding affinity for mu-opioid receptors. The primary metabolites of codeine are morphine, and codeine-6-glucuronide. Not only is codeine converted into morphine in the body, but also several other active compounds. The approximate distribution 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 completely 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 and Dexamethasone.

Law

Under United States law, codeine can appear as both a Schedule II and III substance. The differences are listed below:

• Schedule II - Products containing more than 90 mg per dosage unit.
• Schedule III - Products containing less than 90 mg per dosage unit.

Criteria for Schedules II and III:

In the United States, codeine is sometimes a Schedule II substance, making it illegal to use/possess without a prescription. Schedule II substances, such as dextroamphetamine, morphine, and cocaine, meet the following criteria according to the Controlled Substances Act:

1. The drug or other substance has a high potential for abuse.
2. The drug or other substance has a currently accepted medical use in treatment in the United States (or) a currently accepted medical use with severe restrictions.
3. Abuse of the drug may lead to severe psychological or physical dependence.

In the United States, codeine is sometimes considered a Schedule III substance, making it illegal to use/possess without a prescription. Schedule III substances, such as hydrocodone, buprenorphine, and Marinol, meet the following criteria according to the Controlled Substances Act:

1. The drug or other substance has a potential for abuse less than the drugs or other substances in Schedules I and II.
2. The drug or other substance has a currently accepted medical use in treatment in the United States.
3. Abuse of the drug or other substance may lead to moderate or low physical dependence or high psychological dependence.

Prescription Refills:

• Schedule II - Only refilled with a written prescription.
• Schedule III - May be refilled using a phoned prescription.

Side Effects

Dizziness
Nausea/vomiting
Constipation
Headache
Sweating
Nervousness/anxiety
Euphoria/dysphoria
Urinary retention
Insomnia
Dry mouth

Withdrawal

Withdrawal from codeine typically occurs in 12-24 hours after the last dose. The time it takes for withdrawal to start depends on frequency of use, dosage, as well as 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 the user for weeks or months afterward. Withdrawal is rarely fatal, and is largely dependent upon the user's health, whereas withdrawal from alcohol or benzodiazepines can easily result in death. Symptoms of withdrawal are listed below:

• Cravings
• Muscle/bone pain
• Restlessness
• Goose bumps
• Involuntary leg/arm movements
• Sweating
• Insomnia
• Nausea/vomiting
• Depression

Sources

[1] Codeine. Wikipedia, the free encyclopedia. March 2007. [link] Accessed: March 29, 2007.
[2] Erowid Codeine Vault. Erowid. February 2007. [link] Accessed: March 29, 2007.