Codeine is an analgesic or painkiller that is found in the extracts of opium. It is used to relieve mild or moderate pain. It is also used to reduce coughing in combination with other medications.
Codeine is available alone or as a combination product. It comes as a tablet, a capsule, or a solution taken by mouth.
In sickle cell disease patients, codeine is used to treat moderate pain, either alone or in combination with non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, ketorolac, or diclofenac.
How does codeine work?
Codeine is similar to morphine but has weaker painkilling properties. Codeine is thought to exert its activity through conversion to morphine. Morphine and codeine both bind to mu-type opioid receptors that are located on nerve cells, but compared to codeine, morphine binds more easily to these receptors. This binding inhibits the excitability of nerve cells and, as a result, the transmission of pain signals to the brain.
Some variants increase P450’s activity, while some decrease it. People who carry CYP2D6 gene mutations that result in a very high P450 activity are called ultra-rapid metabolizers.
Because of the rapid conversion of codeine to morphine, they are at risk of toxic systemic concentrations of morphine when used at recommended doses. Respiratory depression, which sometimes occurs in children receiving codeine, and can be severe and fatal, is thought to be associated with the ultra-rapid metabolizer variant.
People with dramatically decreased P450 activity are known as poor metabolizers. They are not able to convert codeine to morphine and should avoid codeine because it has hardly any painkilling effects in these individuals.
Codeine in clinical trials
There are two studies that aimed to assess the effect of specific CYP2D6 gene variants on the effectiveness and safety of codeine use in people with sickle cell disease.
In the first study (NCT00174538), 54 participants received 30 mg of codeine with 200 mL of water. Blood samples were taken 30 minutes before, and one, two, three, four, and six hours after oral codeine intake. Blood samples were used to detect variants of the CYP2D6 gene that are associated with reduced P450 activity and are common in people of Afro-Caribbean descent. These variants are called the *17, *29, and *41 variants. Codeine and its metabolites were also measured.
In 30 participants, morphine had a maximum mean concentration of 2 ng/mL, while in 24 participants, morphine could not be detected.
In the group where morphine could be identified, nine participants (30 percent) had the *17, *29, or *41 variant of the CYP2D6 gene. In the group where morphine was not detectable, 11 participants (46 percent) had one of the three gene variants. The two groups did not differ in the number of emergency room visits, but more hospital admissions were documented in the group without detectable morphine.
The second trial (called PG4KDS) is still ongoing at St. Jude Children’s Research Hospital in Memphis, Tennessee. Participants have their CYP2D6 gene genotyped and are then grouped as poor metabolizers, intermediate metabolizers, normal metabolizers, and ultra-rapid metabolizers. Only intermediate and normal metabolizers are administered codeine.
As of June 2015, 621 children with sickle cell disease have been genetically tested as part of the trial. A total of 1.4 percent of patients were categorized as poor metabolizers and seven percent as ultra-rapid metabolizers.
The remaining 543 patients were either intermediate or normal metabolizers. Of these, 173 patients (32 percent) received codeine. One patient who was categorized as an ultra-rapid metabolizer also received codeine because he tolerated it well in the past. None of the patients who received codeine experienced adverse events.
Common side effects of codeine include a headache, stomach pain, and difficulties urinating.
Additional side effects are difficulties with breathing or swallowing, changes in heartbeat and vision, and seizures. These symptoms can be severe and might require immediate medical attention.
Last updated: Jan. 26, 2020
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