Codeine is a prodrug. It gets broken down to other drugs to provide pain relief. 10% of codeine gets broken down to morphine in a “normal” individual. The enzyme that does this is located in the liver, cytochrome P450 2D6 (CYP2D6). This has been known since the 1980s.
Well, so what?
5-10% of Caucasians lack this enzyme, and therefore achieve little pain relief when given codeine. This varies from 1-20% depending on your racial background.
A smaller percentage of Caucasians (1-2%) are “ultrametabolizers,” that is they break down the codeine very quickly and may either have a varying analgesic response or increased risk of toxicity.
In children, there is almost no CYP2D6 present at birth, and by the age of 5, levels in most children have only reached 25% of the adult level.
This information is so important that the “WHO guidelines on the pharmacological treatment of persisting pain in children with medical illness” dropped Codeine from their recommendations. This created a two step ladder for children: mild pain to be treated with Tylenol (Paracetamol) and ibuprofen; moderate to severe pain, to be treated with opioids such as morphine.
In now in an FDA press release, Bob Rappaport, director of the Division of Anesthesia, Analgesia and Addiction Products in FDA’s Center for Drug Evaluation and Research, is quoted; “The FDA is currently conducting a review of adverse event reports and other information to determine if there are additional cases of inadvertent overdose or death in children taking codeine, and if these adverse events occur during treatment of other kinds of pain, such as post-operative pain following other types of surgery or procedures. The FDA will update the public when more information is available.”
So what could this mean to the FDA (and the rest of the medical community)?
- The WHO has endorsed a 2-step ladder for children with the two steps being “mild” and “moderate-severe” pain. Perhaps another reason to restrict US labeling for opioids to severe pain.
- Codeine is not widely used drug in the US. In Australia, one could buy lower doses of Panadeine (Codeine and paracetamol) over the counter but it now requires a discussion with a pharmacist. Stronger formulations still require a prescription. (ABC Health report Interview with Dr Janette Randall, chair of the National Prescribing Service).
- Hydrocodone, very similar in structure to codeine, is extensively used in the USA, in fact the US is the major user of hydrocodone in the world. It should not be surprising to learn that hydrocodone is a prodrug that is broken down to form hydromorphone (the opioid in Dilaudid). And the enzyme? CYP2D6 (0tton et al, 1993)
- The activity of CYP2D6 can be either blocked or induced (increased) by other very common drugs used daily by many (e.g. antidepressants, and beta-blockers).
- Oxycodone’s metabolism is influenced by CYP2D6 but is stated to not be a factor in pain relief.
Maybe we need more evidence not just on codeine but on hydrocodone. WHat questions would I ask?
- Are there deaths from hydrocodone that are related to the levels of CYP2D6?
- Are there people who get no analgesia from hydrocodone so they stop using it: and it sits in their “medicine cabinet?”
- Is there an association with one’s CYP2D6 level and abuse? If one doesn’t get pain relief and takes more drug (again with no relief), is one placing oneself at increased risk of dependency syndrome (the new term for addiction)?
So many questions? But another illustration of the need to understand the facts and not to make decisions without understanding the complexity of the problems. Yes decisions regarding clinical practice were made in the past at a time that science did not have the level of understanding we have today.
But responsible clinicians would be looking at all of the evidence!
What questions does it raise for you?