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The recent Clinical Report from the AAP Committee on Drugs titled “Codeine: Time to say ‘No’” provides a sobering picture of our current (mis)use of codeine in children.(1) Cases of respiratory depression and death led to FDA label changes, including a “black box warning” against use of codeine after tonsillectomy and/or adenoidectomy. The label also describes that the prodrug codeine is converted to its active metabolite by CYP2D6, an enzyme with variable activity. Despite these warnings, pediatric providers continue to dispense this drug to thousands of children.
Why is it that so many pediatric patients are still being prescribed codeine? One reason may be ignorance of the risks, a problem that must be addressed with widespread and persistent education. However, well-informed providers may be among those who continue to use this drug, prescribing codeine with care as the best alternative for some select children. Compared to alternate opioid medications, the relative merits of codeine include the following:
1. Codeine has a more predictable toxicity profile than the alternative drugs. Data have demonstrated the clinical and genetic risk factors for codeine toxicity. Codeine should not be used in patients with disordered breathing or those who undergo tonsillectomy and/or adenoidectomy. Codeine should also not be given to CYP2D6 ultra-rapid metabolizers; these individuals can be identified through a genetic test, as reported recently in sickle cell patients...
1. Codeine has a more predictable toxicity profile than the alternative drugs. Data have demonstrated the clinical and genetic risk factors for codeine toxicity. Codeine should not be used in patients with disordered breathing or those who undergo tonsillectomy and/or adenoidectomy. Codeine should also not be given to CYP2D6 ultra-rapid metabolizers; these individuals can be identified through a genetic test, as reported recently in sickle cell patients.(2,3) The risk profiles for alternate opioids (e.g. oxycodone, hydrocodone, oral morphine, tramadol, and tapentadol) are not well documented in children.
2. Codeine with acetaminophen is a Drug Enforcement Administration (DEA) Schedule III drug. All other opioid alternatives are DEA Schedule II. This increases accessibility for families, especially for children with chronic or recurrent pain, as prescriptions can be phoned or faxed in and families can be prescribed refills.
3. Codeine has a lower risk for diversion and abuse than the alternative drugs. In the current opioid epidemic, it makes good sense to prescribe analgesics with the lowest “street value.” Oxycodone and hydrocodone are among the most commonly abused prescription drugs, whereas codeine is less often abused given its poor potency to achieve a “high” and frequent combination with acetaminophen; drug abusers are aware of the potential acetaminophen toxicity and avoid codeine.
While we agree that codeine is overused in children, simply saying “No” is an extreme response. Certainly, there are instances where we can say that codeine is “Not for this indication” (e.g. cough suppression, tonsillectomy and/or adenoidectomy); additional restrictions may be warranted to eliminate use in these scenarios. There are also instances where we can say that codeine is “Not for this patient” (e.g. those with genetic risk factors for inefficacy or toxicity); a genetic test that is done one time and predicts responses to many drugs can identify who is at risk. We support the development and study of new analgesics for pediatric use and continued work to identify strategies that can keep codeine, and other drugs with specific risk factors for toxicity, within our already limited armamentarium of analgesics for children.
1. Tobias JD, Green TP, Coté CJ, Section on Anesthesiology and Pain Medicine, Committee on Drugs. Codeine: Time To Say “No.” Pediatrics. September 2016:e20151648. doi:10.1542/peds.2016-2396.
2. Crews KR, Gaedigk A, Dunnenberger HM, et al. Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450 2D6 genotype and codeine therapy: 2014 update. Clin Pharmacol Ther. 2014;95(4):376-382. doi:10.1038/clpt.2013.254.
3. Gammal RS, Crews KR, Haidar CE, et al. Pharmacogenetics for Safe Codeine Use in Sickle Cell Disease. Pediatrics. 2016;138(1):e20153479. doi:10.1542/peds.2015-3479.
I thank Dr. Dansky for his comments regarding our article. I agree that although we should eliminate the use of codeine, the question arises as to what is the best alternative for outpatient analgesia. Although many clinicians are using oral oxycodone, there is still some genomic variation in its metabolism. Outside of the United States, there has been a move toward the use of oral morphine as an outpatient opioid; however, enthusiasm for this may be limited by concerns regarding diversion. Given that, we continue to stress the need for the development of new oral opioid analgesics whose metabolism is not influenced by genomic variations. We also continue to stress the importance of the effective use of non-opioid analgesics such as acetaminophen and ibuprofen.
Thank you for your interest in our article and your question regarding dihydrocodeine (DHC). Although there are limited data regarding the metabolism of this agent, it appears that like codeine, DHC is also a substrate of the polymorphic enzyme CYP2D6 and the formation of the active metabolite dihydromorphine (DHM) is catalyzed mainly by this enzyme. Given these concerns, it appears that excessive production of DHM may result in patients that are ultra-rapid metabolizers.
In Korea, K-FDA(Korean Food and Drug Administration) have two different guidelines between Codeine and Dihydrocodeine. For Codeine containing drugs, K-FDA restricted the prescription of it in children younger than 12 years. But, for Dihydrocodeine containing drugs, K-FDA allowed to prescribe it in children older than 3 months.
So,I was confused when I read this article and I want to know the guideline or stance of AAP for Dihydrocodeine. May I treat Dihydrocodeine as we have caution to use for children??
There is some irony here. Codeine, as you note, is a prodrug for Morphine. Hydrocodone is a prodrug for hydromorphone, or Dilaudid. To eliminate the risk of administering these prodrugs to rapid metabolizers, therefore, would it not make more sense to use the drug itself, rather than the prodrug? I understand that the enthusiasm for using Dilaudid or Morphine in children with cough or pain might be a bit, uh, muted, but this is a conclusion one could draw from the very legimitate concerns you raise. (A second conclusion of course would be for every affected family to keep nasal naloxone at home.)
David Dansky, MD, FACEP
Community Hospital of the Monterey Peninsula
Monterey CA 93940
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