Tag Archives: codeine

Codeine and Tramadol –Additional Warnings

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NY Times: FDA Strengthens Warnings for Painkillers in Children

An excerpt:

The Food and Drug Administration announced on Thursday that any child younger than 12 should not take the opioid codeine, and those 18 and younger should not take tramadol, another painkiller, after certain surgeries. In addition, nursing mothers should avoid both drugs, since they pose dangers to breast-feeding babies, the agency said.

“The problem with both codeine and tramadol is that some people are “ultrarapid metabolizers” whose livers metabolize the drugs way too quickly, causing dangerously high levels of opioids to build up, said Dr. Douglas Throckmorton, the deputy director for regulatory programs at the F.D.A.’s Center for Drug Evaluation and Research.

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Codeine Contraindicated after Adenotonsillectomy

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Due to concerns outlined previously (Why “therapeutic dose” of codeine can kill | gutsandgrowth), the FDA has now placed a boxed warning on all codeine-containing products and is now contraindicated after adenotonsillectomy.  This is reviewed in a recent perspective article: NEJM 2013; 368: 2155-57.

“In the case of codeine, a combination of case reporting and our evolving understanding of genetic influences on drug response has clarified the need to avoid this drug after adenotonsillectomy.”

Bottomline: Due to the variability in codeine metabolism, alternative narcotic agents are usually a better choice even in those who have not undergone adenotonsillectomy.

Why “therapeutic dose” of codeine can kill

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While this blog has described some of the huge problems with the overuse of narcotics (Deadly consequences of pain management), another danger with narcotics occurs especially with codeine due to its metabolism via the CYP2D6 pathway; codeine is particularly risky in young children.  A reminder of this is a recent case report (Pediatrics 2012; 129: e1343-1347).

During my training, I was told by an ENT doctor that he never prescribed codeine in children less than 6 years of age due to safety concerns.  While he could not explain the mechanism, this case report does.  This case report describes three children with severe cases (two were fatal) from North America.  In the two fatal cases, gene duplications encoding Cytochrome P450 2D6 (CYP2D6) caused a significantly greater production of morphine from its parent drug, codeine.  This risk of respiratory depression may be enhanced in ENT cases especially in children with obstructive sleep apnea.

The risk from codeine involves individuals who are ‘ultra-metabolizers’ of CYP2D6; this is because the metabolized drug in this case, morphine, is more potent than the parent drug, codeine.  Other opioids that are similar to codeine, like hydrocodone and oxycodone, may have additional risk as well.  Ultra-metabolizers include up to 7% of all caucasians.  In addition, 5-10% of caucasians are poor-metabolizers which would result in a lack of therapeutic effect with codeine.

While ultra-metabolizers of CYP2D6 function are prone to codeine toxicity, poor-metabolizer individuals will have an exaggerated response when the parent drug is more potent than its metabolites.  In addition, there are numerous drugs (not metabolized by CYP2D6) which interact to inhibit the function of CYP2D6 (eg. diphenhydramine).  Thus, these drugs can potentiate the effect of CYP2D6 on its substrates.

Other drugs commonly used by gastroenterologists and metabolized by CYP2D6 include tricyclic antidepressants, most SSRIs, metoclopropramide, ondansetron, and promethazine.  In ultra-metabolizer individuals, many of these drugs will not work because the quickly-produced metabolites, unlike the parent substrate, do not have therapeutic effects.

Additional references:

  • N Engl J Med 2004; 351: 2827-31.  Codeine Intoxication Associated with Ultrarapid CYP2D6 Metabolism. 62 year old: “12 hours after the last dose of codeine, the blood level of morphine was 20 to 80 times as high as the blood level that would have been expected on the basis of measurements in healthy persons ” due to ultrametabolism of CYP2D6 in combination with inhibition of CYP3A4 activity by other medications
  • CYP2D6 – Wikipedia, the free encyclopedia
  • Drug and Alcohol Dependence 89 (2007) 190–194. Association of CYP2D6 ultrarapid metabolizer genotype with deficient patient satisfaction regarding methadone maintenance treatment
  • What happens when codeine is used with drugs – WorstPills.org –