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October 15, 2012

Why Are Some Patients Sensitive to Narcotics and Others are Not?

Blame cytochrome P450 2D6, also known as CYP2D6.

Found in the liver, it is responsible for metabolizing drugs including many narcotics.

It also determines how "sensitive" a patient is to these drugs.

For example, codeine is not bioactive until it is metabolized by CYP2D6 into morphine, the bioactive form that helps with pain.

As such, how "sensitive" a patient is to codeine is determined by how active their CYP2D6 is. The more active, the more quickly codeine is converted into morphine. The less active it is, the less morphine is created and the less pain control a patient will have when taking codeine as prescribed.

Due to the wide variability in its expression in the liver among patient populations, there will be a correspondingly large variation in how sensitive patients are to such drugs depending on how active CYP2D6 is expressed in the liver.

Such variability accounts for normal, reduced, and non-existent CYP2D6 function in patients.
  • Poor Metabolizers – These patients have little or no CYP2D6 function. (Codeine will provide poor pain control.)
  • Intermediate Metabolizers – These patients metabolize drugs at a rate somewhere between the poor and extensive metabolizers. (Codeine will provide some pain control.)
  • Extensive (Normal) Metabolizers – These patients have normal CYP2D6 function . (Codeine will provide safe and appropriate pain control.)
  • Ultra-Rapid Metabolizers – These patients have multiple copies CYP2D6 and therefore greater-than-normal CYP2D6 function. (Codeine will provide dangerous levels of pain control.)
Additionally, certain genetic variations of CYP2D6 will result in normal, decreased, or no CYP2D6 function.


Additionally, certain medications can inhibit or induce CYP2D6 functionality [read more]. Most importantly to ENT surgeons, decadron which is a steroid commonly given during or after tonsillectomy surgery increases CYP2D6 function.

This CYP2D6 variability and in particular the existence of ultra-rapid metabolizers is the reason why narcotics are strongly discouraged in the pediatric population after surgery. There have been deaths associated with codeine due to respiratory depression in those patients who have a super-active CYP2D6 resulting in too-high morphine production. High morphine levels can potentially lead a patient to stop breathing which ultimately can lead to anoxic brain injury and even death.

There is ethnic variability with CYP2D6 functionality as well. Poor metabolizers are found in less than 10% of whites, asians, and blacks. However, Middle Eastern and North African populations have a relatively higher occurrence of ultra-rapid metabolizers.


References:
More codeine fatalities after tonsillectomy in North American children. Pediatrics. 2012 May;129(5):e1343-7. Epub 2012 Apr 9.

Preventing opioid-related deaths in children undergoing surgery. Pain Med. 2012 Jul;13(7):982-3; author reply 984. doi: 10.1111/j.1526-4637.2012.01419.x. Epub 2012 Jun 13.

Unique CYP2D6 activity distribution and genotype-phenotype discordance in black Americans. Clin Pharmacol Ther. 2002 Jul;72(1):76-89.

Frequent occurrence of CYP2D6 gene duplication in Saudi Arabians. Pharmacogenetics. 1997 Jun;7(3):187-91.

Morphine or Ibuprofen for Post-Tonsillectomy Analgesia: A Randomized Trial. Published online January 26, 2015 (doi: 10.1542/peds.2014-1906)


Fauquier blog
Fauquier ENT

Dr. Christopher Chang is a private practice otolaryngology, head & neck surgeon specializing in the treatment of problems related to the ear, nose, and throat. Located in Warrenton, VA about 45 minutes west of Washington DC, he also provides inhalant allergy testing/treatment, hearing tests, and dispenses hearing aids. Google+ Christopher Chang, MD Bio

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