American Society of Regional Anesthesia and Pain Medicine May 2017 - 19
Table 1: Metabolism and alleles
Metabolism level
Alleles
Activity level
Extensive metabolizer (EM)
2 normal alleles
Normal
Intermediate metabolizer (IM)
1 normal allele and 1 reduced allele or 2 partially deficient
alleles
Intermediate activity
Poor metabolizer (PM)
2 mutant alleles
Very limited or complete loss of activity
Ultra rapid metabolizer (UM)
Multiple copies of functional alleles
Excess activity
Approximately 7-10% of Caucasians are CYP2D6 deficient (poor
metabolizers [PM]); only 1-2% of Asians and 2-4% of African
Americans are PMs. Among Asians and African Americans, 30%
are intermediate metabolizers of CYP2D6. Why are these variations
important? Many of the medications we use to treat chronic pain
are affected by these polymorphisms.
CYP INFLUENCE ON OPIOIDS
Various medications are pro drugs, inactive compounds that
are metabolized to their active forms by CYP enzymes. Other
medications are metabolized by P450 into clinically active
metabolites. Table 2 shows common P450 substrates. Codeine, a
pro drug, is metabolized by CYP2D6 into its active form, morphine.
Therefore, if a patient is a poor metabolizer of CYP2D6, he or
she will not convert codeine into its active form and will get no
analgesic benefit from the drug. On the other hand, a patient who is
an ultra-rapid metabolizer of CYP2D6 may experience dangerously
high levels of morphine in his or her system. Two other commonly
used opioids that are metabolized by CYP2D6 to stronger, more
potent forms are hydrocodone (metabolized into hydromorphone)
Table 2: Commonly used substrates5,6
1A2
2B6
2C19
2D6
3A4
2C9
Amitriptyline
Buproprion
Barbiturates
Codeine
Alprazolam
Valproic Acid
Nabumetone
Methadone
Topirimate
Tramadol
Midazolam
Piroxicam
Desipramine
Ketamine
Diazepam
Merperidine
Cyclosporine
Celecoxib
Tizanidine
Testosterone
Amitriptyline
Oxycodone
Dildenafil
Ibuprofen
Imipramine
Imipramine
Hydrocodone
Indinavir
Warfarin
Acetaminophen
Clomipramine
Dextromethorphan
Verapamil
Cyclobenzaprine
Sertraline
Amitriptyline
Atorvastatin
Clozapine
Citalopram
Nortriptyline
Lovastatin
Fluvoxamine
Phenytoin
Doxepin
Digoxin
Theophylline
Carisoprodol
Tamoxifen
Amiodarone
Melatonin
Clopidogrel
Amphetamines
Methadone
Duloxetine
Duloxetine
Erythromycin
Caffeine
Metoclopramide
Trazadone
Lidocaine
Propranolol
Fentanyl
Warfarin
Venlafaxine
Buprenorphine
Methadone
Modified from Indiana University and Genelex websites.
Reprinted with permission from Tennant F, Hocum B. Pharmacogentics and pain management: clinical use and interpretation of the common
pharmacogentics tests. Pract Pain Manage. 2015;15(7):64. ©2016 Vertical Health Media, LLC.7
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