Utilization of pharmacogenomics and therapeutic drug monitoring for opioid pain management.
OBJECTIVE
The use of medication in pain management currently involves empirical adjustment based on observed clinical outcome and the presence of adverse drug reactions. In this study, pharmacogenomics and therapeutic drug monitoring were used to evaluate the clinical effectiveness of genotyping chronic pain patients on analgesic therapy. It was hypothesized that patients who have inherited polymorphisms in CYP2D6 that make them poor or intermediate metabolizers of opioid medications would have higher steady-state concentrations of those opioids and may be more likely to experience adverse drug reactions.


METHODS
In an attempt to investigate the relationship between the polymorphic enzymes, steady-state drug concentrations, therapeutic effects and side effects, 61 patients were clinically evaluated and genotyped, and drug concentrations were measured and outcomes analyzed. Samples were collected and DNA extracted from whole blood using a Puregene DNA isolation kit. CYP2D6 genotyping (*3, *4, *5, *6, *7, *8 and gene duplication) were carried out using Pyrosequencing. Steady-state plasma concentrations of methadone, oxycodone, hydrocodone and tramadol were determined by HPLC tandem mass spectrometry.


RESULTS
The results demonstrated the prevalence of CYP2D6 polymorphisms in the population undergoing pain management was not statistically different from the general population. The majority of the pain patients (54%) were extensive metabolizers; 41% were intermediate metabolizers and 5% poor metabolizers. Poor metabolizers in general tended to have the highest steady-state drug concentrations compared with extensive metabolizers (poor metabolizers > intermediate metabolizers > extensive metabolizers) although this wasn't statistically significant. Also, a relationship between oxycodone steady-state drug concentrations and pain relief was found. A total of 80% of patients reporting adverse drug reactions also had impaired CYP2D6 metabolism. The remaining 20% with adverse drug reactions had other cofactors (i.e., drug-drug interactions) that could explain the toxicity.


CONCLUSIONS
These results suggest that patient care may be improved by genotyping and following therapeutic drug concentrations. Benefits include increased efficiency in proper drug selection, dose optimization and minimization of adverse drug reactions to improve patient outcome and safety. In addition, this study clearly demonstrated a relationship between oxycodone steady-state drug concentrations and pain relief. Future large-scale prospective studies are needed to confirm the clinical value of using genetic information to guide pain management therapy.
Jannetto
Paul J
PJ
Department of Pathology, Medical College of Wisconsin, Milwaukee, Wisconsin, WI 53226, USA. jannetto@mcw.edu
Bratanow
Nancy C
NC
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000701:Analgesics, Opioid / Q000627:therapeutic use*; D019468:Disease Management; D016903:Drug Monitoring / Q000379:methods*; D005260:Female; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D010146:Pain / Q000188:drug therapy* / Q000235:genetics*; D010597:Pharmacogenetics / Q000379:methods*; D011110:Polymorphism, Genetic / Q000235:genetics*
D000701:Analgesics, Opioid