title: Hydrocodone in postoperative personalized pain management: pro-drug or drug?
abstract: BACKGROUND
  Genetic variations in enzymes that produce active metabolites from pro-drugs are well known. Such variability could account for some of the clinically observed differences in analgesia and side effects seen in postoperative patients. Using genotyping and quantitation of serum concentrations of hydrocodone and its metabolites, we sought to demonstrate the clinical effects of the metabolites of hydrocodone on pain relief. The objective of the current study was to determine whether CYP2D6 genotype and serum hydromorphone levels account for some of the variability in pain relief seen with hydrocodone in a cohort of women post-Cesarean section.
  
  
  METHODS
  In 156 post-Cesarean section patients who received hydrocodone, we assessed serum opioid concentrations and CYP2D6 genotypes. Blood samples were collected at that time for genotyping and determination of concentrations of hydrocodone and metabolites by LC-MS/MS. Multivariate analysis was used to determine the relationship between CYP2D6 genotypes, pain relief, side effects, and serum concentrations of hydrocodone and hydromorphone.
  
  
  RESULTS
  The CYP2D6 genotyping results indicated that 60% of subjects were extensive, 30% intermediate, 3% poor, and 7% ultra-rapid metabolizers. In the poor metabolizers, the mean plasma hydromorphone concentration was 8-fold lower when compared to that of ultra-rapid metabolizers. Hydromorphone, and not hydrocodone concentrations correlated with pain relief.
  
  
  CONCLUSIONS
  This study shows that hydromorphone is generated at substantially different rates, dependent on CYP2D6 genotype. Pain relief correlated with plasma concentrations of hydromorphone, and not with hydrocodone. This suggests that pain relief will vary with CYP2D6 genotype. Inability to metabolize hydrocodone to hydromorphone as seen in the poor metabolizers should alert the clinician to consider alternative medications for managing pain postoperatively.
authors.affiliation: Dept. of Obstetrics and Gynecology, University of Louisville School of Medicine, Louisville, USA.
authors.forename: M Elaine
authors.initials: ME
authors.lastname: Stauble
authors.affiliation: Dept. of Obstetrics and Gynecology, University of Louisville School of Medicine, Louisville, USA.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Moore
authors.affiliation: Dept. of Lab Medicine and Pathology, Mayo Clinic, Rochester, USA.
authors.forename: Loralie J
authors.initials: LJ
authors.lastname: Langman
authors.affiliation: Dept. of Anesthesiology and Perioperative Medicine, University of Louisville School of Medicine, Louisville, USA.
authors.forename: Mark V
authors.initials: MV
authors.lastname: Boswell
authors.affiliation: Dept. of Epidemiology and Population Health, University of Louisville, Louisville, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Baumgartner
authors.affiliation: Dept. of Obstetrics and Gynecology, University of Louisville School of Medicine, Louisville, USA.
authors.forename: Suzanne
authors.initials: S
authors.lastname: McGee
authors.affiliation: Dept. of Obstetrics and Gynecology, University of Louisville School of Medicine, Louisville, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Metry
authors.affiliation: Dept. of Pathology and Laboratory Medicine, University of Louisville School of Medicine, Louisville, USA. Electronic address: sjortani@louisville.edu.
authors.forename: Saeed A
authors.initials: SA
authors.lastname: Jortani
mesh_terms: D000293:Adolescent; D000328:Adult; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D006853:Hydrocodone / Q000097:blood* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D008875:Middle Aged; D059408:Pain Management; D010149:Postoperative Pain / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D057285:Precision Medicine; D011355:Prodrugs / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D011355:Prodrugs; D006853:Hydrocodone; D019389:Cytochrome P-450 CYP2D6
keywords: CYP2D6; Hydrocodone; Hydromorphone; Pain management