title: The role of hydromorphone and OPRM1 in postoperative pain relief with hydrocodone.
abstract: BACKGROUND
  Postoperative pain management remains a challenge for clinicians due to unpredictable patient responses to opioid therapy. Some of this variability may result from single nucleotide polymorphisms (SNPs) of the human opioid mu-1 receptor (OPRM1) that modify receptor binding or signal transduction. The OPRM1 variant with the highest frequency is the A118G SNP. However, previous studies have produced inconsistent results regarding the clinical effects of A118G on opioid response. We hypothesized that measurement of serum opioid concentrations, in addition to determining total opioid consumption, may provide a more precise method of assessing the effects of A118G on analgesic response. The current study evaluated the relationship of analgesia, side effects, total hydrocodone consumption, quantitative serum hydrocodone and hydromorphone concentrations, and A118G SNP in postoperative patients following Cesarean section.
  
  
  METHODS
  158 women scheduled for Cesarean section were enrolled prospectively in the study. The patients had bupivacaine spinal anesthesia for surgery and received intrathcal morphine with the spinal anesthetic or parenteral morphine for the first 24 hours after surgery. Thereafter, patients received hydrocodone/acetaminophen for postoperative pain control. On postoperative day 3, venous blood samples were obtained for OPRM1 A118G genotyping and serum opioid concentrations.
  
  
  RESULTS
  131 (82.9%) of the subjects were homozygous for the 118A allele of OPRM1 (AA) and 27 (17.1%) carried the G allele (AG/GG). By regression analysis, pain relief was significantly associated with total hydrocodone dose in the AA group (P = 0.01), but not in the AG/GG group (P = 0.554). In contrast, there was no association between pain relief and serum hydrocodone concentration in either group. However, pain relief was significantly associated with serum hydromorphone concentration (a metabolite of hydrocodone) in the AA group (P = 0.004), but not in the AG/GG group (P = 0.724). Conversely, side effects were significantly higher (P < 0.04) in the AG/GG group (mean = 6.4) than in the AA group (mean = 4.4), regardless of adjustment for BMI, pain level, or total dose of hydrocodone.
  
  
  CONCLUSIONS
  This study found a correlation between pain relief and total hydrocodone dose in patients homozygous for the 118A allele (AA) of the OPRM1 gene, but not in patients with the 118G allele (AG/GG). However, pain relief in 118A patients did not correlate with serum hydrocodone concentrations, but rather with serum hydromorphone levels, the active metabolite of hydrocodone. This suggests that pain relief with hydrocodone may be due primarily to hydromorphone. Although pain relief did not correlate with opioid dose in AG/GG patients, they had a higher incidence of opioid side effects. The correlations identified in this study may reflect the fact that serum opioid concentrations were measured directly, avoiding the inherent imprecision associated with relying solely on total opioid consumption as a determinant of opioid effectiveness. Thus, measurement of serum opioid concentrations is recommended when assessing the role of OPRM1 variants in pain relief. This study supports pharmacogenetic analysis of OPRM1 in conjunction with serum opioid concentrations when evaluating patient responses to opioid therapy.
authors.affiliation: Dept. of Anesthesiology and Perioperative Medicine, University of Louisville School of Medicine, Louisville, KY, USA.
authors.forename: Mark V
authors.initials: MV
authors.lastname: Boswell
authors.forename: M Elaine
authors.initials: ME
authors.lastname: Stauble
authors.forename: Gary E
authors.initials: GE
authors.lastname: Loyd
authors.forename: Loralie
authors.initials: L
authors.lastname: Langman
authors.forename: Bronwyn
authors.initials: B
authors.lastname: Ramey-Hartung
authors.forename: Richard N
authors.initials: RN
authors.lastname: Baumgartner
authors.forename: William W
authors.initials: WW
authors.lastname: Tucker
authors.forename: Saeed A
authors.initials: SA
authors.lastname: Jortani
mesh_terms: D000293:Adolescent; D000328:Adult; D000701:Analgesics, Opioid / Q000097:blood / Q000627:therapeutic use*; D002853:Chromatography, Liquid; D005260:Female; D005838:Genotype; D006801:Humans; D006853:Hydrocodone / Q000097:blood / Q000627:therapeutic use*; D004091:Hydromorphone / Q000097:blood* / Q000378:metabolism*; D008875:Middle Aged; D013513:Obstetric Surgical Procedures / Q000009:adverse effects; D010149:Postoperative Pain / Q000097:blood / Q000188:drug therapy / Q000235:genetics; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017450:Receptors, Opioid, mu / Q000235:genetics; D053719:Tandem Mass Spectrometry; D055815:Young Adult
chemical_list: D000701:Analgesics, Opioid; C485764:OPRM1 protein, human; D017450:Receptors, Opioid, mu; D006853:Hydrocodone; D004091:Hydromorphone