The Role of Hydromorphone and OPRM1 in
Postoperative Pain Relief with Hydrocodone
Authors: Jortani Dr. Saeed A. 
Published: March 2021

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.
Conclusion: 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.
Key words: Cesarean section, female gender, genetic polymorphisms, hydrocodone,
hydromorphone, opioid Mu 1 receptor, opioid concentrations, serum, OPRM1; rs1799971,
postoperative pain