Both genetic and nongenetic factors, as well as ethnicity-dependent and nonadditive genotypic models, should be evaluated when examining factors that contribute to variability in acute postoperative opioid use, according to research results published in Pain Medicine.

During the acute postoperative period, pain typically requires the use of opioids, particularly if pain is moderate to severe in intensity. During this time, patient-controlled analgesia is a “commonly used delivery modality for opioids such as morphine.” There are substantial, clinically significant interpatient variations in pain severity and patient-controlled analgesia opioid requirements in the 24- to 48-hour postoperative period.

Researchers have begun to look at genetic factors like the mu opioid receptor gene (OPRM1) allelic variant A118G (rs1799971), which has been shown to cause reduced receptor functioning and results in “clinically significantly higher morphine (~40%) doses in Asian patients,” including women who undergo total hysterectomy.


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Recent previous research has demonstrated that in Chinese, Malay, and Indian women who undergo elective cesarean section, postoperative morphine patient-controlled analgesic requirements were both ethnicity and OPRM1 A118G dependent, as well as interleukin (IL)-1B, IL-6, TLR2, and TGFB1 variant dependent.

In the current study, investigators sought to evaluate whether these same or other “innate immune signaling variants” might be factors contributing to pain in morphine requirements in a cohort of Chinese, Malay, and Indian women with higher postoperative pain and larger morphine requirements undergoing hysterectomy.

The cohort included 1046 women of Chinese, Malay, and Indian descent who underwent total hysterectomy. General anesthesia was used in all cases, using body weight-adjusted propofol and fentanyl. Sevoflurane and nitrous oxide were used to maintain anesthesia, supplemented with intravenous (IV) morphine with ondansetron and dexamethasone before completion of the surgery.

After surgery, all patients received IV patient-controlled analgesia that delivered a 1-mg IV bolus of morphine per demand with a lockout time of 5 minutes and no continuous background infusion. Maximum morphine dose allowed was 10 mg/hour. Researchers recorded the cumulative morphine dose administered within every 4-hour period through 24 hours postsurgery.

In total, 750 Chinese, 184 Malay, and 107 Indian women were successfully genotyped for all single nucleotide polymorphisms (SNPs) including COMT.

Within the total cohort, 1041 patients were successfully genotyped for all 21 immune and opioid signaling gene SNPs. Significant ethnic differences were identified in most SNP frequencies.

Significant linkage disequilibrium was seen between all SNPs within each gene, with “near complete and near perfect” linkage disequilibrium between IL1B rs1143627 and rs16944 SNPs, which produced 3 common and 3 rare diplotypes in all ethnic groups.

In previous reports, all 3 COMT SNPs were common in all 3 ethnic groups; variant allele frequencies were about 20%. COMT rs4633 and rs4680 were significant in all 3 ethnic groups.

In each ethnic group, 51% Chinese, 56% Malay, and 59% Indian patients with available preoperative pain tolerance data were classified as having low pain tolerance.

In a combined analysis across ethnic groups, IL10 rs1800871 and TNFA rs1800629 variant genotypes were associated with low and high pain tolerance; TLR4 rs49866791 and IL6R rs8192284 were associated with low pain tolerance dependent on ethnicity.

Among Chinese patients, high preoperative and postoperative pain was associated with significantly increased — and increasing age was associated with significantly decreased — morphine patient-controlled analgesia use in the 24-hour postoperative period. In Malay patients, high preoperative and postoperative pain was associated with increased age, whereas higher age was associated with decreased morphine use.

In Indian patients, high postoperative pain was nonsignificantly associated with increased morphine use, whereas higher age was nonsignificantly associated with decreased morphine use.

“Whilst the genotyping array of this study interrogated only a small fraction of the genetic variability…that might contribute to pain and opioid response, we were able to explain 40% of morphine requirements in the Indian cohort,” the researchers wrote. “The combined genetic component is the highest value reported for genetic contributors to morphine use in the acute postoperative pain setting.”

“Innate immune SNPs were identified alongside known pain/opioid response genes OPRM1 and COMT,” they concluded. “Our findings highlight the need to incorporate both genetic and nongenetic factors and consider ethnicity-dependent and nonadditive genotypic models, when assessing factors that contribute to variability in opioid use.”

Reference

Barratt DT, Sia AT, Tan E-C, Somogyi AA. Innate immune and neuronal genetic markers are highly predictive of postoperative pain and morphine patient-controlled analgesia requirements in Indian but not Chinese or Malay hysterectomy patients. Pain Med. Published online May 20, 2021. doi:10.1093/pm/pnab172