Meta-Analysis Finds Few Genetic Associations With Postsurgical Pain

HOLLYWOOD, Fla.—The largest systematic review and meta-analysis of its kind to date has concluded that finding a strong genetic link to postsurgical pain may be more challenging than originally believed.

The study found that of 499 individual genetic variants in 125 genes, only two variants—OPRM1 rs1799971 and COMT rs4680—showed significant association with postsurgical pain.

According to lead author Stephan Frangakis, MD, PhD, an assistant professor of anesthesiology at the University of Michigan, in Ann Arbor, although the last decade has seen increased investigation into the genetic factors that may affect the development and degree of postsurgical pain, clear identification of these factors has proven difficult due to inconsistent findings and poor replicability of results. Nevertheless, identifying and verifying validated genetic targets has the potential to allow for targeted prediction, prevention and treatment of postsurgical pain.

“And yet, there has yet to be a systematic review examining all genetic determinants of postsurgical pain,” Frangakis noted.

To bridge this knowledge gap, Frangakis and his colleagues searched the PubMed, Embase and Cochrane Central Register of Controlled Trials databases for studies published between 2000 and 2022, using search terms related to genetic variants and postsurgical pain in humans. The search was limited to English-language studies in adult patients.

The researchers then performed a series of meta-analyses on single nucleotide polymorphisms for which data were sufficient (defined as three or more studies with at least 300 subjects), comparable and extractable. Finally, data were obtained from studies for which both means and standard deviations were reported and/or could be derived.

The primary outcome of the analysis was the association of genetic variants with either acute or chronic postsurgical pain, which was measured by patient-reported pain score or consumption of opioids or analgesics.

“Many studies use opioid consumption as a surrogate for postsurgical pain, and some even use NSAIDs [nonsteroidal anti-inflammatory drugs],” Frangakis told Pain Medicine News. “So, we made sure to include those metrics as well as the various different ways that pain scores were measured.”

Presenting at the 2023 spring meeting of the American Society of Regional Anesthesia and Pain Medicine (abstract 4155), Frangakis noted that of 2,929 studies screened, 162 met the inclusion criteria. Among them, six genome-wide association studies (GWAS) evaluated the association with variants across the genome, while the remaining 156 targeted gene or variant association analyses.

“The optimal way to look at genetic data is through GWAS, which examines the entire genome,” Frangakis explained. “But only six studies actually did that. The rest were targeted gene analysis, where the investigators pre-specify the genes or alleles they’re looking at. These studies are good because their data can be very convincing and powerful, but there’s also a potential for selection bias because they miss everything they’re not specifically looking for.” Only one GWAS had a cohort size of more than 500 patients (n=613), and more than 80% of studies had cohort sizes of less than 400 participants.

In total, 125 unique genes and 499 unique genetic variants were evaluated. The most common functions of the examined genes were neurotransmission (n=50; 40%) and immune response (n=28; 22%). The investigators also performed meta-analyses for seven variants: OPRM1 rs1799971, COMT rs4680, COMT rs4818, COMT rs4633, COMT rs6269, ABCB1 rs1045642 and ABCB1 rs2032582. In each case, they assessed the association with postsurgical pain scores and opioid use in the acute and chronic settings, and using dominant and recessive inheritance models.

The results showed that only two variants were associated with postsurgical pain: OPRM1 rs1799971 and COMT rs4680. OPRM1 rs1799971 was associated with both acute postsurgical opioid use (standardized mean difference [SMD]=0.25; 95% CI, 0.16-0.35; P<0.00001) and acute postsurgical pain score (SMD=0.20; 95% CI, 0.09-0.31; P=0.0004) On the other hand, COMT rs4680 was found to be associated with only chronic postsurgical pain score (SMD=0.26; 95% CI, 0.08-0.44; P=0.004).

For his part, Frangakis was surprised by the results.

“I thought we would find more associations, and stronger effects with the ones we did find,” he explained. “All things considered, the degree of effect was fairly small. I would have expected more.”

Nevertheless, he added, the results bolster the notion that the well-studied OPRM1 rs1799971 polymorphism plays a definitive role in the development of postsurgical pain. This is particularly important given its prevalence in certain ethnic populations, Frangakis noted.

“Clinicians should be aware that patients with OPRM1 rs1799971 might suffer increased postsurgical pain, which allows them to then change their treatment plans accordingly,” he said. The findings can also be used to target novel pain therapies.

Finally, the investigators hope to use the findings as a springboard for subsequent research, which they hope will address the current inconsistencies in the literature.

“Our idea is to perform genetic analysis to look for markers for postsurgical pain,” Frangakis added. The researchers anticipate it will be the largest study to date on the subject, comprising several thousand patients.

For Luda Diatchenko, MD, PhD, who has done extensive research into the connections between genetics and pain, the results of the study did not prove particularly surprising, since both OPRM1 rs1799971 and COMT rs4680 have been found to be related to postoperative pain in previous research.

“Those two genes have consistently been the two primary genes to be significantly associated with postoperative pain; they usually account for about half of all such reports,” said Diatchenko, a professor of dentistry and medicine at McGill University, in Montreal. “But they’re not the only important genes; there may well be other genes that are significantly associated with postoperative pain, but we just don’t know about them yet because we don’t have enough data.”

Diatchenko also questioned how long it would take before findings such as these have a meaningful impact on clinical practice.

“The problem is the effect size,” she continued. “Although results like these achieve statistical significance, it’s unclear if there will be a practical implementation because the effect is so small.”

Such questions notwithstanding, Diatchenko said research in the field should continue. “Any evidence that links genetics to pain control is encouraging. Therefore, we need to continue the search for other genetic variants that may contribute to the human response to drugs and postoperative pain.”

—Michael Vlessides

Diatchenko and Frangakis reported no relevant financial disclosures. The abstract was honored as a President’s Choice selection at the meeting. Frangakis’ research is funded by a National Institutes of Health K08 Grant – National Institute of Arthritis and Musculoskeletal and Skin Diseases (K08AR082454). The opinions, beliefs and viewpoints expressed do not necessarily reflect those of the National Institutes of Health or any of its employees.