OPRM1 rs1799971, COMT rs4680, and FAAH rs324420 genes interact with placebo procedures to induce hypoalgesia.
Level 3 - non-randomized controlled study
Controlled experimental laboratory study assessing genetic associations and epistasis in healthy human volunteers.
PubMed 31335650 · doi:10.1097/j.pain.0000000000001578
What was done
Researchers examined whether three single nucleotide polymorphisms involved in opioid, dopamine, and endocannabinoid signaling—OPRM1 rs1799971, COMT rs4680, and FAAH rs324420—and their three-way interaction influenced placebo hypoalgesia. The study tested 160 healthy participants using two experimental placebo procedures: verbal suggestion and a conditioning/learning paradigm. Genotypes and procedure types were analyzed individually and in combination to predict placebo responsiveness.
What was found
Placebo hypoalgesia occurred significantly in individuals with the combined OPRM1 AA and FAAH Pro/Pro genotypes, as well as those carrying COMT met/met combined with FAAH Pro/Pro. Participants carrying the COMT met/val genotype exhibited significant placebo effects regardless of their OPRM1 or FAAH alleles. Combining the specific placebo procedure with genotype data predicted placebo responder status with an area under the curve (AUC) of 0.773, outperforming models based on genetic variants alone.
Why it matters
This study demonstrates that placebo analgesia is shaped by epistatic interactions across multiple neurotransmitter pathways rather than single genes in isolation. It highlights that genetic predisposition interacts with the psychological context and induction method to determine placebo responsiveness.
Limits
The total sample size was modest (n = 160) for testing three-way genetic interactions, meaning specific multi-allele subgroup counts were likely very small. The study was conducted in healthy volunteers exposed to experimental pain, limiting direct generalizability to clinical chronic pain populations.
Cited by
- supports 23andMe measures specific single nucleotide polymorphisms (SNPs) associated with susceptibility to placebo and nocebo effects.