One of the proposed explanations by the authors for our study not replicating their findings is the difference in ethnic background of the participants. Indeed, although our cohort did include primarily European white children, some children with African and Asian ancestries were also included. Our cohort thus represented the multicultural population of Rotterdam. Separate from this potential ethnic influence on the TAOK3 rs795484 and the OPRM1 rs1799971 (118A > G) variant, we believe that with OPRM1 rs1799971 the direction of the effect is most likely substrate dependent. The meta-analysis from Hwang et al.,4 mentioned by Cook-Sather et al., demonstrated an increased exogenous opioid requirement, mainly morphine, in OPRM1 118 G allele carriers.4 This increase in opioid demand is suggestive of reduced efficacy in carriers of the minor allele. On the contrary, a higher potency and affinity with this variant of the receptor has been demonstrated for the endogenous opioid peptide beta-endorphin.1 This increase in the effect of the endogenous opioid peptides1 coupled with an adult study on experimental pain3 support our finding in which we have demonstrated lower thermal pain sensitivity in children with the 118 G allele.5
Half of the children included in our study were exposed to opioids as a neonate, which could indeed have affected experimental pain sensitivity. However, we did not find any differences in thermal pain thresholds when we compared the opioid exposed and nonopioid exposed children in our study. This finding is in line with the original studies including these patients, which addressed the influence of neonatal pain and opioid exposure on brain morphology, pain sensitivity, and neuropsychological functioning.6,7
To our knowledge, our pediatric study was the first to assess the influence of the TAOK3 rs795484 variant on experimental pain. Based on our findings, we agree with the definition of TAOK3 as rather a “pharmacogene” than a “pain” gene, as proposed by Cook-Sather et al. Genetic variability within the pain and analgesic pathway is complex, whereas nongenetic factors (eg, pain phenotype, opioid substrate, and ethnicity) all influence the direction and magnitude of the genetic effect. Research initiated in different ethnic populations that examines pain traits and opioid substrates will hopefully improve our understanding of the genetic role in pain and eventually give us pharmacogenetic tools for optimizing and individualizing pain therapy. We agree with Cook-Sather et al. that further clinical research on TAOK3 on the response of different exogenous opioid substrates and the mechanism is needed.