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Background: The pleiotropic effects of the melanocortin system show promise in overcoming limitations associated with large variations in opioid analgesic effectiveness observed in equine practice. Of particular interest is variation in the melanocortin-1-receptor (MC1R) gene, which dictates pigment type expression through its epistatic interaction with the agouti signalling protein (ASIP) gene. MC1R has previously been implicated in opioid efficacy in other species; however, this relationship is yet to be explored in horses. In this study, analgesic effectiveness was scored (1-3) based on noted response to dura penetration during the performance of cerebrospinal fluid centisis after sedation and tested for association with known genetic regions responsible for pigmentation variation in horses., Results: The chestnut phenotype was statistically significant (P < 0.05) in lowering analgesic effectiveness when compared to the bay base coat colour. The 11bp indel in ASIP known to cause the black base coat colour was not significant (P>0.05); however, six single nucleotide polymorphisms (SNPs) within the genomic region encoding the ASIP gene and one within MC1R were identified as being nominally significant (P<0.05) in association with opioid analgesic effectiveness. This included the location of the known e MC1R variant resulting in the chestnut coat colour., Conclusions: The current study provides promising evidence for important links between pigmentation genes and opioid effectiveness in horses. The application of an easily identifiable phenotype indicating variable sensitivity presents a promising opportunity for accessible precision medicine in the use of analgesics and warrants further investigation., (© 2024. Crown.)