César Margarit (Department of Health of Alicante, Alicante General Hospital), Reyes Roca (Alicante Institute for Health and Biomedical Research),  María-del-Mar Inda (Alicante Institute for Health and Biomedical Research),  Javier Muriel  (Alicante Institute for Health and Biomedical Research),  Pura Ballester (Alicante Institute for Health and Biomedical Research),  Rocío Moreu  (Department of Health of Alicante,
Alicante General Hospital),  Anna Lucia Conde  (Occupational Observatory,Miguel Hernández University of Elche), Domingo Morales (Operational Centre, Miguel Hernández University, Elche) and  Ana M. Peiró (Alicante General Hospital).

Abstract. Objectives: Chronic pain is one of the most common reasons individuals seek medical attention. It is a major issue because of the wide interindividual variability in the analgesic response. This might be partly explained by the presence of variants in genes encoding molecules involved in pharmacodynamics and pharmacokinetics. The aim was to analyze opioid effectiveness in chronic low back pain (CLBP) relief
after opioid titration, unveiling the impact of pharmacogenetics.
Methods: The study included 231 opioid-na€ıve patients from the Spine Unit; age 63  14 years, 64% female, body mass index 29   6 kg/m2, visual analog scale pain intensity score 73  16 mm. Clinical data were collected at baseline, 3 months after opioid titration, and after 2 to 4 years of follow-up concerning pain (intensity and relief), quality of life, disability, comorbidities, and drug prescription (opioid dose, rotations, and adverse events). The genotype influence of OPRM1, COMT, UGT2B7, ABCB1, KCNJ6, and CYP3A5*3A in analgesic response was analyzed by reverse-transcription polymerase chain reaction genotyping.
Results: Patients with the COMT G472A-AA genotype (rs4680) and KCNJ6 A1032G-A allele (rs2070995) CLBP responded differently to opioid titration, with higher pain intensity requiring higher dosing. Furthermore, GG- genotypes of A118G (OPRM1, rs1799971) and A854G (UGT2B7, rs776746) influenced the neuropathic component. After opioid titration, CLBP intensity, neuropathic component, low back pain disability, anxiety, and depression significantly decreased, while quality of life improved.
Conclusion: Single-nucleotide polymorphisms in genes involved in pain transmission and opioid metabolism might predispose to exaggerated sensitivity and differences in the opioid analgesic effect in patients with CLBP. We encourage clinical trials for their clinical application in chronic pain management.

Keywords.  Opioids,; Pharmacogenetics; Chronic low back pain; COMT; KCNJ6; OPRM1; UGT2B7.