Interindividual variability in analgesic response is at least partly due to well-characterized polymorphisms that are associated with opioid dosing and adverse outcomes. The Clinical Pharmacogenetics Implementation Consortium (CPIC) has put forward recommendations for theCYP2D6phenotype, but the list of studied drug-gene pairs continues to grow. This clinical trial randomized chronic pain patients (n= 60), referred from primary care to pain unit care into two opioid prescribing arms, one guided byCYP2D6, μ-opioid receptor (OPRM1), and catechol-O-methyl transferase (COMT) genotypes vs. one with clinical routine. The genotype-guided treatment reduced pain intensity (76 vs. 59 mm,p< 0.01) by improving pain relief (28 vs. 48 mm,p< 0.05), increased quality of life (43 vs. 56 mmp< 0.001), and lowered the incidence of clinically relevant adverse events (3 [1–5] vs. 1 [0–2],p< 0.01) and 42% opioid dose (35 [22–61] vs. 60 [40–80] mg/day,p< 0.05) as opposed to usual prescribing arm. The final health utility score was significantly higher (0.71 [0.58–0.82] vs. 0.51 [0.13–0.67] controls,p< 0.05) by improving sleepiness and depression comorbidity, with a significant reduction of 30–34% for headache, dry mouth, nervousness, and constipation. A large-scale implementation analysis could help clinical translation, together with a pharmaco-economic evaluation.