Background: Polyamines have been identified as pain agonists and interact with NMDA receptors. A prospective, randomized, multicenter, and blinded phase II clinical trial was conducted to evaluate a polyamine-deficient diet for the treatment of perioperative pain in patients during spinal surgery. Material and Methods: All analyses followed the intention-to-treat principle. The trial was designed to evaluate the dose-ranging effect of a low polyamine diet with respect to a total (group 1) or partial (group 2) polyamine diet on perioperative pain (7 days before and 5 days after surgery). Pain (numerical scale at rest and motion), Quality of life questionnaires (Brief Pain Inventory, EIFEL questionnaire, and Short Form-12 acute questionnaire), and tolerance of and compliance with the nutritional program were measured. Results: Compliance (preoperatively: 100% in group 1 and 83% in group 2; postoperatively: 83% in group 1 and 71% in group 2) and tolerance were good. After seven days of the diet before surgery, a trend of decrease on pain was observed in group 1 whereas no effect was observed in group 2 (P = 0.144). This analgesic effect became significant in group 1 in the subgroup of patients with initial high levels of pain (NS ≥ 4) at rest (P = 0.03). and on motion (P = 0.011). Quality of life was significantly improved in group 1 (P = 0.0465). In the post-operative period, pain was significantly decreased in group 1 compared to group 2 at rest (P = 0.022). and on motion (P = 0.029). The effect was significantly better on patients with higher initial pain both at rest (P = 0.013) and on motion (P = 0.005) in group 1 compared to group 2. Conclusion: Suppression of polyamines from the diet offers a nutrition-based treatment option for perioperative pain reduction independent of and complementary to typical analgesic approaches