Background: Chronic post-sternotomy pain after coronary artery bypass grafting (CABG) is an underestimated complication. Pain has a major impact on quality of life. Increasingly, low-dose or even opioid-free anesthesia has been shown to be feasible and in some cases beneficial. Different intraoperative analgesic treatment strategies may significantly impact occurrence of hyperalgesia and subsequent pain in cardiac surgery. Objective: To investigate whether different intraoperative dosing regimens of fentanyl during CABG influence the area of hyperalgesia 24 and 48 hours postoperatively. As secondary endpoints, we investigated whether acute postoperative pain measured by the numerical rating scale (NRS) scores at 24 and 48 hours and the occurrence of chronic pain after 3, 6 and 12 months were influenced by perioperative fentanyl dosing. Design: Prospective, randomized double-blind clinical trial. Setting: A preliminary analysis of a randomized multicenter study (University Hospital of Ghent and the University Hospital of Basel), including patients undergoing elective on-pump CABG in University Hospital of Ghent. Methods: We screened 80 patients, of whom 66 were included and randomized into three groups: a high fentanyl regimen (20 µg.kg-1 IBW (Ideal Body Weight)), a low dosing regimen (3 µg.kg-1 IBW), or a Shibutani continuous dosing regimen. When extubated and responsive, protocolized pin-pricking was performed at 24 and 48h to evaluate the surface area of hyperalgesia. Additionally, patients are asked to report the Numeric Rating Scale (NRS) at 24h, 48h, as well as the occurrence of persistent pain at 3, 6, and 12 months. Additional preoperative rescue fentanyl dosing and postoperative remifentanil dosing were taken into account as possible confounders. Results: Primary endpoint: the difference in the measured area of hyperalgesia between the randomization groups was not significantly different. At 24h a mean area of 88 cm2, 90 cm2 and 96 cm2 was found in the low, high and Shibutani groups, respectively. At 48h areas of 91 cm2, 96 cm2 and 103 cm2 were measured in the respective groups. Secondary endpoints: significantly higher NRS scores were recorded at 24 hours in the low-dose group. A higher NRS score was found at 6 months in the Shibutani group compared to the other groups in the longer term. Postoperative administration of remifentanil is was not found to be a confounding cause of hyperalgesia. Conclusion: More short-term pain was reported in patients administered lower doses of fentanyl intraoperatively. Other clinically relevant differences in outcomes were not found. Our findings suggest that the benefits of opioid low anesthesia may not be as relevant to cardiac surgery with median sternotomy. The total postoperative opioid dosing (including remifentanil) could be a possible cause of hyperalgesia. Trial registration: EudraCT (European Union Drug Regulating Authorities Clinical Trials Database), the European database for all interventional clinical trials on medicinal products authorized in the European Union. Eudra CT number: 2017-003278-15, AGO/2017/005.