Background: The patient-relevant minimal important difference for opioid consumption remains undetermined, despite its frequent use as primary outcome in trials on postoperative pain management. A minimal important difference is necessary to evaluate whether significant trial results are clinically relevant. Further, it can be used as effect size to ensure that trials are powered to find clinically relevant effects. By exploring the dose–response relationship between postoperative opioid consumption and opioid-related adverse effects, we aim to approximate the minimal important difference in opioid consumption anchored to opioid-related adverse effects. Methods: This is a post-hoc analysis of aggregated data from two clinical trials (PANSAID NCT02571361 and DEX2TKA NCT03506789) and one observational cohort study (Pain Map NCT02340052) on pain management after total hip and knee arthroplasty. The primary outcome is the Hodges–Lehmann median difference in opioid consumption between patients with no opioid-related adverse effects and patients experiencing the mildest degree of one or more opioid-related adverse effects (i.e., mild nausea, sedation and/or dizziness or vomiting). Secondary outcomes include the Hodges–Lehmann median difference in opioid consumption that corresponds to one point on a cumulated opioid-related adverse event 0–10 scale. Further, we will explore the proportion of patients that experience opioid-related adverse effects for consecutive opioid dose intervals of 2 mg iv morphine equivalents. Quantile regression will be used to assess any significant interactions with patient baseline characteristics. Conclusions: This study will hopefully bring us one step closer to determining relevant opioid reductions and thereby improve our understanding of intervention effects and planning of future trials.