Background/Objectives: Postoperative pain remains a significant clinical challenge, often requiring multimodal strategies to mitigate opioid-related adverse events. The fixed-dose combination (FDC) of Diclofenac, a non-steroidal anti-inflammatory drug, and Orphenadrine, a muscle relaxant, targets distinct nociceptive pathways to potentially enhance analgesia and reduce opioid consumption. This systematic review aims to evaluate the analgesic efficacy and safety profile of the fixed-dose combination of Diclofenac and Orphenadrine for postoperative pain management and quantify its opioid-sparing effect compared to standard monotherapies or placebo. Methods: A systematic search of electronic databases (MEDLINE, Scopus) and clinical trial registries (including ClinicalTrials.gov and CTIS) was conducted up to 20 September 2025. Fourteen (14) randomized controlled trials (RCTs) involving 981 adult patients undergoing various surgical procedures were included. Due to high clinical and methodological heterogeneity, a Synthesis Without Meta-analysis (SWiM) approach was utilized. The certainty of evidence was assessed using the GRADE methodology. Results: The synthesis demonstrated that the FDC may improve pain relief (measured by the Visual Analog Scale and Numeric Rating Scale scores) and may reduce opioid consumption compared to active comparators and placebo. The opioid-sparing effect could be correlated with a reduced incidence of dose-dependent adverse events, particularly nausea and vomiting. However, the overall certainty of the evidence was graded as “Very Low” due to the high risk of bias and lack of transparency in the included studies. Conclusions: The FDC of Diclofenac and Orphenadrine is a rational addition to multimodal postoperative analgesic regimens, which may potentially reduce the perioperative opioid burden without compromising pain control. Nevertheless, because almost all included studies suffer from severe methodological flaws, these apparent efficacy findings must be interpreted with caution. Future high-quality, pre-registered, and low-bias randomized controlled trials are required to draw firm clinical conclusions.
Christopoulos et al. (Fri,) studied this question.