The effect of adding a second multimodal analgesic component to anesthesia regimens on acute postoperative pain outcomes: a systematic review and meta-analysis

Postoperative pain remains a common clinical challenge, affecting patient recovery, satisfaction, and risk of chronic pain. Conventional analgesics often inadequately address the multifactorial nature of postoperative pain, while opioids carry risks of adverse effects and dependence. Multimodal analgesia, combining agents with complementary mechanisms, aims to improve pain control and reduce opioid consumption, but the incremental benefit of adding a second component is unclear. To evaluate whether adding a second multimodal analgesic component to conventional regimens improves postoperative pain control and reduces opioid consumption in adult patients undergoing non-cardiac surgery. We performed a systematic review and meta-analysis of randomized controlled trials. PubMed and EMBASE (via Ovid) were searched for eligible studies up to August 2, 2024, using search terms related to surgical patients, pain, multimodal analgesia, and ten common multimodal components. We included RCTs in adults (≥ 18 years) undergoing non-cardiac surgery under general anesthesia, comparing standard care plus two multimodal components versus one component, with postoperative opioid consumption measured and pain measured by numeric rating scale (NRS) or visual analog scale (VAS). Twenty-seven trials were included. Meta-analysis of 17 trials (24 comparisons) showed that a second multimodal component reduces 24-hour opioid consumption by 5.2 mg oral morphine equivalents (95% CI[-7.7, -2.7]; p < 0.01; I² = 99%). Nineteen trials (29 comparisons) reported reduced pain scores at 4 h postoperatively by -0.5 points (95% CI[-0.8, -0.2]; I² = 94%). However, heterogeneity was very high. Subgroup analyses did not reveal a superior multimodal component. Adverse events were generally comparable, with some reductions in postoperative nausea and vomiting. Data on long-term outcomes and quality of recovery were limited. Adding a second multimodal analgesic component may modestly improve acute postoperative pain control and may reduce opioid consumption. Further research is needed to determine optimal combinations for specific surgical settings, to systematically evaluate associated adverse effects and to assess long-term outcomes including chronic pain prevention.