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Multimodal analgesia is increasingly considered routine practice in joint arthroplasties, but supportive large-scale data are scarce. The authors aimed to determine how the number and type of analgesic modes is associated with reduced opioid prescription, complications, and resource utilization.Total hip/knee arthroplasties (N = 512,393 and N = 1,028,069, respectively) from the Premier Perspective database (2006 to 2016) were included. Analgesic modes considered were opioids, peripheral nerve blocks, acetaminophen, steroids, gabapentin/pregabalin, nonsteroidal antiinflammatory drugs, cyclooxygenase-2 inhibitors, or ketamine. Groups were categorized into “opioids only” and 1, 2, or more than 2 additional modes. Multilevel models measured associations between multimodal analgesia and opioid prescription, cost/length of hospitalization, and opioid-related adverse effects. Odds ratios or percent change and 95% CIs are reported.Overall, 85.6% (N = 1,318,165) of patients received multimodal analgesia. In multivariable models, additions of analgesic modes were associated with stepwise positive effects: total hip arthroplasty patients receiving more than 2 modes (compared to “opioids only”) experienced 19% fewer respiratory (odds ratio, 0.81; 95% CI, 0.70 to 0.94; unadjusted 1.0% [N = 1,513] vs. 2.0% [N = 1,546]), 26% fewer gastrointestinal (odds ratio, 0.74; 95% CI, 0.65 to 0.84; unadjusted 1.5% [N = 2,234] vs. 2.5% [N = 1,984]) complications, up to a –18.5% decrease in opioid prescription (95% CI, –19.7% to –17.2%; 205 vs. 300 overall median oral morphine equivalents), and a –12.1% decrease (95% CI, –12.8% to –11.5%; 2 vs. 3 median days) in length of stay (all P < 0.05). Total knee arthroplasty analyses showed similar patterns. Nonsteroidal antiinflammatory drugs and cyclooxygenase-2 inhibitors seemed to be the most effective modalities used.While the optimal multimodal regimen is still not known, the authors’ findings encourage the combined use of multiple modalities in perioperative analgesic protocols.