Non-steroidal anti-inflammatories for analgesia in critically ill patients: a systematic review and meta-analysis of randomized control trials

Purpose While opioids are part of usual care for analgesia in the intensive care unit (ICU), there are concerns regarding excess use. This is a systematic review of non-steroidal anti-inflammatories (NSAIDs) use in critically ill adult patients. Methods We conducted a systematic search of MEDLINE, EMBASE, CINAHL, and Cochrane Library. We included randomized control trials (RCTs) comparing NSAIDs alone or as an adjunct to opioids for analgesia. The primary outcome was opioid utilization. We reported mean difference for continuous outcomes and relative risk for dichotomous outcomes with 95% confidence intervals (CIs). We evaluated study risk of bias using the Cochrane risk of bias tool and evidence certainty using GRADE. Results We included 15 RCTs (n=1621 patients). Adjunctive NSAID therapy to opioids reduced 24-hour oral morphine equivalent consumption by 21.4mg (95% CI: 11.8-31.0mg reduction, high certainty) and probably reduced pain scores (measured by visual analogue scale) by -6.1mm (95% CI: -12.2 to +0.1, moderate certainty). Adjunctive NSAIDs probably had no impact on duration of mechanical ventilation (-1.6 hours, 95% CI: -0.4 to -2.7 hours, moderate certainty) and may have no impact on ICU length of stay (-2.1 hours, 95% CI: -6.1 to +2.0 hours, low certainty). Variability in reporting of adverse outcomes (e.g. gastrointestinal bleeding, acute kidney injury) precluded their meta-analysis. Conclusion In critically ill adult patients, NSAIDs reduced opioid use, probably reduced pain scores, but were uncertain for duration of mechanical ventilation or ICU length of stay. Further research is required to characterize the prevalence of NSAID-related adverse outcomes. Take-Home Message In this systematic review and meta-analysis of 15 randomized control trials that included 1621 critically ill adult patients, the addition of non-steroidal anti-inflammatories to an opioid analgesic strategy reduced 24-hour opioid use and modestly reduced pain with no impact on duration of mechanical ventilation or ICU length of stay. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Protocols ### Funding Statement This study did not receive any funding. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present work are contained in the manuscript.