Pain Management
Corey Diamond, PharmD
With over 50 million people receiving surgery each year, there is a major push in the medical community to reevaluate the reliance on opioids as the central backbone of pain management. A new meta-analysis by Bongiovanni and colleagues published in the May 2021 issue of the Journal of the American College of Surgeons claims that NSAIDs are unlikely to be the cause of postoperative bleeding complications.
Even though several clinical pain societies have recommended using non-opioid pharmacotherapy—such as acetaminophen and NSAIDs—as the primary treatment for the management of postoperative pain, surgeons remain reluctant to give them to patients due to theoretical concerns for an increased risk of postoperative bleeding that has yet to be robustly investigated—until now.
Taking a closer look
Bongiovanni and colleagues conducted a systematic review and meta-analysis that included a total of 74 unique studies representing 151,031 patients across 41 randomized controlled trials and 27 cohort studies. They evaluated the effect of administration of perioperative NSAIDs on surgery-associated bleeding in the postoperative period for adult surgical patients.
The authors investigated 3 main outcome measures that they felt represented the aggregate impact of clinically significant bleeding in the postoperative period: the presence of hematoma, a return to the operating room secondary to bleeding, and the need for transfusion in patients who received NSAIDs in the perioperative setting versus patients who did not.
The authors found no significant difference between the groups for any of these outcomes, with relatively low heterogeneity across the included studies, which incorporated different NSAIDs, doses, and areas of the body (I2 = 19.5%, 10.6%, and 0.0% for each outcome respectively).
In the analysis, the study authors looked at a broad range of surgical patient populations—breast surgeries, abdominal surgeries, tonsillectomies, and orthopedic surgeries, among others.
Until recently, the rationale for using NSAIDs for postoperative pain management has mainly been extrapolated from meta-analyses with patients who have had plastic surgery.
A wide variety of different NSAID agents such as ketorolac, diclofenac, ibuprofen, celecoxib, ketoprofen, and parecoxib were part of the meta-analysis as well. Previous research has been for the most part restricted to ketorolac and ibuprofen.
Theoretical concern
The rationale for using NSAIDs as one of the primary components for postoperative pain management stems from their ability to inhibit the inflammatory component of pain.
NSAIDs have long been shown to function peripherally at nociceptors by blocking the cyclooxygenase (COX-1 and COX-2) enzymes, which prevents the conversion of arachidonic acid to prostaglandins—hormone-like chemical pain mediators that signal inflammation.
However, they can also act centrally, as well, via inhibition of COX-2 in regions of the spine and brain, which ultimately results in stimulation of the descending inhibitory pain cascade.
The main concern of using NSAIDs lies in another mechanism of their action. The inhibition of COX-1 and COX-2 enzymes also results in decreased synthesis of thromboxane—specifically thromboxane A2 (TXA2)—by platelet cells. Consequently, this inhibits vasoconstriction and platelet aggregation, which may increase bleed risk and bleeding time.
Limitations
The results of Bongiovanni and colleagues’ meta-analysis should be interpreted within the context of its methodology.
The meta-analysis did not provide sub-group analyses beyond its 3 main outcome measures, with the outcomes being a composite of many different bleeding events and surgical procedures.
Pharmacists should use caution in applying the results as a blanket
recommendation for using any NSAID for all postoperative patients’ pain management.
The unique pharmacology between individual NSAID agents can differ significantly. For example, the antiplatelet activity of long-acting NSAIDs, such as naproxen, celecoxib, or piroxicam, may persist for several days after the drug is stopped due to its long half-life. Consider that approximately 50% of the NSAIDs analyzed from all the included studies within the analysis consisted of ketorolac as the sole investigatory agent.
In addition, the study authors did not investigate risks beyond postoperative bleeding. NSAIDs may still confer other risks to certain postoperative patient populations that are not yet fully understood. For instance, there have been multiple publications that have linked the use of NSAIDs and COX-2 inhibitors to an increased rate of anastomotic leak in colonic resection patients, which often requires reoperation.
Finally, many surgeries will necessitate relatively long-term pain medication regimens at discharge. Since the research team only included studies investigating bleed rates in the immediate postoperative period, the safety outcomes do not provide information on relatively long-term NSAID use following an operation.
Contextual considerations
Despite results of this meta-analysis, hospital pharmacists should, of course, always consider patient factors that may contraindicate NSAID use. For instance, patients with von Willebrand disease, thrombocytopenia, and hemophilia will often have exaggerated bleeding times that NSAIDs may exacerbate.
NSAIDs may not be safe for patients who have a history of alcohol abuse as well, and pharmacists should exercise caution in extrapolating the results of the analysis in this context since this specific sub-group population was not included in the study. Patients with a history of alcohol abuse should be monitored closely for postoperative bleeding regardless.
Patients who have undergone cardiovascular surgery may also need to be scrutinized more closely before a NSAID is recommended perioperatively. Cardiovascular surgeries have a much higher baseline risk of bleeding relative to other types of procedures, and the safety of using NSAIDs perioperatively in this setting cannot be extrapolated to this population based solely on Bongiovanni and colleagues’s meta-analysis since cardiovascular procedures were not well-represented.
Take aways
The authors concluded that “with regard to surgical bleeding, our results suggest that NSAIDs can be safely adopted as part of a multimodal analgesic strategy in the postoperative period.” If they are indeed referring to all NSAIDs, this conclusion is hard to agree with, considering the lack of a sub-group analysis on the specific NSAID agents. The ubiquity of ketorolac as the primary NSAID in the majority of the trials may have masked safety events from the other agents included in this study. Regardless, this analysis certainly adds value to the current body of literature and could help thrust non-opioid pain management modalities forward for patients who have undergone surgery.