Beneficial Immune-modulating Effects of Nsaids
Effects on the Surgical Stress Response
Surgical injury activates the immune system in a direct manner by the binding of danger-associated molecular patterns to pattern recognition receptors of the innate immune system and indirectly via surgical injury induced activation of the neuroendocrine system, through the hypothalamic–pituitary–adrenal axis. Activation then involves the release of hormones, cytokines, chemokines, and prostanoids, which are essential to restore homeostasis and are involved in tissue repair and the host's response against invading pathogens. An exaggerated surgical stress response may lead to a systemic inflammatory response syndrome, is associated with postoperative morbidity and a higher risk of infections and organ failure, and may be detrimental to long-term survival after oncological surgery. In response to surgical injury, the T helper 1/T helper 2 balance (between T helper 1 cells and T helper 2 cells) shifts toward T helper 2 cells, suggesting that cell-mediated immunity is downregulated and antibody/humoral-mediated immunity is upregulated. This also affects the cytolytic function of natural killer cells, which is enhanced by a T helper 1 cell response. In a study examining the immunologic effects of parecoxib (a selective COX-2 inhibitor) in adults undergoing laparoscopic cholecystectomy, the balance between T helper 1 cells, T helper 2 cells, T helper 17 cells, and regulatory T cell cytokines was restored after administration of parecoxib, suggesting an important role for prostanoids in the polarization of T helper cells.
In two randomized controlled trials, the effect of intravenous ibuprofen on the surgical stress response during cholecystectomy was assessed.[33,34] Although administration strategies were different (500 mg ibuprofen, 12 and 2 h before surgery and every 8 h until the third postoperative day vs. a single preoperative dose of 800 mg ibuprofen), a reduced endocrine response and cytokine release were observed in both studies in patients receiving ibuprofen. Both trials, however, observed increased intraoperative levels of tumor necrosis factor α, which the authors ascribe to the direct stimulation of mononuclear cells and the release of tumor necrosis factor α by NSAIDs, thereby causing a subsequent short-term intraoperative increase. Ibuprofen attenuated postoperative anti-inflammatory interleukin 10 release, suggesting a reduction of the proinflammatory response, requiring less interleukin 10 modulation. Although the study of Le et al. could not demonstrate a difference in perioperative interleukin 6 levels, several other studies, administering ibuprofen, diclofenac, and parecoxib perioperatively, demonstrated an association between the use of NSAIDs and lower interleukin 6 levels.[33,35,36] Moreover, high perioperative levels of interleukin 6 are associated with postoperative complications in different types of surgery.[37,38] According to clinicaltrials.gov (accessed January 2, 2021), there are no current randomized controlled trials assessing the effect of NSAIDs on the surgical stress response.
The effects of NSAIDs in septic patients undergoing surgery has not been investigated. In (animal) sepsis models, however, aspirin and other NSAIDs are associated with improved hemodynamic parameters, organ function, and survival.[39,40] There are several hypotheses about the potential beneficial effect of NSAIDs or aspirin in systemic inflammatory response syndrome/sepsis patients. The immune response in systemic inflammatory response syndrome/sepsis is a dynamic process and differs between an immune-activated state and a paralyzed state. Effects will therefore depend on the time of administration and the current immunologic state of the patient. During an exaggerated immune response, one could hypothesize that it might be beneficial to have NSAIDs mitigating this response. The positive effect of aspirin might be explained by the ability of aspirin to stimulate the production of anti-inflammatory and proresolving mediators, a feature that is not shared by other NSAIDs. On the other hand, aspirin has been shown to potentiate leukocytic cytokine production in human endotoxemia trials.[41,42] This proinflammatory response might be beneficial in a sepsis-induced immunoparalysis and could contribute to the improved survival found in a meta-analysis that included 17,065 patients from observational studies: aspirin use before the onset of sepsis resulted in a 7% decrease in mortality. In a recent double-blind, placebo-controlled follow-up study, in which 16,703 patients aged above 70 yr were randomized to receive either 100 mg aspirin or placebo, these beneficial effects could not be confirmed. After follow-up with a median of 4.6 yr, a total of 203 deaths were considered to be associated with sepsis, with no differences between the two groups. These studies, however, have a different design (meta-analysis of observational studies vs. randomized controlled trial), which may explain the difference in outcome. In a randomized, double-blind, placebo-controlled trial that included 455 septic patients, treatment with ibuprofen (10 mg/kg given every 6 h for eight doses) decreased fever, tachycardia, oxygen consumption, and lactic acidosis but was not associated with improved survival or development of shock. With a maximum of eight doses of ibuprofen, longer-lasting therapy might have produced different results. Comparing these studies is difficult due to major methodologic differences such as duration and start of treatment and type of NSAID. Administration of NSAIDs might even have negative consequences, since the use of NSAIDs in patients with septic shock led to a delayed administration of antibiotic therapy by masking the signs of sepsis. Moreover, various case reports have suggested that NSAIDs in septic patients might increase the severity of infection, which might be due to the immune suppression seen in these patients.[47,48] According to clinicaltrials.gov (accessed January 2, 2021), there is currently one randomized controlled trial (NCT01784159) in septic patients assessing the effect of aspirin on the reduction of intensity of organ dysfunction, measured by the variation of the Sequential Organ Failure Assessment score, starting from the day of admission to day 7.
Taken together, there is no beneficial effect of NSAIDs in patients with sepsis and in those with an exaggerated surgical stress response. These responses are highly dynamic, not only changing over time but also differing between subjects. In addition, prostaglandins possess pro- and anti-inflammatory properties, again dependent on type, time of release, and context (Table 1). The ultimate effect, tempering or enhancing the immune response, therefore, most likely depends on the cause of sepsis, patient characteristics (immune status, comorbidity), type of NSAID (COX-1 and/or COX-2, aspirin), dosage, and time point of administration (studies are summarized in Table 2).
Acute Respiratory Distress Syndrome
Aspirin and, to a lesser extent, other NSAIDs might have beneficial effects on patients with acute respiratory distress syndrome (ARDS) due to their effect on platelet activation and anti-inflammatory properties. Aspirin covalently and irreversibly binds to platelet cyclooxygenase, whereas other NSAIDs reversibly inhibit platelet cyclooxygenase. Platelets are activated in the presence of lipopolysaccharides and thrombin, both sepsis mediators, resulting in pulmonary microcirculatory thrombosis, increasing pulmonary vascular dead space, ventilation perfusion mismatch, and worse outcomes in patients with ARDS. The interaction between activated platelets and leukocytes results in production of proinflammatory cytokines (interleukins 1β and 8 and tumor necrosis factor α) and pulmonary edema. Aspirin has the ability to modify these pathways and might be used both preventively and therapeutically. Furthermore, aspirin-triggered specialized proresolving mediators can potentially contribute to regulation of the immune response during ARDS. These effects are further enhanced by the fact that aspirin has the ability to regulate leukocyte traffic by aspirin-triggered lipoxins. In different in vitro, animal, and observational studies, the administration of aspirin was related to the prevention of or an improvement in patients with ARDS. In a review of preclinical models and a meta-analysis of clinical studies, the authors concluded that the administration of aspirin in animal studies was associated with improved survival and attenuated inflammation and pulmonary edema. In clinical trials, there was an association with a reduced incidence of ARDS. The differences between preclinical and clinical studies may be explained by differences in dosage and timing of administration. In preclinical studies, higher doses of aspirin have generally been administered compared to clinical studies in which lower doses were used. A higher dose provides a greater COX-2 blockade, while a lower dose provides a greater COX-1 blockade. A 2015 review by Toner et al. concluded that ongoing randomized controlled trials would elucidate the role of aspirin in treating ARDS. Afterward, a multicenter double-blind, placebo-controlled, randomized controlled trial including 390 patients at risk of ARDS was performed: in contrast to former research, the use of aspirin compared with placebo did not reduce the risk of ARDS at 7 days, nor were there any differences in secondary outcomes or adverse events. Patients in this study were administered a loading dose of 325 mg aspirin, followed by 81 mg/day for up to 7 days after admission. Although, or perhaps because, patients were enrolled in the emergency department, the incidence of ARDS was lower than expected (9.5% vs. 18%), resulting in an insufficient power. Another randomized controlled trial (NCT02326350), investigating the effect of 75 mg aspirin on oxygenation index at day 7 in patients diagnosed with ARDS, was terminated prematurely due to slow recruitment (clinicaltrials.gov). Recently, Chow et al. examined the relationship between aspirin and clinical outcomes in patients with ARDS due to COVID-19. In this retrospective study of 412 patients, patients who received aspirin (N = 98) were less likely to need mechanical ventilation (35.7% vs. 48.4%) and intensive care unit admission (38.8% vs. 41.0%), despite a higher rate of comorbidities in the aspirin group. These results, however, should be interpreted with caution, since COVID-19 patients display a hypercoagulatory state, the study only concerns a small number of patients, and the differences are small, making the clinical relevance minimal. Currently, the Effect of Aspirin on REducing iNflammation in Human in vivo Model of Acute Lung Injury (ARENA) trial is including patients (according to clinicaltrials.gov accessed January 2, 2021; 33 patients after 8 yr of inclusion) and examines the effect of aspirin on inflammation in acute lung injury (NCT01659307). In conclusion, despite a pathophysiologic explanation for a beneficial effect of aspirin or other NSAIDs in patients with ARDS, the only performed randomized controlled trial does not show a protective effect (the studies are summarized in Table 2).
Inflammation and Pain
Surgical injury leads to activation and sensitization of the nociceptive system through the release of different mediators, like bradykinin, prostanoids, and cytokines. Activated prostanoids, in particular PGE2 and PGI2, are involved in peripheral and central sensitization and in (neuro)inflammatory pain. PGE2 serves as an important proinflammatory mediator and is involved in development of all physical signs of inflammation. Peripheral sensitization by PGE2 involves the activation of E-prostanoid receptors (EP1, EP2, and EP4), which mediate pain responses from noxious and innocuous stimuli. These receptors are also found in the spinal cord, highlighting the central sensitization activity of PGE2, where it is considered the dominant prostaglandin in the spinal nociceptive system. PGI2 causes hyperalgesia by activating the prostacyclin (IP) receptor, which acts directly on the peripheral afferent nociceptors. In addition, PGE2 and PGI2 also have sensitizing properties through other mechanisms. For instance, PGE2 enhances the sensitization of nociceptors by lowering the threshold of the tetrodoxin-resistant sodium channels (found in the cell bodies of many peripheral nervous systems). Second, the transient receptor potential vanilloid 1 channel, which is involved in heat sensation, iS potentiated severalfold by PGE2 and PGI2 in afferent neurons. Finally, PGE2 sensitizes afferent neurons to produce bradykinin, which is involved in lowering the heat threshold of bradykinin 2 receptors and is therefore responsible for long-lasting pain associated with inflammation. In addition to activated prostanoids, proinflammatory cytokines, like tumor necrosis factor α and interleukins 1β, 6, and 17, secreted at and recruited to the site of injury, have the ability to activate and to increase the sensitivity to pain stimuli. Receptors for these specific cytokines are located on the nociceptive neurons and, together with other noxious stimuli, stimulate the primary afferent A-delta and C-nerve fibers and synapse with neurons in the dorsal horn of the spinal cord. Neutralization of these cytokines results in a quick reduction of pain. In addition, these cytokines not only play a role in mechanical pain stimulation but also are involved in the development of neuropathic pain.
NSAIDs as Preemptive Analgesics. NSAIDs are widely used in the treatment of acute (perioperative) or chronic pain but are also used as a preemptive analgesic agent. NSAIDs might be ideal for this purpose due to their anti-inflammatory effects and by preventing the establishment of peripheral and central sensitization in nociceptive pathways. In a systematic review, the authors concluded that some aspects of postoperative pain control were improved by preemptive treatment in 4 of the 20 randomized controlled trials, but overall, the effect was moderate. Moreover, there was no analgesic benefit to preemptive administration of NSAIDs compared with postincisional administration. Despite including only randomized controlled trials, the studies displayed a wide heterogeneity, ranging from abdominal to orthopedic surgery, and many different NSAIDs (for example, ibuprofen, diclofenac, ketorolac, naproxen, and flurbiprofen) were used. In a more recent systemic review and meta-analysis, the authors examined the effect of preemptive drug administration on postoperative analgesic consumption during the 24 h postsurgery. A significant reduction of postoperative analgesic consumption was observed using COX-2 inhibitors but not for nonselective NSAIDs. Comparable results were found in a meta-analysis that examined the efficiency of selective COX-2 inhibitors in patients undergoing total knee arthroplasty. The authors found a beneficial effect on the visual analog scale score (24 and 72 h postoperatively) and a decreased opioid consumption. The clinical relevance, however, of both meta-analyses is not clear, since there were no statements about the reduction in the visual analog scale or opioid consumption. Based on the included studies in these meta-analyses, it is also unclear whether preemptive administration has advantages over postincisional administration. This question, however, is not about the efficacy of NSAIDs but about the most ideal time to administer them. This most likely will remain difficult to answer due to small differences in direct clinical outcome measures and many different covariates. Furthermore, interpretation of current literature is hampered by a high degree of heterogeneity with differences in dose and timing, type of postoperative rescue analgesic, postoperative analgesia therapy, type of surgery, and reported outcomes.
NSAIDs in Multimodal Management of Acute Postoperative Pain. While it is uncertain whether preemptive administration of NSAIDs is beneficial over postincisional administration, these drugs have been given an important role in the multimodal management of acute postoperative pain. The American Society of Anesthesiologists (ASA; Schaumburg, Illinois) recommend administration, unless contraindicated, of multimodal pain management consisting of acetaminophen combined with an NSAID or selective COX-2 inhibitor during the perioperative period. In contrast to opioids, which mainly act in the central nervous system, NSAIDs alleviate pain by reducing the inflammatory response caused by tissue damage and by preventing peripheral and central sensitization. The effects of NSAIDs are predictable and suitable for most surgical procedures and have, in contrast to opioids, no risk of addiction. Moreover, the administration of NSAIDs leads to a shorter recovery period, higher patient satisfaction, and a reduction in postoperative morbidity.
Several meta-analyses have been performed to demonstrate the efficiency of NSAIDs or COX-2 inhibitors. In a meta-analysis from 2005, four conclusions emerge regarding the perioperative use of NSAIDs: nonopioid analgesics are opioid-sparing, the visual analog scale score is significantly decreased, and their use is associated with a reduction of opioid-related adverse effects. However, there was also an increased risk of rare but important adverse effects related to the use of nonselective NSAIDs/selective COX-2 inhibitors, such as renal failure in cardiac patients (odds ratio, 4.86; 95% CI, 1.01 to 23.4; nonselective NSAIDs/COX-2 inhibitors) and increased surgical bleeding (odds ratio, 4.54; 95% CI, 1.54 to 13.42; nonselective NSAIDs). To determine which class of nonopioid analgesic is the most effective in reducing morphine consumption and morphine-related adverse effects, a systematic review was conducted by Maund et al. The authors concluded that, in combination with a patient-controlled analgesia with morphine, NSAIDs (mean difference, −10.18 mg) and COX-2 inhibitors (mean difference, −10.92 mg) were related to a reduced morphine consumption. Furthermore, nausea and postoperative vomiting were significantly reduced by adding NSAIDs to a multimodal management. In another meta-analysis, the authors focused on the effect of NSAIDs on opioid-related adverse effects. They observed a reduction in nausea (12%), vomiting (32%), and sedation (29%). There was no reduction in pruritus, urinary retention, and respiratory depression. The authors tried to limit the degree of heterogeneity as much as possible but still included different NSAIDs and type of surgeries. In addition, their primary endpoints were scored differently throughout the included studies. In conclusion, these meta-analyses demonstrate a reduction in the visual analog scale score, opioid consumption, and various opioid-related adverse effects when administered in a multimodal regimen. It is, however, important to realize that studies investigating the effect of multimodal analgesic regiments all suffer from the same weakness: namely, if something changes in the model, it is nearly impossible to conclude whether this is due to one drug versus another drug, which makes it difficult to draw firm conclusions.
NSAIDs in Preventing Chronic Pain After Surgery. Persistent postoperative pain is a major problem and affects health-related quality of life. The exact pathophysiology is not fully understood but has recently been discussed in several reviews.[90–92] In summary, it is a multifactorial disorder involving (neuro)inflammation, which is characterized by the activation of glial cells and results in the release of cytokines and chemokines, and peripheral and central sensitization due to persistent noxious signaling, leading to nociceptive and neuropathic pain. Under normal circumstances, the immune response, elicited by surgical injury, resolves after several days, resulting in baseline nociceptive receptor sensitivity. In patients with persistent postoperative pain, these receptors remain overstimulated. Prolonged augmented action potentials will lead to central sensitization and results in allodynia and hyperalgesia. In addition, proinflammatory cytokines and chemokines in the central nervous system, released by glial cells, also play a role in the development of central sensitization. Moreover, this neuroinflammatory condition will contribute to allodynia, hyperalgesia, and widespread pain throughout the body. The importance of prostaglandins in persistent pain has been confirmed in a mouse model in which hyperalgesic doses of PGE2 induced long-lasting sensitization of afferent nociceptors. Since NSAIDs interfere with these processes, there is a theoretical basis for a beneficial effect in preventing chronic pain after surgery. Nevertheless, studies examining the long-lasting effects of perioperative NSAID administration could not demonstrate a positive effect on persistent postoperative pain.[60–63] In a recent meta-analysis and systematic review, the effects of various perioperative pharmacologic strategies to prevent chronic pain after surgery were assessed. The included studies differed in type of NSAID, duration of administration, type of surgery, but also outcome measures such as reported time endpoints to score the prevalence of pain ranged from 3 to 12 months. The authors concluded that none of the examined pharmacologic interventions could be recommended to prevent chronic pain after surgery.
Tumor Growth and Metastasis
In various epidemiologic studies, it has been shown that the long-term use of aspirin or other NSAIDs is associated with a reduction in the incidence of cancer.[94,95] In a large systemic review of epidemiologic studies, the relative risk was decreased by 43% for colon cancer, 25% for breast cancer, 28% for lung cancer, and 27% for prostate cancer. Of the two cyclooxygenase isoforms, COX-2 expression is dysregulated in many types of cancer and is associated with carcinogenesis, invasiveness, and angiogenesis. With elevated levels of COX-2, the metastatic potential also seems to increase. Of the prostanoids, PGE2 seems to be the most important prooncogenic prostanoid. PGE2 is involved in tumor angiogenesis, cell migration or invasion, and inhibition of apoptosis. In addition to its effect on prostanoids, aspirin activates aspirin-triggered specialized proresolving mediators, including resolvins and lipoxins. These anti-inflammatory mediators inhibit primary tumor growth and metastasis by enhancing endogenous macrophage clearance and cytokine response. In addition to the long-term protective properties of NSAIDs against certain cancer types, these drugs also interfere with the immune response against circulating tumor cells during the surgical resection of a solid tumor. The likelihood of circulating tumor cells is dependent on several factors, including the immune response of the patient. Local inflammation increases the level of circulating tumor cells in the bloodstream, and an adequate functioning immune response is pivotal for the first-line defense against circulating tumor cells. The elimination of cancer cells takes place through natural killer cells, cytotoxic T cells, and dendritic cells. Their activity is inhibited by PGE2, which is overexpressed by many tumors, such as colorectal, breast, cervical, bladder, and ovarian. In addition, surgical injury increases a number of proinflammatory cytokines such as interleukins 1β and 6 and tumor necrosis factor α, which also suppress the activity of immune cells necessary for the elimination of circulating tumor cells. Theoretically, NSAIDs have the ability to reduce these effects. The inhibition of PGE2 synthesis in tumor cells leads directly to an impaired capacity to survive and proliferate and leads indirectly to an increased cytotoxic activity of natural killer and T cells. Brunda et al. showed that in vivo administration of indomethacin or aspirin resulted in a marked restoration of natural killer activity in tumor-bearing animals. In a meta-analysis of animal studies, the authors concluded that treatment with analgesics significantly decreased the number and risk of metastases, which was mainly the consequence of NSAIDs.
Recently, five randomized controlled trials (NCT00888797, NCT02141139, NCT00502684, NCT01806259, and NCT03172988; clinicaltrials.gov) were conducted to assess the effect of perioperative NSAIDs on cancer recurrence. These trials differed in the type of cancer, the duration of NSAID administration, whether administration started preoperatively, the coadministration of a β-adrenergic antagonist, and the NSAID type (COX-1 and/or COX-2). The status of four of these randomized controlled trials (NCT00888797, NCT02141139, NCT01806259, and NCT03172988) is either unknown or lacking in sufficient power due to early termination, protocol violation, or a lower recurrence rate than anticipated. The positive effect of NSAIDs in the perioperative period was shown in a randomized controlled trial (NCT00502684) that combined a COX-2 inhibitor with a β-adrenergic antagonist (propranolol), using study outcome points of cellular and molecular responses related to metastasis and disease recurrence. Cata et al. conducted a systemic review and found mainly observational and retrospective studies, all dealing with a high degree of heterogeneity, and concluded that the current evidence was equivocal regarding the effects of short-term NSAIDs on cancer recurrence after major cancer surgery. However, these observational and retrospective studies claim a reduced recurrence rate, longer disease-free survival, or overall survival due to the effects of perioperative NSAIDs.[104–112] In conclusion, despite the positive effect of NSAIDs in epidemiologic studies, immune-based perioperative antitumor effects, and positive observational and retrospective studies, there is insufficient or inconclusive evidence from high-quality clinical studies to support the experimental data (studies are summarized in Table 2).
Neuroinflammation is an important underlying mechanism in several neurologic disorders. Affecting this pathophysiologic process through the anti-inflammatory effects of NSAIDs is of general interest. Regarding the perioperative period, postoperative cognitive dysfunction is a common complication, particularly affecting the elderly population. Postoperative elevated levels of proinflammatory cytokines are associated with the development of postoperative cognitive dysfunction in both animal and human studies.[113–120] The hypothesis is that proinflammatory cytokines disrupt the blood–brain barrier via upregulation of COX-2 and matrix metalloproteinases, upon which these cytokines can enter the central nervous system. After surgical injury, increased inflammatory activity was found in plasma and in human cerebrospinal fluid. In a study by Peng et al., administration of parecoxib, a selective COX-2 inhibitor thought to have good central nervous system distribution, resulted in reduced surgery-induced levels of interleukin 1β and tumor necrosis factor α in the hippocampus in aged rats. Improvements in memory function in mice were demonstrated by Kamer et al., who administered meloxicam 24 h after surgical splenectomy. A recent meta-analysis included eight randomized controlled trials assessing the effect of parecoxib on the incidence of postoperative cognitive dysfunction in geriatric patients undergoing orthopedic surgery. The authors concluded that perioperative administration of parecoxib was effective in reducing the incidence of postoperative cognitive dysfunction and improving the score on the Mini-Mental State Examination. The methodologic quality of the included studies was assessed as moderate to good. Nevertheless, only one of the eight randomized controlled trials was sufficiently powered, parecoxib was administered pre- or postoperatively, and postoperative cognitive dysfunction definitions were different between studies. Furthermore, it is unclear whether these results can be extrapolated to other surgical interventions.
NSAIDs are also associated with reduced cerebral ischemic injury in patients with aneurysmal subarachnoid hemorrhage.[125,126] Encouraging results of NSAIDs were found in animal models of aneurysmal subarachnoid hemorrhage, which showed an overall better control of cerebral vasospasm.[127–132] After propensity score matching of 178 patients, positive effects were observed by Nassiri et al., who concluded that administration of NSAIDs after aneurysmal subarachnoid hemorrhage was associated with reduced mortality and improved functional outcome. In this study, no distinction was made between the different types of NSAIDs, nor is it clear how long NSAIDs were administered. An important limitation, however, concerns the indication for administration of NSAIDs. Patients with a better neurologic status are more likely to report pain and therefore receive more NSAIDs than patients with a poorer neurologic status. A randomized controlled trial by Ghodsi et al., however, could not demonstrate significant differences in cerebral vasospasm, hospital stay, or mortality after administration of meloxicam (7.5 mg for 7 days) in patients with subarachnoid hemorrhage. This study may have been underpowered (N = 81), since no sample size calculation was made. Regarding the safety of NSAIDs, several studies have shown that there is no association with higher rates of rebleed in aneurysmal subarachnoid hemorrhage patients.
Neuroinflammation is an important underlying mechanism in the pathophysiology of various neurologic disorders. NSAIDs might have additional value in the multimodal treatment approach in patients at risk of postoperative cognitive dysfunction, but well-designed clinical trials are needed to determine whether these effects are clinically relevant. Encouraging results of NSAIDs in patients with aneurysmal subarachnoid hemorrhage are not yet sufficiently substantiated to justify any advice (studies are summarized in Table 2).
Anesthesiology. 2022;136(5):843-860. © 2022 American Society of Anesthesiologists | Lippincott Williams & Wilkins