NSAIDs

NSAIDs and Resolution of Inflammation

Recent research regarding the mechanisms by which NSAIDs impact inflammation suggests the possibility that when NSAIDs are used during the period of inflammation resolution they may paradoxically result in contributing to chronic inflammation and chronic pain. Based on the mechanisms involved, the use of omega-3 EPA and DHA supplements and other nutraceuticals may mitigate concerns over this unresolved question. This section reviews some of the research evaluating this.

Please note this document has been prepared with the assistance of an AI. There may be some errors.

 

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Definitions and Terms Related to Pain

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NSAIDs and Resolution of Inflammation

There is evidence summarized here across three domains: the resolvin/specialized pro-resolving mediators (SPMs) mechanism, the clinical evidence for NSAIDs promoting chronic pain, and the potential for the use of omega-3 EPA and DHA supplements and other nutraceuticals to mitigate this effect.

The Resolvin/SPM Hypothesis: Mechanistically Compelling but Largely Preclinical

The foundational concept is that inflammation resolution is an active biosynthetic process — not simply the passive fading of pro-inflammatory signals — mediated by specialized pro-resolving mediators (SPMs) including resolvins, protectins, and maresins, which are enzymatically synthesized from omega-3 fatty acids (EPA and DHA).[1][2] COX-2, the very enzyme that NSAIDs inhibit, plays a dual role: it produces pro-inflammatory prostaglandins during the early phase of acute inflammation, but it is also required for the biosynthesis of key pro-resolving mediators during the later resolution phase.[3] This creates a paradox: COX-2 inhibitors may transiently exhibit anti-hyperalgesic effects but may also prolong post-treatment pain by disrupting endogenous resolution circuits.[3]

A recent in vitro and in vivo study demonstrated this directly — NSAID treatment reduced pro-inflammatory eicosanoid production but simultaneously downregulated levels of pro-resolving lipids including epoxyeicosatrienoic acids (EETs), lipoxins (LXs), and E-series resolvins (RvEs), and failed to restore pain thresholds in a validated chronic pain mouse model.[4] A 2025 review in Frontiers in Immunology confirms that SPMs exert potent anti-nociceptive effects in diverse pain models — including postoperative pain — through suppression of inflammatory cytokines, modulation of TRP channels, and interactions with immune cells.[5]

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The Parisien et al. (2022) Study: The Key Translational Evidence

The landmark study by Parisien et al. (2022) in Science Translational Medicine provides the most direct evidence linking anti-inflammatory drug use to chronic pain development.[6] Key findings:

  • Transcriptome-wide analysis of peripheral immune cells in 98 patients with acute low back pain showed thousands of dynamic transcriptional changes over 3 months in patients whose pain resolved, but none in those whose pain persisted
  • Transient neutrophil-driven up-regulation of inflammatory responses was protective against the transition to chronic pain
  • In mouse pain assays, early treatment with a steroid or NSAID led to prolonged pain despite being analgesic in the short term — an effect not observed with other analgesics
  • Neutrophil depletion delayed pain resolution in mice, while injection of neutrophils or S100A8/A9 proteins (normally released by neutrophils) prevented the development of long-lasting pain induced by anti-inflammatory drugs
  • Analysis of pain trajectories in the UK Biobank identified elevated risk of pain persistence for subjects taking NSAIDs

A 2026 narrative review in Pain and Therapy synthesizes this evidence, concluding that “premature suppression of acute inflammation with NSAIDs or corticosteroids may paradoxically promote chronification by disrupting endogenous resolution pathways mediated by specialized pro-resolving mediators and regulatory immune cells.”[7]

However, a 2025 systematic review and meta-analysis of preclinical studies on neutrophils and pain found a more nuanced picture: while neutrophil depletion reduced inflammatory, joint, neuropathic, and visceral pain, it did not significantly alleviate postoperative pain specifically, suggesting the neutrophil-resolution mechanism may be model-dependent.[8]

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The Argument for Withholding NSAIDs Postoperatively

The argument is mechanistically compelling but clinically premature for several reasons:

1. No clinical trial has tested the hypothesis directly. The Cochrane review of pre-emptive and preventive NSAIDs (2021) found that no included study reported chronic pain as an outcome. The Carley et al. (2021) updated systematic review of pharmacotherapy for chronic post-surgical pain (CPSP) prevention found some statistically significant reductions in CPSP with NSAIDs, though of “unclear clinical relevance.” This is the opposite direction from what the resolvin hypothesis would predict.[9][10]

2. Current guidelines uniformly recommend NSAIDs as a core component of multimodal postoperative analgesia. The AAOS, ERAS, ASCRS, and APS/ASRA/ASA guidelines all support perioperative NSAID use with strong-to-moderate evidence for reducing pain and opioid consumption. A 2022 JAAOS review confirms beneficial effects for alleviating pain and reducing opioid consumption after orthopedic surgery.[11][12][13]

3. The Parisien study has important limitations. It was conducted in acute low back pain (a non-surgical model), the UK Biobank analysis was observational with significant confounding potential (patients taking NSAIDs likely had more severe pain at baseline), and the mouse models used inflammatory pain paradigms that may not directly translate to postoperative surgical pain.

4. The healing concern is largely unsubstantiated in humans. A 2021 review specifically addressing whether NSAIDs interfere with healing after surgery concluded that while animal data suggest some potentially harmful effects, “human data are limited and of poor quality” and “the limited human data available are not precluding the use of NSAIDs postoperatively, in particular, short-term for less than 2 weeks.”[14]

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The Nutriceutical Mitigation Strategy

Omega-3/EPA/DHA

The rationale for omega-3 supplementation to mitigate potential NSAID-induced resolvin deficiency is biologically well-grounded:

  • EPA and DHA are the direct biosynthetic precursors for resolvins (E-series from EPA, D-series from DHA), protectins, and maresins. Increasing EPA/DHA intake results in greater membrane incorporation at the expense of arachidonic acid, and EPA/DHA compete with arachidonic acid for COX and LOX enzymes, shifting the balance toward anti-inflammatory and pro-resolving mediator production.[15][16][17][18]
  • In a rat model of persistent inflammatory pain, fish oil supplementation increased resolvin levels by 1,654–3,347% compared to controls and significantly reduced TNF-α and pain behaviors.[19]
  • An RCT of preoperative omega-3 supplementation (10 days before surgery) demonstrated significantly lower postoperative pain scores (VAS 10.9 vs 25 mm, p=0.015) and lower CRP levels at 24 hours compared to controls.[20]
  • – A 2026 expert panel consensus supports the rationale for enriching nutrition with preformed SPMs or their stable precursors to overcome compromised endogenous biosynthesis, noting that “SPM biosynthesis is often impaired in disease states.”[21]

However, no study has directly tested whether concurrent omega-3 supplementation prevents the potential chronic pain-promoting effects of NSAIDs in a postoperative setting. The hypothesis that omega-3 supplementation could “rescue” resolvin production despite COX-2 inhibition is plausible because resolvins are also synthesized through lipoxygenase (LOX) pathways that are not inhibited by NSAIDs, and because increased substrate availability (more EPA/DHA in cell membranes) could partially compensate for reduced COX-2-mediated synthesis.[15][17][18]

Curcumin and Boswellia Supplementation

Resolution-Compatible Analgesic Adjuncts

A key distinction between NSAIDs and certain nutraceuticals lies in their differential effects on the lipid mediator network. Whereas NSAIDs broadly inhibit COX-2, blocking both pro-inflammatory prostaglandin and pro-resolving mediator production, curcumin and Boswellia serrata extracts appear to modulate the lipid mediator network in a manner that may preserve or even enhance pro-resolving pathways.

Curcumin: Curcumin regulates COX-2 predominantly at the transcriptional level rather than through direct enzymatic inhibition, which may allow residual COX-2 activity for SPM biosynthesis.[11] Curcuminoid analogues have been shown to trigger a lipid mediator class switch from pro-inflammatory leukotrienes to pro-resolving SPMs in activated human macrophages.[12] A modified curcumin compound (CMC2.24) increased resolvin D production and promoted M1-to-M2 macrophage phenotype switching — acting as a “switch” to promote the pro-resolving phenotype rather than simply suppressing inflammation.[13] Clinical evidence supports curcumin’s analgesic efficacy: an RCT in post-surgical third molar extraction patients found curcumin superior to mefenamic acid for acute postoperative pain.[14] A double-blind RCT after laparoscopic cholecystectomy showed significantly lower pain scores and dramatically reduced rescue analgesic use (7 vs 39 tablets) with curcumin supplementation.[15] A systematic review and meta-analysis of 59 studies (29 preclinical, 30 clinical) confirmed that curcumin and nano-curcumin are effective in reducing pain, with enhanced-bioavailability formulations showing the strongest effects.[16]

Boswellia serrata: Boswellic acids, particularly AKBA, have a unique mechanism that is especially relevant to the resolution paradigm. Rather than simply inhibiting 5-LOX, AKBA binds to an allosteric site on 5-LOX and shifts its regiospecificity from producing pro-inflammatory leukotrienes to generating 12/15-LOX products, while simultaneously activating 15-LOX-1 — the enzyme most directly responsible for SPM biosynthesis.[17][18] Targeted metabololipidomics in human macrophages and neutrophils confirmed that Boswellia extracts suppress pro-inflammatory 5-LOX products (including LTB4) while strongly elevating SPM levels, and this effect is synergistically enhanced when combined with exogenous EPA and DHA.[17][19] This represents a fundamentally different pharmacological profile from NSAIDs: Boswellia actively promotes the lipid mediator class switch rather than blocking it.

Curcumin-Boswellia combination: The combination of curcumin and Boswellia has demonstrated synergistic anti-inflammatory and analgesic effects. In adjuvant-induced arthritis, micellar curcumin combined with Boswellia produced superior anti-inflammatory activity compared to either agent alone.[20] An RCT of a curcumin-Boswellia co-delivery system showed significant reductions in pain, stiffness, and inflammatory markers (NLRP3, IL-1β) by day 14.[21] An RCT in exercise-induced acute musculoskeletal pain demonstrated that a turmeric-Boswellia formulation provided meaningful pain relief within approximately 3 hours, with 93% of participants achieving ≥50% pain relief.[22]

Importantly, a 2025 study screening 29 anti-inflammatory natural products identified several compounds — when combined with omega-3 PUFA supplementation — that synergistically enhanced SPM formation in human macrophages, with the combination confirmed to elevate SPM levels in vivo.[23] This provides a mechanistic rationale for combining omega-3 supplementation with resolution-compatible nutraceuticals.

Proposed role in the 4-D Protocol: Given their potential to provide analgesia while preserving or enhancing pro-resolving pathways, curcumin and Boswellia supplementation may serve as resolution-compatible analgesic adjuncts during the critical early postoperative period. This is particularly relevant during the first 48–72 hours when the neutrophil-driven inflammatory response and lipid mediator class switch are most active. These agents could be used to:

  • Provide supplemental analgesia that reduces the total NSAID dose required during the early postoperative period
  • Support the lipid mediator class switch through 15-LOX activation (Boswellia) and M2 macrophage polarization (curcumin), complementing the omega-3 substrate strategy
  • Synergize with the existing omega-3 supplementation to maximize SPM production through NSAID-independent pathways

Note on bioavailability: Standard curcumin has poor oral bioavailability. Enhanced-bioavailability formulations (e.g., BCM-95, nano-curcumin, micellar formulations, or sesame oil-based delivery systems) should be used for clinical effect.[24][16][20] For Boswellia, absorption of AKBA is increased more than twofold when taken with a high-fat meal.[25]

      References for Curcumin and Boswellia Supplementation

  1. Non-Steroidal Anti-Inflammatory Drugs After Abdominal Surgery: An Umbrella Review of Existing Evidence. Kowal MR, Nicholls A, Jayne DG, Chapman SJ. ANZ Journal of Surgery. 2026;96(3):537-548. doi:10.1111/ans.70468.
  2. Reprogramming Inflammation: Mechanisms and Therapeutic Targeting of Eicosanoids and Pro-Resolving Mediators. Kolawole OR, Kashfi K. European Journal of Pharmacology. 2025;1003:177924. doi:10.1016/j.ejphar.2025.177924.
  3. Eicosanoids and Inflammation: A Delicate Balance of Pro-Inflammatory and Pro-Resolving Mediators. Park WH. Biochemical Pharmacology. 2025;:117662. doi:10.1016/j.bcp.2025.117662.
  4. Human Inflammatory and Resolving Lipid Mediator Responses to Resistance Exercise and Ibuprofen Treatment. Markworth JF, Vella L, Lingard BS, et al. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology. 2013;305(11):R1281-96. doi:10.1152/ajpregu.00128.2013.
  5. Prostanoids and Resolution of Inflammation – Beyond the Lipid-Mediator Class Switch. Schmid T, Brüne B. Frontiers in Immunology. 2021;12:714042. doi:10.3389/fimmu.2021.714042.
  6. The Immune System in Tissue Environments Regaining Homeostasis after Injury: Is “Inflammation” Always Inflammation?. Kulkarni OP, Lichtnekert J, Anders HJ, Mulay SR. Mediators of Inflammation. 2016;2016:2856213. doi:10.1155/2016/2856213.
  7. Proresolving Lipid Mediators: Endogenous Modulators of Oxidative Stress. Leuti A, Maccarrone M, Chiurchiù V. Oxidative Medicine and Cellular Longevity. 2019;2019:8107265. doi:10.1155/2019/8107265.
  8. Clinical Practice Guidelines for Enhanced Recovery After Colon and Rectal Surgery From the American Society of Colon and Rectal Surgeons and the Society of American Gastrointestinal and Endoscopic Surgeons. Irani JL, Hedrick TL, Miller TE, et al. Diseases of the Colon and Rectum. 2023;66(1):15-40. doi:10.1097/DCR.0000000000002650.
  9. American Society for Enhanced Recovery and Perioperative Quality Initiative Joint Consensus Statement on Perioperative Opioid Minimization in Opioid-Naïve Patients. Wu CL, King AB, Geiger TM, et al. Anesthesia and Analgesia. 2019;129(2):567-577. doi:10.1213/ANE.0000000000004194.
  10. Immunometabolic role of long‐chain omega‐3 fatty acids in obesity‐induced inflammation. Flock MR, Rogers CJ, Prabhu KS, Kris-Etherton PM. Diabetes/Metabolism Research and Reviews. 2013;29(6):431-45. doi:10.1002/dmrr.2414.
  11. Regulation of COX and LOX by Curcumin. Rao CV. Advances in Experimental Medicine and Biology. 2007;595:213-26. doi:10.1007/978-0-387-46401-5_9.
  12. Rotational Constriction of Curcuminoids Impacts 5-Lipoxygenase and mPGES-1 Inhibition and Evokes a Lipid Mediator Class Switch in Macrophages. Rao Z, Caprioglio D, Gollowitzer A, et al. Biochemical Pharmacology. 2022;203:115202. doi:10.1016/j.bcp.2022.115202.
  13. A Novel Modified-Curcumin 2.24 Resolves Inflammation by Promoting M2 Macrophage Polarization. Deng J, Golub LM, Lee HM, et al. Scientific Reports. 2023;13(1):15513. doi:10.1038/s41598-023-42848-x.
  14. The efficacy of curcumin in managing acute inflammation pain on the post‐surgical removal of impacted third molars patients: A randomised controlled trial. Maulina T, Diana H, Cahyanto A, Amaliya A. Journal of Oral Rehabilitation. 2018;45(9):677-683. doi:10.1111/joor.12679.
  15. Efficacy of Turmeric (Curcumin) in Pain and Postoperative Fatigue After Laparoscopic Cholecystectomy: A Double-Blind, Randomized Placebo-Controlled Study. Agarwal KA, Tripathi CD, Agarwal BB, Saluja S. Surgical Endoscopy. 2011;25(12):3805-10. doi:10.1007/s00464-011-1793-z.
  16. The Analgesic Effect of Curcumin and Nano-Curcumin in Clinical and Preclinical Studies: A Systematic Review and Meta-Analysis. Hajimirzaei P, Eyni H, Razmgir M, et al. Naunyn-Schmiedeberg’s Archives of Pharmacology. 2025;398(1):393-416. doi:10.1007/s00210-024-03369-0.
  17. Frankincense Preparation Promotes Formation of Inflammation-Resolving Lipid Mediators by Manipulating Lipoxygenases in Human Innate Immune Cells. Nischang V, Witt FM, Börner F, et al. Frontiers in Pharmacology. 2023;14:1332628. doi:10.3389/fphar.2023.1332628.
  18. Structural and Mechanistic Insights Into 5-Lipoxygenase Inhibition by Natural Products. Gilbert NC, Gerstmeier J, Schexnaydre EE, et al. Nature Chemical Biology. 2020;16(7):783-790. doi:10.1038/s41589-020-0544-7.
  19. Boswellia Serrata Extract With Low 3o-Acetyl-11-Keto-Β-Boswellic Acid-Content Causes Efficient Lipid Mediator Class Switch. Nischang V, Bachmann V, Perkowski BJ, et al. Phytomedicine : International Journal of Phytotherapy and Phytopharmacology. 2025;148:157342. doi:10.1016/j.phymed.2025.157342.
  20. Micellar Solubilisation Enhances the Antiinflammatory Activities of Curcumin and Boswellic Acids in Rats With Adjuvant-Induced Arthritis. Khayyal MT, El-Hazek RM, El-Sabbagh WA, et al. Nutrition (Burbank, Los Angeles County, Calif.). 2018;54:189-196. doi:10.1016/j.nut.2018.03.055.
  21. A Full-Spectrum Boswellia Serrata Extract With Enhanced Bioavailability, and Its Co-Delivered System With Curcumin Alleviate Pain and Stiffness Associated With Moderate Spondylitis: A Randomized Double-Blind, Placebo-Controlled, 3-Arm Study. Mamatha K, Prabhakaran P, Syam Das S, Kanjoormana Aryan M, Thomas J. Frontiers in Pharmacology. 2025;16:1577429. doi:10.3389/fphar.2025.1577429.
  22. Fast Pain Relief in Exercise-Induced Acute Musculoskeletal Pain by Turmeric-Boswellia Formulation: A Randomized Placebo-Controlled Double-Blinded Multicentre Study. Rudrappa GH, Murthy M, Saklecha S, et al. Medicine. 2022;101(35):e30144. doi:10.1097/MD.0000000000030144.
  23. Uncovering Anti-Inflammatory Natural Products That Synergize With Supplemented Omega-3 PUFA for Eliciting Endogenous Inflammation Resolution Signals. Jordan PM, Peltner LK, Bachmann V, et al. Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie. 2025;188:118190. doi:10.1016/j.biopha.2025.118190.
  24. The Non-Surgical Management of Hip & Knee Osteoarthritis (OA) (2020). Matthew Bair MD MS, John Cody MD, Jess Edison MD, et al. Department of Veterans Affairs.
  25. Boswellic Acids and Their Role in Chronic Inflammatory Diseases. Ammon HP. Advances in Experimental Medicine and Biology. 2016;928:291-327. doi:10.1007/978-3-319-41334-1_13.
  26. Non-Drug Pain Relievers Active on Non-Opioid Pain Mechanisms. Marchesi N, Govoni S, Allegri M. Pain Practice : The Official Journal of World Institute of Pain. 2022;22(2):255-275. doi:10.1111/papr.13073.
  27. On the Interference of Boswellic Acids With 5-Lipoxygenase: Mechanistic Studies in Vitro and Pharmacological Relevance. Siemoneit U, Pergola C, Jazzar B, et al. European Journal of Pharmacology. 2009;606(1-3):246-54. doi:10.1016/j.ejphar.2009.01.044.
  28. Efficacy of Curcumin and Boswellia for Knee Osteoarthritis: Systematic Review and Meta-Analysis. Bannuru RR, Osani MC, Al-Eid F, Wang C. Seminars in Arthritis and Rheumatism. 2018;48(3):416-429. doi:10.1016/j.semarthrit.2018.03.001.

 

Clinical Bottom Line

The current evidence does not support withholding NSAIDs in the postoperative period based on the resolvin hypothesis alone. The acute analgesic and opioid-sparing benefits of NSAIDs are well-established and guideline-supported, and the CPSP risk from NSAID use remains unproven in surgical populations. However, the mechanistic evidence is strong enough to justify two practical strategies:

  1. Continue perioperative omega-3 supplementation (EPA/DHA) through the postoperative period, as already incorporated in the 4-D Protocol. This provides substrate for resolvin biosynthesis through LOX-dependent pathways even in the presence of COX inhibition, and has independent evidence for reducing postoperative pain and inflammation.[20][21]
  2. Limit NSAID duration to the period of clinically significant acute surgical pain (typically 7–14 days), consistent with existing safety recommendations, rather than extending use beyond the acute recovery period. This aligns with the temporal biology of inflammation resolution — the transition from pro-inflammatory to pro-resolving mediator production typically occurs within the first 1–2 weeks after tissue injury.[14][13]

Addendum _ The Timing Paradox

There is an internal tension in the timing of the NSAIDs use:

  1. NSAIDs may disrupt resolution pathways by inhibiting COX-2-dependent SPM biosynthesis
  2. The lipid mediator class switch occurs within the first 1–2 weeks
  3. Therefore, NSAIDs should be used during this same 1–2 week window and stopped afterward

The concern is that NSAIDs interfere with the resolution machinery that is being assembled during the first 1–2 weeks, then logically, this is the very period when NSAID use is most problematic from a resolution biology standpoint. The recommendation to limit NSAIDs to this window is primarily a pragmatic, guideline-concordant approach (acute pain is worst during this period, and current AAOS/ERAS/APS guidelines support short-term NSAID use) — but it does not fully resolve the mechanistic concern it raises.[5]

Why the approach is still defensible (though imperfect)

  • No clinical trial has demonstrated that withholding NSAIDs postoperatively reduces chronic postsurgical pain, so abandoning them during the period of greatest acute pain would sacrifice proven analgesic and opioid-sparing benefits based on preclinical and observational data alone.[5]
  • The strategy of concurrent omega-3 supplementation is designed to partially compensate by providing SPM precursors through LOX pathways that are not inhibited by NSAIDs.
  • Stopping NSAIDs after 7–14 days at least avoids continued COX-2 inhibition during the later resolution and tissue remodeling phases.

What would be more biologically consistent regarding the timing of NSAIDs use

One approach more aligned with the resolvin hypothesis would be to delay NSAID initiation for the first 48–72 hours (when the neutrophil-driven inflammatory response and lipid mediator class switch are most critical) and use non-anti-inflammatory analgesics (acetaminophen, gabapentinoids, regional anesthesia) during that early window — then introduce NSAIDs once the initial resolution program has been established. This is essentially what Sisignano and Geisslinger (2023) proposed.[4] However, this approach has not been validated in clinical trials and would represent a departure from current multimodal analgesia guidelines.

In summary, there is a logical inconsistency in the original strategy to recommend to use NSAIDs during the first 7–14 days that represents a pragmatic compromise between current guideline-supported practice and emerging mechanistic concerns, rather than a strategy that is fully aligned with the inflammation resolution biology. The recommendation prioritizes proven acute analgesic benefit while the omega-3 supplementation strategy is intended to mitigate the theoretical resolution-pathway disruption.

References for the the Addendum – The Timing Paradox

  1. Acute Inflammatory Response via Neutrophil Activation Protects Against the Development of Chronic Pain. Parisien M, Lima LV, Dagostino C, et al. Science Translational Medicine. 2022;14(644):eabj9954. doi:10.1126/scitranslmed.abj9954.
  2. Biological Roles of Resolvins and Related Substances in the Resolution of Pain. Lim JY, Park CK, Hwang SW. BioMed Research International. 2015;2015:830930. doi:10.1155/2015/830930.
  3. Human Inflammatory and Resolving Lipid Mediator Responses to Resistance Exercise and Ibuprofen Treatment. Markworth JF, Vella L, Lingard BS, et al. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology. 2013;305(11):R1281-96. doi:10.1152/ajpregu.00128.2013.
  4. Rethinking the Use of NSAIDs in Early Acute Pain. Sisignano M, Geisslinger G. Trends in Pharmacological Sciences. 2023;44(4):193-195. doi:10.1016/j.tips.2023.01.001.

 

References

  1. Role of Specialized Pro-Resolving Mediators in Neuropathic Pain. Leuti A, Fava M, Pellegrini N, Maccarrone M. Frontiers in Pharmacology. 2021;12:717993. doi:10.3389/fphar.2021.717993.
  2. Specialized Pro-Resolving Mediators as Resolution Pharmacology for the Control of Pain and Itch. Ji RR. Annual Review of Pharmacology and Toxicology. 2023;63:273-293. doi:10.1146/annurev-pharmtox-051921-084047.
  3. Biological Roles of Resolvins and Related Substances in the Resolution of Pain. Lim JY, Park CK, Hwang SW. BioMed Research International. 2015;2015:830930. doi:10.1155/2015/830930.
  4. A Cautionary Tale: Non-Steroidal Anti-Inflammatory Drug Use and Localized Provoked Vulvodynia. Chrysilla E, Fischer S, Jang JM, et al. The Journal of Pain. 2025;:105559. doi:10.1016/j.jpain.2025.105559.
  5. The Mechanisms of Specialized Pro-Resolving Mediators in Pain Relief: Neuro-Immune and Neuroglial Regulations. Chen Y, Wu X, Li J, et al. Frontiers in Immunology. 2025;16:1634724. doi:10.3389/fimmu.2025.1634724.
  6. Acute Inflammatory Response via Neutrophil Activation Protects Against the Development of Chronic Pain. Parisien M, Lima LV, Dagostino C, et al. Science Translational Medicine. 2022;14(644):eabj9954. doi:10.1126/scitranslmed.abj9954.
  7. Immuno-Inflammatory Mechanisms in the Chronification of Pain. Moncada MAA, Tamayo MAN, Encinas MAN, Leoni MLG, Varrassi G. Pain and Therapy. 2026;15(2):443-464. doi:10.1007/s40122-026-00818-x.
  8. The Role of Neutrophils in Pain: Systematic Review and Meta-Analysis of Animal Studies. Huerta MÁ, Molina-Álvarez M, García MM, et al. Pain. 2025;166(6):1230-1249. doi:10.1097/j.pain.0000000000003450.
  9. Pre-Emptive and Preventive NSAIDs for Postoperative Pain in Adults Undergoing All Types of Surgery. Doleman B, Leonardi-Bee J, Heinink TP, et al. The Cochrane Database of Systematic Reviews. 2021;6:CD012978. doi:10.1002/14651858.CD012978.pub2.
  10. Pharmacotherapy for the Prevention of Chronic Pain After Surgery in Adults: An Updated Systematic Review and Meta-Analysis. Carley ME, Chaparro LE, Choinière M, et al. Anesthesiology. 2021;135(2):304-325. doi:10.1097/ALN.0000000000003837.
  11. Non-Steroidal Anti-Inflammatory Drugs After Abdominal Surgery: An Umbrella Review of Existing Evidence. Kowal MR, Nicholls A, Jayne DG, Chapman SJ. ANZ Journal of Surgery. 2026;96(3):537-548. doi:10.1111/ans.70468.
  12. Clinical Practice Guidelines for Enhanced Recovery After Colon and Rectal Surgery From the American Society of Colon and Rectal Surgeons and the Society of American Gastrointestinal and Endoscopic Surgeons. Irani JL, Hedrick TL, Miller TE, et al. Diseases of the Colon and Rectum. 2023;66(1):15-40. doi:10.1097/DCR.0000000000002650.
  13. Safety and Efficacy of Postoperative Nonsteroidal Anti-Inflammatory Drugs in Sports Medicine. Trasolini NA, Yanke AB, Verma NN, Cole BJ. The Journal of the American Academy of Orthopaedic Surgeons. 2022;30(12):535-542. doi:10.5435/JAAOS-D-21-01228.
  14. Do NSAIDs Really Interfere With Healing After Surgery?. Schug SA. Journal of Clinical Medicine. 2021;10(11):2359. doi:10.3390/jcm10112359.
  15. Omega-3 Fatty Acids and Inflammatory Processes: From Molecules to Man. Calder PC. Biochemical Society Transactions. 2017;45(5):1105-1115. doi:10.1042/BST20160474.
  16. N-3 PUFA and Inflammation: From Membrane to Nucleus and From Bench to Bedside. Calder PC. The Proceedings of the Nutrition Society. 2020;:1-13. doi:10.1017/S0029665120007077.
  17. Polyunsaturated Fatty Acids, Specialized Pro-Resolving Mediators, and Targeting Inflammation Resolution in the Age of Precision Nutrition. Al-Shaer AE, Buddenbaum N, Shaikh SR. Biochimica Et Biophysica Acta. Molecular and Cell Biology of Lipids. 2021;1866(7):158936. doi:10.1016/j.bbalip.2021.158936.
  18. Immunometabolic role of long‐chain omega‐3 fatty acids in obesity‐induced inflammation. Flock MR, Rogers CJ, Prabhu KS, Kris-Etherton PM. Diabetes/Metabolism Research and Reviews. 2013;29(6):431-45. doi:10.1002/dmrr.2414.
  19. Fish Oil Attenuates Persistent Inflammatory Pain in Rats Through Modulation of TNF-α and Resolvins. Lobo BW, Lima CK, Teixeira MS, et al. Life Sciences. 2016;152:30-7. doi:10.1016/j.lfs.2016.03.034.
  20. Preoperative Administration of Omega-3 Fatty Acids on Postoperative Pain and Acute-Phase Reactants in Patients Undergoing Roux-en-Y Gastric Bypass: A Randomized Clinical Trial. Ruiz-Tovar J, Blanca M, Garcia A, et al. Clinical Nutrition (Edinburgh, Scotland). 2019;38(4):1588-1593. doi:10.1016/j.clnu.2018.07.026.
  21. Integrating Downstream Mediators of Omega-3 Fatty Acids Into Enteral Nutrition for Improved Patient Care: An Expert Panel Consensus. Martindale R, Mundi MS, Waitzberg D, et al. Clinical Nutrition (Edinburgh, Scotland). 2026;56:106529. doi:10.1016/j.clnu.2025.11.014.

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