Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) and Their Effect on Musculoskeletal Soft-Tissue Healing

Abstract

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are being increasingly employed as a part of multimodal non-opioid strategies to treat postoperative pain. In the present study, we sought to review the effects of short-term NSAID use on musculoskeletal softtissue healing. Methods: We performed a scoping review of all studies that included the use of NSAIDs and their effect on healing of soft tissues, which for the purpose of this review refers to non-osseous musculoskeletal tissue such as ligament, tendon, labrum, and meniscus. The inclusion criteria encompassed all studies (human, animal, and in vitro) that evaluated the effect of NSAIDs on soft-tissue healing. Subgroup analyses, wherever applicable, were conducted on the basis of the type of NSAID (cyclooxygenase [COX]-specific or nonspecific) and the type of study (human, animal, or in vitro). Relevant metadata from each study were abstracted, and descriptive statistics were used to summarize the results. Results: A total of 44 studies met the inclusion criteria, including 3 human studies, 33 animal studies, and 8 in vitro studies. These studies included 4 different NSAIDs in the human subgroup, 16 different NSAIDs in the animal subgroup, and 7 different NSAIDs in the in vitro subgroup. The majority of reported studies (including 1 of 2 human studies, 10 of 14 animal studies, and 3 of 3 in vitro studies) demonstrated that COX-2-selective inhibitors had negative impact on soft-tissue healing. In contrast, the majority of human and animal studies (2 of 2 and 19 of 30, respectively) demonstrated that nonselective COX inhibitors had no negative effect on the healing of labrum, tendons, and ligaments. The majority of in vitro studies demonstrated that NSAIDs have a harmful effect on biological processes involved in tendon-healing and regeneration (tenocyte proliferation, collagen and glycosaminoglycan synthesis). Conclusions: Current limited evidence demonstrates that selective COX-2 inhibitors can negatively affect healing of musculoskeletal soft tissue after surgical repair. In contrast, the majority of studies demonstrate that nonselective COX inhibitors have no negative effect on musculoskeletal soft-tissue healing. Additional highquality human clinical trials are necessary to provide more definitive conclusions.

Graft healing after anterior cruciate ligament reconstruction (ACLR)

“…A recent systematic review indeed demonstrated that the selective COX-2 inhibitors could negatively affect the healing process, though some other studies demonstrated no negative effect. 56 That's why cautions is needed for surgeons when administering NSAIDs/COX-2 inhibitors after ACL reconstruction, probably good to keep the duration and dosage of NSAIDs as short and low as possible to while avoiding unpleasant effect on the graft. 57 …”

Reparative and Maladaptive Inflammation in Tendon Healing

“…NSAIDs inhibit prostaglandin synthesis by inactivation of cyclooxygenase-I (COX1) or COX2 enzymes. Prostaglandins produced by COX1 are involved in platelet aggregation, gastric mucosal integrity, and renal blood flow, while COX2 derived prostaglandins contribute to pain and inflammation ( FitzGerald, 2003 ; Ghosh et al, 2019 ). Therefore, the result of non-specific COX inhibition is decreased inflammation and analgesia but with non-desirable secondary effects.…”

“…In rat models of Achilles tendon tear, post-operative treatment for 14 or 18 days with both indomethacin (COX1 and COX2 inhibition) and celecoxib (COX2 inhibition) improved tendon tensile strength ( Forslund et al, 2003 ). However, in a systematic review of randomized control trials in humans, selective COX2 inhibition was consistently associated with impaired tendon, labrum, and ligamentous healing, suggesting a requirement for inflammation in reparative healing ( Ghosh et al, 2019 ). While the role of COX2 related prostaglandins in tendon repair is unclear, timing appears to be a critical factor.…”

Effect of vacuum sealing drainage on healing time and inflammation‐related indicators in patients with soft tissue wounds

“…Soft‐tissue wound healing follows the pattern of the four phases of haemostasis, inflammation, proliferation, and maturation/matrix remodelling 10 . There are many interfering factors, which will impede the progress of wound healing 11 . For the treatment of soft‐tissue injury, the wound is usually cleaned thoroughly and then covered with gauze directly.…”