Treating Skeletal Pain: Limitations of Conventional Anti-inflammatory Drugs, and Anti-neurotrophic Factor as a Possible Alternative

Cory J. Xian; Xin-Fu Zhou


Nat Clin Pract Rheumatol. 2009;5(2):92-98. 

In This Article

NSAIDS as Post-traumatic or POST-operative Analgesia

Conventional, nonselective NSAIDs, which inhibit COX-mediated production of prostaglandins, are widely used to treat pain and reduce inflammation in patients with chronic inflammatory or autoimmune disorders.[2] The management of acute post-operative pain, however, remains suboptimal, despite the increasing use of clinical acute pain services; furthermore, there are disparities in opinion, both between clinicians and in the clinical practice guidelines, regarding the use of the newer modalities in this setting.[3,4,5] Conventional NSAIDS have become an important component of both post-traumatic and post-operative analgesia, and are used frequently in the treatment of acute athletic injury.[6,7,8,9] The proven efficacy of these agents in the management of post-operative pain, together with their opioid-sparing role in multimodal analgesia, have led to significantly reduced levels of opioid-related side effects.[10]

The therapeutic effects of nonselective NSAIDs are mediated by inhibition of injury-induced or inflammation-induced COX-2 expression.[11] Clinical studies have shown that, as a result of inhibition of the physiological enzyme, COX-1, NSAIDs can be associated with an increased risk of fracture in patients with rheumatic disease.[12] In addition, their use has been called into question following concerns about the associated increased risks of gastrointestinal and cardiovascular adverse events, increased bleeding, impaired wound healing, and increased bone nonunion rates.[3,13,14] Furthermore, evidence from experimental research conducted over the past two decades suggests that NSAIDs have an inhibitory effect on fracture repair.[11]

The newer NSAIDS, which specifically inhibit COX-2, are as effective as classical NSAIDs and are associated with a lower risk of gastrointestinal adverse events, as well as a lack of inhibitory effects on platelet function and, therefore, a reduced risk of blood loss.[1,3,9] Large-scale studies, however, have shown that these newer agents can increase the risk of adverse cardiovascular events.[1,15,16,17]

Effects of COX-2-specific Inhibitors on Bone Fracture Healing

Bone healing is a complex process that involves the coordinated actions of various cell types. The initial hematoma formation and inflammatory response result in the release of cytokines and growth factors that are important in regulating subsequent healing events, such as infiltration of progenitor cells. In the reparative and remodeling phases, bone formation and remodeling involve angiogenesis and the formation and functions of bone-forming cells (i.e. osteoblasts) and bone-resorptive cells (i.e. osteoclasts). It is now clear that all these events are regulated by prostaglandins, the products of COX enzymes.[11] When COX-2 is induced during the inflammatory response, increased prostaglandin expression upregulates various inflammation mediators and regulates the formation and activities of osteoblasts and osteoclasts.[18]

Given the central role of prostaglandins in the bone healing process and the widespread use of NSAIDs in the management of post-injury and post-surgery orthopedic pain, the possible adverse effects of these agents in bone healing, particularly the COX-2-specific inhibitors, are concerning. Blockade of COX-2 function has been associated with variable outcomes in experimental models of bone, ligament and tendon repair.[19] One clinical study showed that short-term use of the COX-2 inhibitor celecoxib had no effect on rates of nonunion following spinal fusion surgery;[20] however, another clinical study indicated that longer-term COX-2 inhibition could increase the risk of fracture and delay healing.[11]

Experimental studies suggest that COX-2 inhibitors can impair tissue repair and recovery of mechanical strength following acute skeletal injury, which could have important clinical implications for the rates of ongoing morbidity and future susceptibility to injury.[21] Accumulating evidence suggests that COX-2 activity in the early stages of bone healing is critical for efficient bone repair. Indeed, fracture healing was shown to be impaired in mice with mutated COX-2.[22] Furthermore, administration of celecoxib during the early stages of fracture repair in rats (but not before or 14 days after fracture) significantly reduced the mechanical strength of the fracture callus and often caused bone nonunion.[23] Similarly, early post-operative administration of COX-2 inhibitors in rodent bone fracture models resulted in increased fibrous tissue at fracture sites, limited blood flow across the fracture, delayed remodeling of calcified cartilage, and reduced bone formation in the fracture callus, or delayed allograft healing and incorporation.[24,25,26,27]

Interestingly, it has been shown that COX-2-specific drugs inhibit fracture healing to a greater degree than classical NSAIDS.[27] Moreover, the magnitude of this effect seems to be related to treatment duration, as the inhibitory effect was reversible after discontinuation of short-term treatment.[27] Up to 10% of bone fractures can result in delayed union or nonunion;[28] however, the extent of the contribution of COX-2 inhibitors to this rate of delayed union or nonunion remains to be investigated.

Guidelines on the use of NSAIDS in Fractures and Orthopedic Surgery

As NSAIDS are known to inhibit bone healing,[29] and opiates cause cognitive dysfunction and respiratory depression, the available treatment options for pain related to bone fractures or surgery remain limited. Based on animal and clinical studies, practical management guidelines have been generated to assist orthopedic surgeons and sports physicians with regard to the use of NSAIDS for analgesia. Clinicians are advised to carefully evaluate individual patient risk factors and the pharmacokinetics of individual NSAIDS when assessing the risks and benefits of discontinuing NSAID therapy in the perioperative setting.[14] NSAIDS can be used appropriately in the management of acute ligament sprains, muscle strains, tendinitis, and eccentric muscle injury, with the length of treatment being kept as short as possible. However, these agents are not recommended, or should be used with caution or only for a short duration,[6,27] in the treatment of fractures and stress fractures, which are associated with higher risks of nonunion or delayed union due to osseous, vascular, or patient-related factors,[25] or in the treatment of chronic muscle injury.[8]


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