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

Cory J. Xian; Xin-Fu Zhou

Disclosures

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

In This Article

Anti-NGF Therapy for Injury-INDUCED or Surgery-induced Pain

Despite the development of new technologies to aid post-operative pain control,[4] safer and more effective modalities for pain management after skeletal trauma or surgery are still needed. As most of the CGRP-positive sensory nerve fibers innervating the bone express the NGF receptors TrkA and p75,[57,58] blocking the sensitization and activation of these fibers and nociceptors would represent an attractive approach to relieving musculoskeletal pain induced by trauma, injury or surgery. Increasing attention, therefore, has focused on evaluating the potential efficacy of anti-NGF therapy in pain management.

In a mouse model of femur fracture, treatment with anti-NGF antibody on the first day after fracture resulted in a 50% reduction in pain-related behavior and did not seem to interfere with bone healing, as assessed by mechanical testing and histomorphometric analysis.[40] A similar study showed that administration of anti-NGF antibody reduced fracture-induced pain-related behaviors by over 50%, a level of reduction also achieved with a dose of 10 mg/kg of morphine.[29] Moreover, bone healing was not impaired, as measured by callus formation, fracture site bridging or mechanical bone strength. This study also indicated that NGF is likely to be involved in the maintenance, but not the acute generation, of fracture pain. As CGRP-positive and TrkA-positive fibers constitute the majority of sensory fibers innervating the bone, the antihyperalgesic action of an anti-NGF antibody could be effective in attenuating pain resulting from bone fracture or bone surgery. However, although anti-NGF treatment reduced nociceptive sensitization and preserved some bone mass in a rat model of tibial fracture, it did not decrease hindpaw edema, warmth or cytokine production, suggesting that anti-NGF treatment reduced some, but not all, signs characteristic of the complex regional pain syndrome.[45] This finding might have been due to the complexities involved in the pathogenesis of injury-induced skeletal pain and NGF signaling.[45]

Furthermore, anti-NGF therapy seems to be efficacious in reducing pain associated with spinal cord injury or bone cancer. Administration of anti-NGF antibodies attenuated mechanical hyperalgesia following spinal cord injury in rats, suggesting that anti-NGF therapy is a potential analgesic treatment for central pain.[59] In a mouse prostate model of bone metastasis, where significant bone formation and bone destruction occur simultaneously, NGF-blocking antibody produced a significant reduction in both the early and late stages of bone cancer pain-related behaviors.[57] Interestingly, this therapy did not influence tumor-induced bone remodeling, formation of osteoblasts and osteoclasts, tumor growth, or markers of sensory or sympathetic innervation in the skin or bone. In a similar mouse model of bone cancer, administration of an anti-NGF antibody was found to produce a profound reduction in both ongoing and movement-evoked pain-related behaviors.[58]

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