Orthopedic surgery and bone fracture pain are both significantly attenuated by sustained blockade of nerve growth factor

Abstract

The number of patients suffering from postoperative pain due to orthopedic surgery and bone fracture is projected to dramatically increase because the human life span, weight, and involvement in high-activity sports continue to rise worldwide. Joint replacement or bone fracture frequently results in skeletal pain that needs to be adequately controlled for the patient to fully participate in needed physical rehabilitation. Currently, the 2 major therapies used to control skeletal pain are nonsteroidal anti-inflammatory drugs and opiates, both of which have significant unwanted side effects. To assess the efficacy of novel therapies, mouse models of orthopedic and fracture pain were developed and evaluated here. These models, orthopedic surgery pain and bone fracture pain, resulted in skeletal pain-related behaviors that lasted 3 weeks and 8 to 10 weeks, respectively. These skeletal pain behaviors included spontaneous and palpation-induced nocifensive behaviors, dynamic weight bearing, limb use, and voluntary mechanical loading of the injured hind limb. Administration of anti-nerve growth factor before orthopedic surgery or after bone fracture attenuated skeletal pain behaviors by 40% to 70% depending on the end point being assessed. These data suggest that nerve growth factor is involved in driving pain due to orthopedic surgery or bone fracture. These animal models may be useful in developing an understanding of the mechanisms that drive postoperative orthopedic and bone fracture pain and the development of novel therapies to treat these skeletal pains.

Figure 1

Representative radiographs of a healing femur in a young adult (3 months old at the time of fracture) C3H mouse following a 3-point closed fracture procedure. A stainless steel pin is implanted into the intramedullary space of the femur 4 weeks before the mid-diaphyseal fracture. Callus formation is radiographically apparent by day 10. Cortical union becomes apparent at week 7, and by week 11, palpation-induced pain behaviors return to baseline. Notice the intact patella throughout each time point, a key inclusion criterion.

Figure 2

Anti-NGF treatment reduces the spontaneous nocifensive behaviors after orthopedic surgery and bone fracture in mice. (A) Time course for orthopedic surgery pain followed by fracture pain. Note that anti-NGF significantly reduces orthopedic surgery–induced skeletal pain by approximately 50% (B) and is effective at reducing moderate-to-severe pain as it reduces fracture pain by approximately 55% (C). Data are presented as mean ± SEM (*P < 0.05, t test, vs vehicle-treated mice figures [B and C]).

Figure 3

Palpation as an indicator of bone fracture healing in pain-related behaviors. (A) On week 3 after fracture, palpation-induced nocifensive behaviors were significantly higher and remained elevated through week 9 when compared with spontaneous behaviors. (B) The number of rears after palpation was significantly lower on weeks 3, 7, and 9 when compared to spontaneous behaviors. By week 11, all spontaneous and postpalpation pain behavioral responses become equalized (*P < 0.05 vs spontaneous behavior). Note that palpation-induced pain behaviors continue after cortical union has occurred.

Figure 4

Influence of patellar displacement on nocifensive behaviors after orthopedic surgery. While the surgical procedure to implant the stabilizing pin causes a short-lived orthopedic pain, if displacement of the patella occurs (from A to B and from C to D), surgical pain is significantly more severe and longer lasting ([E]: with patella displacement, as seen by the black squares) when compared to mice with intact patella position ([E]: no patella displacement, white triangles). Note that orthopedic surgical pain and radiographs need to be assessed in models of fracture pain to be able to differentiate the pain arising from surgical procedures, a displaced patella or bone fracture. Patella displacement most often occurs in the first 7 days after surgery when muscle tissues have not yet healed (*P < 0.05 vs naive, **P < 0.05 vs no patella displacement).

Figure 5

Group-housing mice aggravated fracture. Representative radiographs display examples of a femur with an initial simple fracture ([A] day 0) that became nonsimple ([A] day 7) when animals were group housed and an initial simple fracture ([B] day 0) that remained a simple fracture ([B] day 7) when animals were housed singly. Note that after fracture production, mice need to be housed singly, as 73% of simple fractures become nonsimple fractures within 7 days when animals are group housed (3 mice per cage) vs <10% of mice when singly housed (C). The fractures shown in panel (A) (day 7) meet the exclusion criteria for this study (*P < 0.05).