Evaluation of pain-related behavior, bone destruction and effectiveness of fentanyl, sufentanil, and morphine in a murine model of cancer pain

Abstract

The present study was conducted to evaluate the pain development and bone destruction during bone cancer growth in a murine model of bone cancer pain and to evaluate the analgesic efficacy of fentanyl, sufentanil, and morphine in this model. C3H/HeNCrl mice were inoculated into the intramedullary space of the femur with osteolytic NCTC 2472 fibrosarcoma cells, and followed during a 3-week period to assess pain behaviors (spontaneous lifting and limb-use during forced ambulation on rotarod) and bone destruction (parameters indicative of bone lesions determined by μCT-scans of the tumor-bearing bones) during bone cancer growth. The results showed that in this murine model of cancer-induced bone pain, behavioural manifestations of pain emerge in parallel with the progression of bone destruction. The subcutaneous administration of fentanyl (0.025–0.64 mg/kg), sufentanil (0.005–0.04 mg/kg), and morphine (2.5–40 mg/kg) on the test days 15 and 22 post-inoculation reduced pain-related behaviors in a dose dependent manner. A complete relief from pain-related behaviors was achieved with the following doses: ≥ 0.16 mg/kg fentanyl, 0.02 mg/kg sufentanil, and 20 mg/kg morphine. In conclusion, the results showed a clear link between tumor growth-induced bone destruction and behavioral pain manifestations, the latter was effectively controlled by the opioids fentanyl, sufentanil, and morphine.

Introduction

Cancer pain resulting from bone metastatic infiltration and destruction remains difficult to treat and contributes significantly to increased morbidity and reduced quality of life of patients (Thurlimann and de Stoutz, 1996). The resulting symptoms of bone cancer-related pain consist generally of localized ongoing spontaneous pain, and more commonly, occur as a result of movement or weight-bearing of the affected limb (Mercadante, 1997). The pathogenic mechanism underlying bone cancer pain is not completely understood, but tumor metastasis often stimulates osteoclast activity resulting in bone resorption, which may result in microfractures due to weakened skeletal strength (Kanis et al., 1991, Mantyh et al., 2002). Such fractures, together with nerve root compression due to vertebral collapse and the release of soluble factors that may sensitize primary nociceptive afferents, are significantly contributing factors to pain associated with bone metastases (Portenoy and Lesage, 1999).

At present, the management of early bone pain involves the use of simple analgesics such as acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs), and weak opioids, but increasing doses are usually required as the cancer progresses. As the disease becomes more advanced and problematic, the management requires strong opioids and adjuvant drugs (Cherney, 2000), such as antidepressants and anticonvulsants, benzodiazepines, corticosteroids, and neuroleptic drugs (for review, see Mantyh et al., 2002). In cancer patients who do not receive adequate pain relief with oral or transdermal medications, options include nerve blocks, chemotherapy, hormone manipulation, radiation, and surgery. However, biphosphonates and systemic radioisotopes can be very helpful in the long term management of bone metastatic cancer pain. Although ongoing pain may respond relatively well to a variety of available therapies, breakthrough or movement-evoked pain can be problematic and remains particularly difficult to control even with high doses of opioids (Mercadante, 1997, Portenoy, 1999, Portenoy et al., 1999). The incomplete understanding of the mechanisms that drive bone cancer pain may be attributed in part to the lack of specific animal models to explore novel pharmacological treatment strategies based on advances in the knowledge of pain conditions other than those associated with cancer, such as neuropathic or inflammatory pain (Mantyh, 2002).

The development in recent years of a murine models of osteosarcoma able to produce pain behavior (Schwei et al., 1999) leads to a rapid knowledge progression of the pathophysiology of bone cancer pain compared to established models of neuropathic and inflammatory pain (Honore et al., 2000a, Luger et al., 2002). In this model, implantation of mouse osteosarcoma tumor cells into the intramedullary space of the femur results in significant bone destruction due to tumor growth and is associated with pain-related behaviors (Honore et al., 2000a, Schwei et al., 1999, Vermeirsch et al., 2004) similar to that observed in human patients with metastatic bone cancer pain. Moreover, this model may also be used to evaluate novel pharmacological approaches to treatment.

In this study we evaluated the pain-related behaviors in relation to bone destruction progression during bone tumor growth in a murine model of bone cancer pain. We therefore present here a quantitative evaluation over-time of pain behavior and bone destruction and tried to establish whether there was a link between tumor growth-induced bone destruction and behavioral pain manifestations. We thereafter evaluated whether the bone cancer-related pain behavior was effectively controlled by opioids such us: fentanyl, sufentanil, and morphine.