No abstract

No abstract

Bone cancer pain is common among cancer patients and can have a devastating effect on their quality of life. A chief problem in designing new therapies for bone cancer pain is that it is unclear what mechanisms drive this distinct pain condition. Here we show that osteoprotegerin, a secreted 'decoy' receptor that inhibits osteoclast activity, also blocks behaviors indicative of pain in mice with bone cancer. A substantial part of the actions of osteoprotegerin seems to result from inhibition of tumor-induced bone destruction that in turn inhibits the neurochemical changes in the spinal cord that are thought to be involved in the generation and maintenance of cancer pain. These results demonstrate that excessive tumor-induced bone destruction is involved in the generation of bone cancer pain and that osteoprotegerin may provide an effective treatment for this common human condition.

Pain is the cancer related event that is most disruptive to the cancer patient's quality of life. Although bone cancer pain is one of the most severe and common of the chronic pains that accompany breast, prostate and lung cancers, relatively little is known about the mechanisms that generate and maintain this pain. Recently, we developed a mouse model of bone cancer pain and 16 days following tumor implantation into the intramedullary space of the femur, significant bone destruction and bone cancer pain-related behaviors were observed. A critical question is how closely this model mirrors human bone cancer pain. In the present study we show that, as in humans, pain-related behaviors are diminished by systemic morphine administration in a dose dependent fashion that is naloxone-reversible. Humans suffering from bone cancer pain generally require significantly higher doses of morphine as compared to individuals with inflammatory pain and in the mouse model, the doses of morphine required to block bone cancer pain-related behaviors were ten times that required to block peak inflammatory pain behaviors of comparable magnitude induced by hindpaw injection of complete Freund's adjuvant (CFA) (1-3mg/kg). As these animals were treated acutely, there was not time for morphine tolerance to develop and the rightward shift in analgesic efficacy observed in bone cancer pain vs. inflammatory pain suggests a fundamental difference in the underlying mechanisms that generate bone cancer vs. inflammatory pain. These results indicate that this model may be useful in defining drug therapies that are targeted for complex bone cancer pain syndromes.

No abstract

Pain is the most common presenting symptom in patients with bone cancer and bone cancer pain can be both debilitating and difficult to control fully. To begin to understand the mechanisms involved in the generation and maintenance of bone cancer pain, we implanted 3 well-described murine tumor cell lines, 2472 sarcoma, B16 melanoma and C26 colon adenocarcinoma into the femur of immunocompromised C3H-SCID mice. Although each of the tumor cell lines proliferated and completely filled the intramedullary space of the femur within 3 weeks, the location and extent of bone destruction, the type and severity of the pain behaviors and the neurochemical reorganization of the spinal cord was unique to each tumor cell line injected. These data suggest that bone cancer pain is not caused by a single factor such as increased pressure induced by intramedullary tumor growth, but rather that multiple factors are involved in generating and maintaining bone cancer pain. It is estimated by the World Health Organization (WHO) that over 10 million new cases of cancer will be reported and 6.2 million people worldwide will die each year of cancer. 1 Pain is the first symptom of cancer in 20 -50% of all cancer patients and 75-90% of advanced or terminal cancer patients must cope with chronic pain syndromes related to failed treatment or tumor progression. [2][3][4] Partly because of treatment-associated side effects, it is suspected that many cancer patients have inadequate pain management and in fact, it has been reported that 45-80% of all cancer patients have inadequate and undermanaged pain control. [5][6][7] Of all the different types of cancer pain, pain that is due to bony metastasis is one of the most difficult to manage. In light of this data, it is difficult to overstate the negative impact that cancer pain has on the quality of life of cancer patients.The most common presenting symptom of bone metastases is bone pain. 8,9 Over months to years, as the tumor grows and the bone is remodeled, the pain progressively becomes more severe. This excessive bone remodeling is first associated with an ongoing pain that is referred to the tumor-bearing area and is described as dull in character, constant in presentation and with time, increases in intensity. 3,10,11 As bone remodeling progresses, breakthrough pain, which is also known as episodic or movement-evoked pain, can occur spontaneously or more commonly during weight-bearing or movement of the affected bone and is particularly difficult to control with standard therapies. 2,9,[11][12][13][14][15] What remains unclear is why bone cancer pain can be so severe and recalcitrant to current modes of therapy. What is clear is that bone cancer pain is highly heterogeneous so that although there is a general correlation between the extent of bone remodeling and the extent of pain, one frequently finds patients with significant bone remodeling but little pain and patients with scant bone remodeling but with significant pain. 15 These clinical findings suggest that not all bone cancer pains ...

No abstract

No abstract