Novartis' COX-2 inhibitor, Lumiracoxib reduces cancer pain

Approximately 26 million patients are affected with neuropathic pain. This condition is associated with a variety of etiologies including trauma, infection, diabetes, immune deficiencies, ischemic disorders, and toxic neuropathies and precipitates other serious pathologies such as depression. The lifestyle of patients can be severely impeded, a problem compounded by the lack of efficacy and frequent incidence of side effects associated with current treatment options (click here for an insight neuropathic pain or here for an evaluation of the neuropathic pain markets).

Like neuropathic pain, cancer pain is also an unmet market. The condition can be associated with the cancer itself or with conventional cancer treatments such as chemotherapy or surgery, and it affects over 3 million people in the US alone. Currently, there is a vast range of drugs used in the treatment of cancer pain including opioids, NSAIDs, antidepressants and anticonvulsants, yet most physicians consider morphine to be the current gold standard (for a full analysis of cancer pain click here). Cancer pain when associated with metastatic progression to the bone is chronic, consisting generally of ongoing spontaneous pain, and breakthrough pain occurring as a result of movement or weight bearing on the affected limb. Whilst ongoing pain may respond relatively well to opiates, breakthrough pain remains particularly difficult to control even with high doses (note that investigation of the treatment of breakthrough pain is one of the focuses of the cancer pain report mentioned above).

It is known that bone cancer is associated with pronounced osteoclastic bone resorption, which may result in microfractures due to the weakened skeletal strength. Such fractures, together with nerve root compression due to vertebral collapse, are a significant contributing factor to pain associated with bone metastases. The lack of animal models means that underlying causes of bone cancer pain in the absence of such mechanical factors are poorly understood, although they are generally assumed to involve the release of algesic chemicals from the tumor itself or associated inflammatory cells.

Recently, models have been described involving the injection of tumor cells into the femur or tibia. This results in significant bone destruction due to tumor growth and associated behavioral allodynia and hyperalgesia, as well spontaneous pain-related behaviors. The use of these models is rapidly advancing our knowledge of the pathophysiology of bone cancer pain and it is now clear that this type of pain differs behaviorally and neurochemically from neuropathic and inflammatory pain.

Whilst opiates remain the mainstay of bone cancer pain treatment, non-steroidal anti-inflammatory drugs (NSAIDs) are frequently used as conjunctive therapies, with beneficial effects presumed to result from a reduction in prostaglandin-mediated edema leading to increased intraosseous pressure, as well as a direct analgesic activity. COX-2 inhibitors represent a novel class of compounds that have been shown to have potent anti-inflammatory and anti-hyperalgesic activity in animal models of arthritis and inflammatory pain. Considerable recent interest has focussed on the role of the COX-2 isoenzyme in cancer. Numerous studies have shown that cancer cells and tumor-associated macrophages express COX-2, leading to high levels of prostaglandin production. As described in the “Focus on Oncology” and “Focus on Matabolic Disorders” sections of this edition of TherapeuticAdvances NSAIDs may prevent the initiation and progression of tumor development as well as cachectic muscle wasting later on in the disease process. In their recent Pain Journal article, Alyson Fox and colleagues from the Novartis Institute of Medical Sciences and Novartis Pharmaceuticals investigate the role of COX-2 in the chronic pain associated with malignancies.

Lumiracoxib is a novel selective inhibitor of COX-2 developed by Novartis. Fox et al demonstrated that mechanical hyperalgesia associated with intra-tibial injection of cancer cells was attenuated by the repeated administration of lumiracoxib. A similar reduction in mechanical hyperalgesia, as determined by measuring the weight bearing threshold, was observed following administration of valdecoxib. The reduction in weight bearing in this model is reminiscent of hyperalgesia in cancer patients and its reversal by lumaricoxib and valdecoxib could therefore be predictive of clinical efficacy.

In addition to producing mechanical hyperalgesia this model was also associated with mechanical allodynia and once again lumiracoxib was analgesic with respect to this measure of pain. Although bone loss was observed in this model and COX-2 inhibition reduced this effect it was only significant at a later time point that at which analgesia was observed suggesting that these analgesic effects were at least in part direct and were not entirely secondary to a reduction on bone destruction.

The global market for COX-2 inhibitors surpassed $6 billion in sales in 2002 (click here for an analysis of the COX market). Given the increasing and multimodal role that COX-2 is being found to play in cancer, this market that initially focused on the pain and inflammation market is likely set to expand as it enters the oncology arena.

Entry date Wednesday, April 14, 2004

Adapted from Fox et al, Pain. 2004 Jan;107(1-2):33-40.