Paclitexel-induced neuropathic pain - McGill study may lead to the identification of novel targets for analgesia and improved cancer therapeutics

DailyUpdates 14th April: Neuropathic pain affects 26 million patients including a sub-population of cancer patients being treated with cytotoxics.  McGill researchers have published the results of a study looking at neuropathic pain in various strains of mice.  These data show that neuropathic pain has a genetic component suggested to be equally relevant to paclitaxel and surgically-induced pain.  The study also advances the use of paclitaxel-induced hyperalgesia as a model for the development of novel analgesics as well as improved derivatives or formulations of paclitaxel.

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 into neuropathic pain or here for a full analysis of the neuropathic pain market).

Like neuropathic pain, cancer pain is also an unmet market affecting 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).  

Cytotoxics represent a mainstay of cancer therapeutics and of the five major cytotoxic classes, vinca alkaloids, which include the taxanes, represent the largest in terms of sales. BMS’s Taxol (paclitaxel) once dominated not only the class but also the cytotoxic market as a whole. However, because of its patent expiry, it has lost its leading position to its rival drug, Aventis’s Taxotere (docetaxel). The entry of generic and reformulated paclitaxel onto the market will is further eroding the market for Taxol (for an analysis of the cytotoxic therapeutics market place click here).  Cancer pain can be associated with the cancer itself or with conventional cancer treatments and pain is a frequent problem of paclitaxel.  Overcoming this problem would significantly advance the taxanes as a class of cytotoxic agent.

Studies in rodents have demonstrated that paclitaxel causes neuropathic pain beginning within days and lasting for several weeks.  Although treatment causes neurodegeneration at high doses, neurogenic pain remains evident at lower doses in the absence of nerve damage.  Hyperalgesia appears to be mediated by protein kinase C epsilon and protein kinase A.  These findings provide insight into the mechanism of Taxol-induced painful peripheral neuropathy that may help control side effects of chemotherapy and improve its clinical efficacy.

In their recent Life Science report Smith and colleagues from McGill University investigate the phenomenon of paclitaxel-induced neuropathic pain in greater detail.  In particular they investigated the cause of the large inter-individual differences have been observed in neuropathic pain, both in susceptibility to its development and in its severity. 

In their study Smith et al investigated the responses of 10 inbred mouse strains to paclitaxel injections. Virtually all strains developed statistically significant mechanical allodynia, with one strain, DBA/2J, exhibiting especially robust changes. Strain sensitivities to paclitaxel-induced mechanical allodynia were similar to those obtained previously using a surgical model of neuropathic pain, supporting the concept that genetic sensitivity to mechanical allodynia is independent of the precise mode of induction. Using sensitive DBA/2 mice and a resistant strain, C57BL/6J, for comparison, the McGill group further characterized the paclitaxel model in mice by examining cold allodynia and thermal hyperalgesia. Both strains displayed equivalent cold allodynia but neither strain developed thermal hyperalgesia. The present data confirm a genetic component in mechanical allodynia using this model, while dissociating mechanical hypersensitivity from other pain modalities.

This study is important for a number of reasons.  Although many animal models of neuropathic pain following peripheral nerve injury have been developed, most involve intricate surgeries.  The paclitaxel model is considerably simpler and is therefore of potentially greater use in the context of the higher throughput requisites of modern day drug development.  This study also demonstrates a genetic component of neuropathic pain and this may lead to the selection and dose adjustment of patients considered for treatment by medications known to cause neuropathic pain.  Thirdly, the presence of a hereditary component of pain suggests that genetic studies could identify new targets for the treatment of neuropathic pain.  The availability of the paclitaxel model could facilitate such studies.  Finally, this body of data could help in the development of paclitaxel analogues or reformulated versions of paclitaxel less susceptible to neuropathic pain.

Source DailyUpdates 14th April; for a full abstract of the original papers see  Life Sci. 2004 Apr 9;74(21):2593-604.

Recommended further reading:

• Neuropathic Pain - Comparative Overview of Treatment Preferences Across the Seven Major Markets
• Neuropathic Pain Insight - Life Beyond Gabapentin
• Cancer Pain - Physician Awareness and Novel Drug Delivery Will Drive Market Opportunities
• Cytotoxics - Third-Generation Cytotoxics To Offset Taxol’s Generic Woes