New data reveals that the anti-epileptic drug ethosuximide is an effective treatment for chemotherapy-evoked pain

Cancer pain affects over 3 million people in the US alone. The treatment of this condition, whether it is due to bone metastasis or a result of the use of cytotoxic therapies is challenging. Researchers from McGill University have now demonstrated that ethosuximide, an anti-epileptic and relatively selective T-type calcium channel blocker, is highly effective in reversing neuropathic pain caused by the commonly employed cytotoxics paclitaxel or vincristine. This contrasted with the limited efficacy afforded to morphine and opens up new avenues for clinical and drug development approaches to this area of oncology.

Cancer pain represents a large and 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.

Considerable effort is currently being placed on developing models of metastatic bone pain and in a recent editorial produced by LeadDiscovery, the use of such a model has demonstrated the therapeutic potential of COX-2 inhibitors. In particular Novartis’ Lumiracoxib has been shown to attenuate the mechanical hyperalgesia associated with intra-tibial injection of cancer cells.

Just as the identification of therapeutics able to treat metastatic pain would be enormous clinical use, so to would the discovery of agents that can limit the pain associated with many cytotoxics.

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).

The use of paclitaxel is associated with three principal serious side effects: myelosuppression; kidney damage and peripheral neurotoxicity. The first two of these adverse effects can be controlled however the latter which is characterized by neuropathic pain is a frequent problem of paclitaxel which is difficult to control and can continue long after cessation of treatment. Overcoming this problem would considerably increase the clinical utility of paclitaxel and provide some resistance to the erosion of its market.

Studies in rodents have demonstrated that although treatment causes neurodegeneration at high doses, neurogenic pain remains evident at lower doses in the absence of nerve damage. The mechanism of taxol-induced painful peripheral neuropathy is unknown at present and there are currently no generally accepted strategies for limiting the pain associated with cytotoxic agents.

In their May Pain journal article, Flatters & Bennett report that ethosuximide reverses paclitaxel- and vincristine-induced painful peripheral neuropathy.

The McGill University researchers employed a rodent model in which paclitaxel treatment produces a marked and long-term mechanical allodynia. Using this model Flatters & Bennet reported that paclitaxel-induced pain was relatively resistant to opioid therapy. At a dose 8 mg/kg, morphine had only a partial effect on mechanical allodynia/hyperalgesia. In contrast, ethosuximide, an anti-epileptic and relatively selective T-type calcium channel blocker, elicited a near complete reversal of mechanical allodynia/hyperalgesia. Repetitive dosing with ethosuximide showed a dose-related consistent reversal of mechanical allodynia/hyperalgesia with no evidence of tolerance. Ethosuximide also reversed paclitaxel-induced cold allodynia and vincristine-induced mechanical allodynia/hyperalgesia.

These data suggest that T-type calcium channels may play a role in chemotherapy-induced neuropathy and moreover identify ethosuximide as a new potential treatment for chemotherapy-induced pain.

A second class of therapeutic agent, the NMDA antagonists have been shown to be effective in the treatment of neuropathic pain. However although the potent NMDA receptor antagonist MK-801 has been shown to reduce mechanical allodynia in nerve constriction models of neuropathic pain it had no effect in the McGill study. This finding is highly important. Pfizer's blockbuster, gabapentin has generated annual sales exceeding $2bn due in part to efficacy as a treatment of neuropathic pain. As this therapeutic approaches patent expiry and the sale of generics looms numerous companies are competing for the neuropathic pain market. Analysts now believe that the treatment of neuropathic pain will be related to the underlying neuropathy and will be unlikely to focus on a "one analgesic fits all" concept. Relevant points of entry, especially for smaller companies, into this market will therefore involve the targeting of specific neuropathic pain sectors (see for example our recent features on HIV-related pain and diabetic pain or our more general features "Neuropathic Pain - Comparative Overview of Treatment Preferences Across the Seven Major Markets" and "Neuropathic Pain Insight - Life Beyond Gabapentin"). Thus the McGill study has broader implications. Firstly it demonstrates that cytotoxic neuropathic pain differs from other neuropathies in terms of pathophysiology and treatment options and secondly the development of T-type calcium channels may offer a specific and niche approach to the treatment of this common condition.

Entry date Friday, June 04, 2004

Adapted from Flatters & Bennett, Pain. 2004 May;109(1-2):150-6.