Cancer-Related and Cancer Treatment-Induced Peripheral Neuropathy

Peripheral neuropathy, either from the tumor itself, or, more commonly, from cancer treatment, is another significant side effect experienced by cancer patients. CIPN rates vary considerably by therapeutic regimen, but the most frequently associated agents include platinum compounds, vinca alkaloids, taxanes, bortezomib, thalidomide, lenalidomide, and ixabepilone. Importantly, drug-related neuropathy may cause treatment delays or dose reductions that may compromise survival outcomes. While no agent has been specifically approved for the treatment of CIPN, the condition is traditionally managed with opioid therapy (eg, oxycodone, morphine, methadone, tramadol), antiepileptic medications (eg, gabapentin, pregabalin), local anesthetics (eg, lidocaine), and antidepressants (duloxetine, amitriptyline, nortriptyline, desipramine); however, results are variable and definitive efficacy has not been established.10 Indeed, only 25% of patients with neuropathic pain are believed to experience 50% of pain relief, resulting in a substantial need for improved analgesic efficacy.11

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Alternative agents being evaluated for the management of peripheral neuropathy may be useful for patients who fail to benefit from or are unable to tolerate side effects related to conventional therapy.  AmiKet, a topical formulation consisting of 2% ketamine and 4% amitriptyline, is currently completing Phase 2 testing for the treatment of peripheral neuropathy, including CIPN. One Phase 2b, double-blind, placebo-controlled study conducted in patients with diabetic peripheral neuropathy revealed that AmiKet therapy significantly reduced pain intensity compared with placebo. Similarly, another Phase 2b trial comparing the safety and efficacy of AmiKet with both gabapentin and placebo among patients with postherpetic neuralgia found that AmiKet-associated pain reduction was superior to placebo and not inferior to gabapentin; in addition, patients treated with AmiKet experienced significantly less dizziness and somnolence than those receiving gabapentin.12 As a result, AmiKet is expected to become the first topical ointment for peripheral neuropathy to enter the market.11

Sativex (GW Pharma), an oral-mucosal mouth spray, is a cannabis extract that is currently undergoing Phase 3 evaluation for the treatment of peripheral neuropathy.13 Based on findings that this agent significantly reduces neuropathic pain associated with multiple sclerosis, Sativex therapy is being evaluated for use in patients with advanced cancer who are unable to achieve adequate pain relief with opioid therapy.13,14

Tetrodotoxin (TTX)-based drugs (Wex Pharmaceuticals), or agents that selectively block voltage-gated sodium channels to inhibit pain impulse conduction, are also being studied for the treatment of neuropathic pain.  Specifically, TTX-CINP-201 is expected to undergo Phase 2 evaluation for the treatment of moderate-to-severe CINP, while TEC-006 will be assessed as an opioid alternative for patients with moderate-to-severe cancer pain.  Importantly, TTX-related medications lack the neurological and gastrointestinal side effects commonly associated with opioid therapy.13

Finally, KRN5500 (DARA Biosciences), a spicamycin derivative, is currently under development for the treatment of CIPN. A placebo-controlled, Phase 2a study recently revealed that this agent significantly reduced neuropathic pain and increased the number of patients achieving pain reduction, compared to placebo. Moreover, KRN5500 was well-tolerated, with nausea and vomiting being the only noteworthy adverse events. As a result, this product has been granted Fast Track designation by the FDA, and may be a promising addition to the CIPN armamentarium.15