Botulinum Toxin A for the Treatment of Chemotherapy Induced Peripheral Neuropathy

Chemotherapy Induced Peripheral Neuropathy Chemotherapy induced peripheral neuropathy (CIPN) is a common adverse effect of cancer therapy, effecting over half of all patients who receive chemotherapy. CIPN typically manifests as a symmetrical, predominately sensory peripheral neuropathy, and is most common in taxanes, vinca-alkaloids, and/or platinum compounds. Taxanes are microtubule stabilizing agents and are effective in the treatment of many solid organ cancers, often used as first line therapy in the treatment of breast cancer. Taxanes cause peripheral neuropathy by injuring neurons, disrupting axonal transport, and causing wide spread macrophage activation both in the periphery as well as at the dorsal root ganglion (DRG) and microglial activation in the spinal cord. The incidence of CIPN is high following taxane administration, and often occurs before patients have completed the prescribed course. In severe cases it can lead to dose modifications and early treatment discontinuation, effecting overall survivorship. Additionally, it has been demonstrated to have a profound effect on quality of life, found to correlate with increased fatigue, malaise, increased psychological distress and a less sense of well being and satisfaction with life. Current treatment options are inadequate, with suboptimal treatment effect size and dose limiting adverse effects. Various neuroprotective regimens have been trialed, including co-administration of thiols, neurotrophic factors, antioxidants and vitamin E; however none of these approaches are consistently effective in reducing peripheral neuropathy.

Botulinum Toxin (BoNT) Botulinum toxin (BoNT) is routinely used to treat a wide variety of disorders, traditionally by decreasing muscle activity through inhibiting the release of acetylcholine from the presynaptic nerve terminal. There has been a recent increase and growing body of evidence for the use of botulinum toxin in the treatment of neuropathic pain including postherpetic neuralgia, diabetic neuropathy, complex regional pain syndrome, trigeminal neuralgia, phantom limb pain, spinal cord injury-induced neuropathic pain, and central post-stroke pain.

The mechanism by which BoNT effects neuropathic pain is independent than the effect of BoNT on muscle relaxation. There are several proposed mechanisms by which BoNT decreases neuropathic pain, all of which likely contributing to the antinociceptive effect. First, it has been shown that BoNT inhibits the release of sensory neurotransmitters such as substance P, calcitonin gene related peptide, and glutamate from nerve endings into the peripheral nerve terminal. This not only directly mediates pain, but has also been shown to result in decreased inflammation. In addition, recent work in the rat model suggests that the antinociceptive mechanism of BoNT may in part be due to a reduction of TRPV1 expression. TRPV1 is a well-known pain receptor which responds to mechanical, thermal and chemical stimuli, is heavily expressed on the DRG. BoNT has been shown to exhibit retrograde axonal transport from the periphery, so effects on the DRG and central nervous system cannot be overlooked and likely play a role in the mechanism.

Recently, intradermal BoNT injections were found efficacious in treating diabetic peripheral neuropathy. Multiple studies have demonstrated a reduction in Visual Analog Scale (VAS) scores following intradermal BoNT injections on the dorsal aspect of the foot in diabetic patients with peripheral neuropathy. Similar to CIPN, diabetic neuropathy presents in a stocking-glove distribution with a predominant sensory neuropathy. BoNT has additionally been proven to be safe and efficacious when used specifically in a cohort of head, neck, and breast cancer patients who developed post surgical and post radiation neuropathic pain. In this study, affected patients underwent intradermal BoNT injections which resulted in improvement in VAS and clinical global impressions of change (CGI-C) scales. Together, this evidence suggests that intradermal BoNT injections are efficacious in the treatment of neuropathic pain, and is safe for use in the cancer population. If our hypothesis proves correct, we will demonstrate the efficacy of BoNT for treatment of CIPN, allowing for improved treatment options. An antihyperalgesic effect following intradermal BoNT injections was additionally observed in rats with Paclitaxel induced peripheral neuropathy, again suggesting that BoNT will be an effective treatment specifically in the CIPN patient population.

In controlled studies, BoNT has consistently demonstrated a minimal adverse effect profile. Typically, adverse effects occur within one week of BoNT injection and are transient. As with any injection, localized pain, infection, bleeding may be associated. A metaanalysis of two studies using BoNT for the treatment of diabetic neuropathic pain concluded that there were no statistically significant adverse effects associated with BoNT treatment. Intradermal injections for the treatment of hyperhidrosis have FDA approval, and the most common adverse events associated (3-10% of adult patients) were injection site pain and hemorrhage.