Botulinum Toxin Type A in Painful Focal Neuropathy
Abstract & Commentary
By Panida Piboolnurak, MD, Assistant Professor, Department of Neurology and Neuroscience, Weill-Cornell Medical College. Dr. Piboolnurak reports no financial relationships relevant to this field of study.
Synopsis: There is promising evidence that botulinum toxin type A provides analgesia in patients with painful focal neuropathy independent of its neuromuscular blocking action.
Sources: Ranoux D, Attal N, Morain F, et al. Botulinum toxin type A induces direct analgesic effects in chronic neuropathic pain. Ann Neurol 2008;64:274-283; Murinson BB. Botulinum toxin type A treatment of painful focal neuropathies: new evidence for efference of afferents. Ann Neurol 2008;64:236-238.
Botulinum toxin type A (BTX-A) has been used for dystonia, spasticity, and glandular hyperactivity. Ranoux and colleagues investigated the analgesic effects of one-time intradermal injections of BTX-A in patients with focal neuropathic pain associated with allodynia, using a randomized, double-blind, placebo-controlled, parallel group design.
In the BTX-A group (n=12), the mean number of injection sites was 20 ± 8.3, with doses ranging from 20 to 190 units. In the placebo group (n=10), the number of injection sites was 19.8 ± 5.2, with total volumes of injection similar to the BTX-A group (3.9 ± 1.1 for placebo and 4.4 ± 1.6 for BTX-A).
BTX-A improved average pain intensity 2 weeks after the injections. The effect increased for up to 4 weeks and was sustained for up to 14 weeks. The area and intensity of allodynia to brush and cold pain thresholds were reduced, without an effect on thresholds to non-painful thermal and mechanical stimuli, or on heat and mechanical pain thresholds. Although burning, paroxysmal pain, and allodynia were improved by BTX-A, deep pain, paresthesia, and dysesthesia were unaffected. BTX-A also improved general activity and anxiety. However, depression was unchanged.
The analgesic effects of BTX-A did not correlate with sex, age, pain duration or intensity, or neuropathic symptoms. But, it was inversely related with the magnitude of thermal deficits, burning pain, and brush-evoked pain. Besides pain due to injections, there was no other local or systemic side effect. The pain was greater when the injections were to the hand or elbow.
Preclinical data showed that BTX-A blocks protein kinase C potentiation of transient receptor potential vanilloid 1, a capsaicin and heat-sensitive ion channel expressed in nociceptors. So, it is possible that BTX-A acts on sensitized nociceptive fibers to produce analgesic effects. However, there are discrepancies in the results of studies concerning BTX effects on pain due to different preparations of BTX, different experimental stimuli, and different binding capacity of BTX to the receptors in acute and chronic conditions (probably greater in chronic conditions). A possible central effect of BTX-A cannot be ruled out.
The authors concluded that BTX-A may induce direct analgesic effects on nociceptive fibers in patients with chronic focal neuropathic pain independent of its effects on muscle tone.
In an accompanying editorial, Murinson commented that this study is an important landmark in the treatment of neuropathic pain. However, the application to a broader patient population is limited because neuropathic pain in the patients in this study was only due to postherpetic neuralgia or focal nerve injury.
Although it is known that BTX-A blocks cholinergic transmission at the neuromuscular junction, many studies show that BTX-A effects are not limited to cholinergic neurons and that its effects on pain control are likely independent of neuromuscular blocking property. For instance, BTX-A can block calcitonin gene-related peptide (CGRP) release from rat trigeminal neurons. In addition, cultured dorsal root ganglion neurons are highly sensitive to BTX-A effects on potassium-evoked substance P release. For basic signaling of painful sensations, it is clear that exocytic signaling in the periphery is not required. However, there is evidence supporting a role for exocytosis in painful inflammatory conditions. Moreover, there has been some controversy about whether primary pain afferents contain the machinery necessary to support the exocytic signaling in the periphery and whether primary pain afferents synthesize and package compounds, that if released, would produce pain or augment pain signaling.
Murinson suggested that each of the pain models needs to be considered separately and weighed for relevance to human forms of neuropathic pain. She recommended a multicenter trial to confirm the effects of BTX-A on neuropathic pain. Finally, she noted that its efficacy, long-lasting effects, and freedom from cognitive side effects are the advantages of treatment with BTX-A.
While the effects of BTX-A on neuromuscular junction and glandular secretion are well known, its effects on sensory systems are debated in the literature. Although exocytic signaling (releasing of neuropeptides such as substance P, glutamate, and CGRP) in the periphery is not required in basic pain signaling, it plays a role in the pain induced by an inflammatory process. Interestingly, in vitro studies have shown that BTX-A can block release of substance P, glutamate, and CGRP, which can explain the analgesic effects of BTX-A. In keeping with in vitro studies, the study by Ranoux and colleagues has shown that intradermal BTX-A injections can reduce focal neuropathic pain. However, because this study is small and the etiologies of pain are limited to postherpetic neuralgia and post-traumatic/post-operative pain, further studies in a broader range of painful conditions are required for better understanding of BTX-A effects on pain control. Given the focal effect of BTX-A, its duration of action, and relatively low systemic side effects, BTX-A is a promising treatment option for focal neuropathic pain.