Background: Diabetic neuropathy is a common complication in diabetes, with patients typically experiencing diverse sensory symptoms including dysesthesias in the feet and usually accompanied by sleep disturbance. There is still no comprehensive understanding of the underlying biologic processes responsible for diabetic neuropathic pain. Thus, the current symptomatic therapy remains unsatisfactory. Recent experimental evidence suggests that botulinum toxin type A (BoNT/A) may not only inhibit the release of acetylcholine at the neuromuscular junctions, but also modulate afferent sensory fiber firing, thereby relieving neuropathic pain.
Methods: A double-blind crossover trial of intradermal BoNT/A for diabetic neuropathic pain in 18 patients was conducted to evaluate the effectiveness.
Results: We find significant reduction in visual analog scale (VAS) of pain by 0.83 +/- 1.11 at 1 week, 2.22 +/- 2.24 at 4 weeks, 2.33 +/- 2.56 at 8 weeks, and 2.53 +/- 2.48 at 12 weeks after injection in the BoNT/A group, as compared to the respective findings for a placebo group of 0.39 +/- 1.18, -0.11 +/- 2.04, 0.42 +/- 1.62, and 0.53 +/- 1.57 at the same timepoints (p < 0.05). Within the BoNT/A group, 44.4% of the participants experienced a reduction of VAS >/=3 within 3 months after injection, whereas there was no similar response in the placebo group. At the 4-week postinjection stage, improvement in sleep quality was measured using the Chinese version of the Pittsburgh Sleep Quality Index.
Conclusions: This pilot study found that botulinum toxin type A significantly reduced diabetic neuropathic pain and transiently improved sleep quality. Further large-scaled study is warranted.
Comment by Claudia Sommer
In spite of major advances in recent years, there is still a need to improve treatment of neuropathic pain. Specifically, most drugs that are efficient in producing pain relief also have CNS side effects. Botulinum toxin acts locally and by modulating the firing of nociceptive neurons. Diabetic neuropathy is a common condition often leading to neuropathic pain. For these reasons, Yuan and colleagues (1) performed a double-blind crossover pilot trial of intradermal botulinum toxin type A (BoNT/A) in 20 patients with painful diabetic neuropathy. All patients had type II diabetes. BoNT/A or normal saline was injected into the dorsum of the foot, and 12 weeks later, patients received the respective other treatment. The injections were distributed in a grid pattern covering a total of 12 sites. 50 units of BoNT/A were used per foot, resulting in about 4 units per injection site. Outcome measures were visual analogue scale (VAS) for pain, the Chinese version of the Pittsburgh Sleep Quality Index (CPSQI), and the Short Form–36 (SF-36) quality-of-life questionnaire. These were performed at 1-week, 4-week, 8-week, and 12-week intervals after the initial injection.
Of 20 patients enrolled, 18 completed the study. Between week 4 and 12 after BoNTA injection, patients had a pain reduction by 2.2 to 2.5 points on the VAS. In the placebo group, the maximal response was a VAS reduction of 0.5 points. The difference between BoNTA and placebo was significant. Surprisingly, sleep did not improve significantly, nor was there a difference between the groups. Also, improvements in quality of life were only transient, and again not different between BoNTA and placebo.
This small trial confirms a previous study suggesting an effect of botulinum toxin in neuropathic pain (2). Also, since then, a new trial indicating an effect of BoNTA in postherpetic neuralgia has been published (3). Thus, BoNTA may be a promising new agent for the treatment of neuropathic pain. One caveat is that the study by Yuan et al. (1) had a very low placebo response, which is unusual in neuropathic pain trials (4, 5). Larger trials will be needed to judge the potential role of botulinum toxin in neuropathic pain treatment.
(1) Yuan RY, Sheu JJ, Yu JM, Chen WT, Tseng IJ, Chang HH, Hu CJ. Botulinum toxin for diabetic neuropathic pain: a randomized double-blind crossover trial. Neurology. 2009;72:1473-8.
(2) Ranoux D, Attal N, Morain F, Bouhassira D. Botulinum toxin type A induces direct analgesic effects in chronic neuropathic pain. Ann Neurol. 2008;64:274-83.
(3) Xiao L, Mackey S, Hui H, Xong D, Zhang Q, Zhang D. Subcutaneous injection of botulinum toxin a is beneficial in postherpetic neuralgia. Pain Med. 2010;11:1827-33.
(4) Quessy SN, Rowbotham MC. Placebo response in neuropathic pain trials. Pain. 2008;138:479-83.
(5) Irving G. The placebo response: relationship to outcomes in trials of postherpetic neuralgia. Clin Drug Investig. 2010;30:739-48.
Claudia Sommer is Professor of Neurology at the Universitätsklinikum Würzburg, Germany and past-chairperson of the EFNS Scientist Panel on Neurpathic Pain.