Diener S A, Breimhorst M, Vogt Th, Krämer H H, Drummond P D, Geber C, Birklein F
Department of Neurology, University Medical Center of the Johannes Gutenberg University Mainz, Germany.
Department of Neurology, Kantonsspital St. Gallen, Switzerland.
Eur J Pain. 2017 Sep;21(8):1326-1335. doi: 10.1002/ejp.1031. Epub 2017 Apr 25.
The effectiveness of Botulinum-neurotoxin A (BoNT/A) to treat pain in human pain models is very divergent. This study was conducted to clarify if the pain models or the route of BoNT/A application might be responsible for these divergent findings.
Sixteen healthy subjects (8 males, mean age 27 ± 5 years) were included in a first set of experiments consisting of three visits: (1) Visit: Quantitative sensory testing (QST) was performed before and after intradermal capsaicin injection (CAPS, 15 μg) on one thigh and electrical current stimulation (ES, 1 Hz) on the contralateral thigh. During stimulation pain and the neurogenic flare response (laser-Doppler imaging) were assessed. (2) Four weeks later, BoNT/A (Xeomin , 25 MU) was injected intracutaneously on both sides. (3) Seven days later, the area of BoNT/A application was determined by the iodine-starch staining and the procedure of the (1) visit was exactly repeated. In consequence of these results, 8 healthy subjects (4 males, mean age 26 ± 3 years) were included into a second set of experiments. The experimental setting was exactly the same with the exception that stimulation frequency of ES was increased to 4 Hz and BoNT/A was injected subcutaneously into the thigh, which was stimulated by capsaicin.
BoNT/A reduced the 1 Hz ES flare size (p < 0.001) and pain ratings (p < 0.01), but had no effect on 4 Hz ES and capsaicin-induced pain, hyperalgesia, or flare size, regardless of the depth of BoNT/A injection (i.c./s.c). Moreover, i.c. BoNT/A injection significantly increased warm detection and heat pain thresholds in naive skin (WDT, Δ 2.2 °C, p < 0.001; HPT Δ 1.8 °C, p < 0.005).
BoNT/A has a moderate inhibitory effect on peptidergic and thermal C-fibers in healthy human skin.
The study demonstrates that BoNT/A (Incobotulinumtoxin A) has differential effects in human pain models: It reduces the neurogenic flare and had a moderate analgesic effects in low frequency but not high frequency current stimulation of cutaneous afferent fibers at C-fiber strength; BoNT/A had no effect in capsaicin-induced (CAPS) neurogenic flare or pain, or on hyperalgesia to mechanical or heat stimuli in both pain models. Intracutaneous BoNT/A increases warm and heat pain thresholds on naïve skin.
A型肉毒杆菌神经毒素（BoNT/A）在人类疼痛模型中治疗疼痛的效果差异很大。本研究旨在阐明疼痛模型或BoNT/A的应用途径是否可能是导致这些不同结果的原因。
16名健康受试者（8名男性，平均年龄27±5岁）被纳入第一组实验，该实验包括三次访视：（1）访视：在一侧大腿进行皮内注射辣椒素（CAPS，15μg）前后以及对侧大腿进行电流刺激（ES，1Hz）前后进行定量感觉测试（QST）。在刺激过程中，评估疼痛和神经源性 flare 反应（激光多普勒成像）。（2）四周后，在两侧皮内注射BoNT/A（Xeomin，25MU）。（3）七天后，通过碘淀粉染色确定BoNT/A的应用区域，并精确重复（1）访视的程序。基于这些结果，8名健康受试者（4名男性，平均年龄26±3岁）被纳入第二组实验。实验设置与第一组完全相同，只是ES的刺激频率增加到4Hz，并且将BoNT/A皮下注射到由辣椒素刺激的大腿中。
BoNT/A减小了1Hz ES的flare大小（p<0.001）和疼痛评分（p<0.01），但对4Hz ES以及辣椒素诱导的疼痛、痛觉过敏或flare大小均无影响，无论BoNT/A的注射深度是皮内/皮下。此外，皮内注射BoNT/A显著提高了未受刺激皮肤的热觉检测和热痛阈值（WDT，Δ2.2°C，p<0.001；HPT Δ1.8°C，p<0.005）。
BoNT/A对健康人皮肤中的肽能和热C纤维具有中等抑制作用。
该研究表明BoNT/A（incobotulinumtoxin A）在人类疼痛模型中具有不同的作用：它可减少神经源性flare，并在低频但非高频电流以C纤维强度刺激皮肤传入纤维时具有中等镇痛作用；BoNT/A对辣椒素诱导的（CAPS）神经源性flare或疼痛，或对两种疼痛模型中的机械或热刺激痛觉过敏均无影响。皮内注射BoNT/A可提高未受刺激皮肤的热觉和热痛阈值。
