Botulinum Toxin A reduces neurogenic flare but has almost no effect on pain and hyperalgesia in human skin

Abstract

Botulinum toxin A (BoNT/A) has been used therapeutically to treat muscular hypercontractions and sudomotor hyperactivity. There is increasing evidence that BoNT/A might also have analgesic properties, in particular in headache. In the present investigation we tested the often cited hypothesis that BoNT/A-induced analgesia can be attributed to inhibition of neuropeptide release from nociceptive nerve fibers. In 15 healthy volunteers BoNT/A (5, 10, 20 mouse units BOTOX) or saline (contralateral side) was injected intracutaneously on the volar forearm. On day zero, the day of injection, no further tests were performed. We repeatedly elicited pain, mechanical hyperalgesia and neurogenic flare by transcutaneous electrical stimulation simultaneously on the BoNT/A and saline treated side on day 1, 2, 3, 7 and 14 after injection. Before each session, sweating and local anhidrosis was assessed by iodine starch staining.BoNT/A suppressed sweating as early as from the second day after injection (p < 0.001). The size of electrically induced flare was smaller on the BoNT/A treated arm (BoNT/A side: 21.46 cm(2) +/- 3.58, saline side 24.80 +/- 3.46, p < 0.005) and BoNT/A reduced electrically-induced pain by about 10 % (p < 0.001). However, hyperalgesia to pin-prick and allodynia after electrical stimulation were unchanged. In conclusion our results indicate that peripheral neuropeptide release is attenuated by BoNT/A. In contrast, the analgesic effect of BoNT/A was very limited. Therefore we assume that other than neuropeptide mechanisms must be important for BoNT/A induced pain relief in clinical pain syndromes.

Botulinum Toxin type A reduces capsaicin-evoked pain and neurogenic vasodilatation in human skin

“…In contrast, the flare response/increase in CBF produced by capsaicin was inhibited by BoNT/A either if capsaicin was applied to the same area or in an area adjacent to that treated with BoNT/A. Present data confirm, in part, a previous study which shows that pretreatment with BoNT/A reduced the flare response by painful transcutaneous electrical stimulation (Kramer et al, 2003). However, the reduction in vasodilatation observed in BoNT/A treated side does not seem to contribute significantly to capsaicin-induced pain.…”

“…In particular, results obtained from the measurement of thermal and electric pain thresholds, acute pain perception, hyperalgesia and flare in response to capsaicin application to the human skin seemed to rule out a direct analgesic effect of BoNT/A (Voller et al, 2003). However, findings obtained in facial pain (Borodic et al, 2001;Borodic and Acquadro, 2002) and in a rat model of inflammatory pain (Cui et al, 2002;Aoki, 2003;Cui et al, 2004) and in humans by transcutaneous electrical stimulation (Kramer et al, 2003) focused on the possibility that BoNT/A somehow limits the functioning of a subset of capsaicin-sensitive and neuropeptide-containing primary sensory neurons (Durham et al, 2004).…”

Botulinum toxin A, brain and pain

“…Based on this observation the authors proposed that the toxin's antiinflammatory effect on neurogenic flare and vasodilatation do not significantly contribute to BoNT/A-mediated pain reduction (Tugnoli et al, 2007). Similar conclusion was proposed in the human study of Krämer et al (2003) which reported that BoNT/A reduced neurogenic flare evoked by cutaneous electrical stimulation, however, with very limited analgesic effect.…”

“…The authors suggested that the neuropeptide-mediated reduction of peripheral neurogenic inflammation does not contribute significantly to BoNT/A analgesic effects observed in clinical pain syndromes (Krämer et al, 2003).…”

Botulinum Toxin Off-Label Use in Dermatology: A Review

“…The promising experience of Swartling and Vahlquist led the same authors to an interesting retrospective evaluation of the effects of BoNT-A injections in 14 patients with EBS and PC with foot blisters and painful callosities [47] . They observed analogues results in improvement of blisters and pain; the hypothesis that explains these effects was that BoNT-A can affects nociceptive C-fibers in the skin via inhibition of neuropeptide release from sensory nerve axons and also inhibits the neurogenic inflammation [48] . Recently, 2 new cases of PC treated with BoNT-A injection have been described [49] .…”