The effects of Botulinum Toxin type A on capsaicin-evoked pain, flare, and secondary hyperalgesia in an experimental human model of trigeminal sensitization

Abstract

The trigeminovascular system is involved in migraine. Efficacy of Botulinum Toxin type A (BoNT-A) in migraine has been investigated in clinical studies but the mechanism of action remains unexplored. It is hypothesized that BoNT-A inhibits peripheral sensitization of nociceptive fibers and indirectly reduces central sensitization. We examined the effect of intramuscular injection of BoNT-A on an experimental human model of trigeminal sensitization induced by intradermal capsaicin injection to the forehead. BoNT-A (BOTOX) or saline was injected intramuscularly in precranial, neck and shoulder muscles to 32 healthy male volunteers in a double blind-randomized manner. Intradermally capsaicin-induced pain, flare and secondary hyperalgesia were obtained before and 1, 4 and 8 weeks after the above treatments. A significant suppressive effect of BoNT-A on pain, flare and hyperalgesia area was observed. The pain intensity area was significantly smaller in BoNT-A group (9.16+/-0.83 cm x s) compared to saline group (15.41+/-0.83cm x s) (P=0.011). The flare area was also reduced significantly in BoNT-A group (29.81+/-0.69 cm2) compared to saline group (39.71+/-0.69 cm2) (P<0.001). Similarly, the mean area of secondary hyperalgesia was significantly smaller in BoNT-A group (4.25+/-0.91 cm2) compared to saline group (7.03+/-0.91 cm2) (P=0.040). Post hoc analysis showed significant differences across the trials with a remarkable suppression effect of BoNT-A on capsaicin-induced sensory and vasomotor reactions as early as week1 (P<0.001). BoNT-A presented suppressive effects on the trigeminal/cervical nociceptive system activated by intradermal injection of capsaicin to the forehead. The effects are suggested to be caused by a local peripheral effect of BoNT-A on cutaneous nociceptors.

Botulinum toxin A, brain and pain

“…The authors hypothesized that BoNT/A may reduce the peripheral release of not only glutamate, but also of neuropeptides involved in neurogenic inflammation such as substance P (SP) and calcitonin gene-related peptide (CGRP) (in the report of Cui et al humans. The differences between the described studies might be related to the experimental setup regarding the mode of toxin injection (subcutaneous, intramuscular or intradermal) or different BoNT/A doses (Gazerani et al, 2006;Gazerani et al, 2009;Schulte-Mattler et al, 2003;Tugnoli et al, 2007;Voller et al, 2007). Additionally, BoNT/A does not reduce the experimental inflammatory pain evoked by UV light in humans (Sycha et al, 2006).…”

Long-term benefits of botulinum toxin type A (BOTOX) in chronic daily headache: a five-year long experience

“…Eross et al demonstrated the efficacy of reducing headache frequency in patients affected by episodic and chronic migraine [14]. Besides, suppressive effects of BoNT-A on intradermal capsaicinevoked pain and secondary hyperalgesia have been demonstrated, suggesting a local peripheral effect on cutaneous nociceptors [15].…”

Synaptobrevin I mediates exocytosis of CGRP from sensory neurons and inhibition by botulinum toxins reflects their anti-nociceptive potential

“…Sbr I in rat is unusual in being resistant to BoNT/B owing to a mutation at the fission site (Foran et al, 2003;Schiavo et al, 1992;Yamasaki et al, 1994). Gaining data on the action of the toxins in sensory neurons should yield insights into the basis of toxin A therapy for certain types of pain (Gazerani et al, 2006;Gupta, 2005). Initial investigations using animal pain models have indicated that inhibition of the release of transmitters from nerves by BoNT/A in the periphery can attenuate peripheral sensitisation (Aoki, 2003).…”