Botulinum toxin type A in the treatment of Raynaud’s phenomenon: A three-year follow-up study

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Abstract

Objective

Raynaud’s phenomenon consists of vasospastic disease of the digital arteries after exposure to cold or stress. It causes an important reduction in the patient’s quality of life when severe. The available treatments do not always offer favorable results.

Methods

A 3-year retrospective study was presented. A total of 15 patients with severe Raynaud’s phenomenon who required infiltration with botulinum toxin type A participated in the study. In the first and follow-up visits (30 min, 7 days, 3 months, 6 months, and annual), the overall response by the patient was assessed as was the reduction in the number of weekly episodes of Raynaud’s phenomenon, improvement in pain by means of the Visual Analogue Scale, and resolution of ulcers and necrosis as efficacy variables.

Results

A total of 15 patients were included in the study. After 30 min of infiltration, the immediate results showed a very good perception of response in four patients. After 1 month of treatment, eight patients had obtained and maintained a very good response, persisting throughout the study. A statistically significant reduction in pain was obtained, as well as the number of weekly episodes of Raynaud’s phenomenon. Of the seven patients with basal ulcers, five were completely healed at 3 months. Of the patients, 64.3% showed an overall satisfaction level of >8 at the end of treatment. No serious adverse events were observed.

Conclusion

Botulinum toxin is a useful treatment for severe Raynaud’s phenomenon that is generally well tolerated. Its mechanism of action is not based exclusively on vasodilation. Further studies are necessary to define the ideal patient for this treatment, the most appropriate method of administration, and the number of units and frequency of the infiltrations.

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Most cited references 23

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Regulation of calcitonin gene-related peptide secretion from trigeminal nerve cells by botulinum toxin type A: implications for migraine therapy.

Paul L Durham, Ryan J Cady, Roger Cady (2004)

To determine the effect of botulinum toxin type A on calcitonin gene-related peptide secretion from cultured trigeminal ganglia neurons. The ability of botulinum toxins to cause muscle paralysis by blocking acetylcholine release at the neuromuscular junction is well known. Previous studies and clinical observations have failed to demonstrate sensory changes related to botulinum toxins or the disease of botulism. Recent studies, however, have suggested that botulinum toxin type A injected into pericranial muscles may have a prophylactic benefit in migraine. This observation has renewed the debate of a mechanism of sensory inhibition mediated by botulinum toxin type A. Primary cultures of rat trigeminal ganglia were utilized to determine whether botulinum toxin type A could directly decrease the release of calcitonin gene-related peptide, a neuropeptide involved in the underlying pathophysiology of migraine. Untreated cultures or cultures stimulated with a depolarizing stimulus (potassium chloride) or capsaicin, an agent known to activate sensory C fibers, were treated for 3, 6, or 24 hours with clinically effective doses of botulinum toxin type A or a control vehicle. The amount of calcitonin gene-related peptide secreted into the culture media following the various treatments was determined using a specific radioimmunoassay. A high percentage (greater than 90%) of the trigeminal ganglia neurons present in 1- to 3-day-old cultures was shown to express calcitonin gene-related peptide. Treatment with depolarizing stimuli (potassium chloride), a mixture of inflammatory agents, or capsaicin caused a marked increase (4- to 5-fold) in calcitonin gene-related peptide released from the trigeminal neurons. Interestingly, overnight treatment of trigeminal ganglia cultures with therapeutic concentrations of botulinum toxin type A (1.6 or 3.1 units) did not affect the amount of calcitonin gene-related peptide released from these neurons. The stimulated release of calcitonin gene-related peptide following chemical depolarization with potassium chloride or activation with capsaicin, however, was greatly repressed by the botulinum toxin, but not by the control vehicle. A similar inhibitory effect of overnight treatment with botulinum toxin type A was observed with 1.6 and 3.1 units. These concentrations of botulinum toxin type A are well within or below the range of tissue concentration easily achieved with a local injection. Incubation of the cultures with toxin for 24, 6, or even 3 hours was very effective at repressing stimulated calcitonin gene-related peptide secretion when compared to control values. These data provide the first evidence that botulinum toxin type A can directly decrease the amount of calcitonin gene-related peptide released from trigeminal neurons. The results suggest that the effectiveness of botulinum toxin type A in the treatment of migraine may be due, in part, to its ability to repress calcitonin gene-related peptide release from activated sensory neurons.

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Review of a proposed mechanism for the antinociceptive action of botulinum toxin type A.

K. Aoki (2005)

Botulinum toxin type A (BOTOX) has been used to treat pathological pain conditions although the mechanism is not entirely understood. Subcutaneous (s.c.) BOTOX also inhibits inflammatory pain in the rat formalin model, and the present study examined whether this could be due to a direct action on sensory neurons. BOTOX (3.5-30 U/kg) was injected s.c. into the subplantar surface of the rat hind paw followed 1-5 days later by 50 mL of 5% formalin. Using microdialysis, we found that BOTOX significantly inhibited formalin-induced glutamate release (peak inhibitions: 35%, 41%, and 45% with 3.5, 7, and 15 U/kg, respectively). BOTOX also dose dependently reduced the number of formalin-induced Fos-like immunoreactive cells in the dorsal horn of the spinal cord and significantly (15 and 30 U/kg) inhibited the excitation of wide dynamic range neurons of the dorsal horn in Phase II but not Phase I of the formalin response. These results indicate that s.c. BOTOX inhibits neurotransmitter release from primary sensory neurons in the rat formalin model. Through this mechanism, BOTOX inhibits peripheral sensitization in these models, which leads to an indirect reduction in central sensitization.

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Sensitivity of embryonic rat dorsal root ganglia neurons to Clostridium botulinum neurotoxins.

Mary Welch, John Purkiss, Keith Foster (2000)

Clostridium botulinum neurotoxins (BoNT) are zinc dependent endopeptidases which, once internalised into the neuronal cytosol, block neurotransmission by proteolysis of membrane-associated proteins putatively involved in synaptic vesicle docking and fusion with the plasma membrane. Although many studies have used a variety of cellular systems to study the neurotoxins, most require relatively large amounts of toxin or permeabilisation to internalise the neurotoxin. We present here a primary culture of embryonic rat dorsal root ganglia (DRG) neurons that exhibits calcium-dependent substance P secretion when depolarised with elevated extracellular potassium and is naturally BoNT sensitive. The DRG neurons showed a different IC50 for each of the toxins tested with a 1000 fold difference between the most and least potent neurotoxins (0.05, 0.3, 30 and approximately 60 nM for A, C, F and B, respectively). BoNT/A cleavage of SNAP-25 was seen as early as 2 h, but substance P secretion was not significantly inhibited until 4 h intoxication and the effects of BoNT/A were observed for as long as 15 days. This primary neuronal culture system represents a new and sensitive cellular model for the in vitro study of the botulinum neurotoxins.

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Author and article information

Journal

Journal ID (nlm-ta): Eur J Rheumatol

Journal ID (iso-abbrev): Eur J Rheumatol

Title: European Journal of Rheumatology

Publisher: Medical Research and Education Association

ISSN (Print): 2147-9720

ISSN (Electronic): 2148-4279

Publication date (Print): December 2018

Publication date (Electronic): 12 October 2018

Volume: 5

Issue: 4

Pages: 224-229

Affiliations

[1 ]Department of Dermatology, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain

[2 ]Department of Dermatology, Hospital Universitario del Sureste, Arganda del Rey, Madrid, Spain

[3 ]Department of Rheumatology, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain

[4 ]Department of Radiology, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain

Author notes

Address for Correspondence: Susana Medina; Department of Dermatology, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain. E-mail: susana.medina@ 123456salud.madrid.org