Botulinum Neurotoxins for the Treatment of Chronic Pain and Headaches

A special issue of Toxins (ISSN 2072-6651). This special issue belongs to the section "Bacterial Toxins".

Deadline for manuscript submissions: 30 June 2026 | Viewed by 9648

Special Issue Editor


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Guest Editor
Headache Research, Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE1 1UL, UK
Interests: neurobiology of primary and secondary headaches
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Special Issue Information

Dear Colleagues,

We invite researchers to contribute to the growing body of knowledge on the role of botulinum toxins in the treatment of headaches and pain. While botulinum toxin A is currently approved for the treatment of chronic migraine, its use has expanded widely as an off-label therapy for various other pain conditions, offering promising outcomes for patients who struggle with these complex disorders. Current clinical trials from various industries and research groups in the field of botulinum toxins are exploring the broader potential of their products in treating both episodic and chronic migraine, as well as exploring novel applications in the field of other chronic pain conditions. Further research offering clarity on the mechanism of action of botulinum toxins in sensory systems and their CNS pathways is urgently needed. Looking ahead, the future of botulinum toxin therapies is particularly exciting with the development of recombinant botulinum toxins and non-paralytic formulations. These advancements may further enhance treatment precision and patient outcomes, offering new hope for those who have not found adequate relief through conventional therapies. As the field continues to evolve, your contributions to this important area of research could shape the next generation of headache pain management solutions.

Dr. Anna P. Andreou
Guest Editor

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Keywords

  • botulinum toxins
  • migraine 
  • chronic pain
  • pain management
  • headaches
  • neuropathic pain

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Published Papers (4 papers)

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Research

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21 pages, 6994 KB  
Article
Cholera Toxin-Mediated Targeting of Botulinum Neurotoxin Activity to Pain-Associated Sensory Neurons
by Eve Corrie, Rebecca Bresnahan, Ciara Doran, Charlotte Leese, Matthew R. Balmforth, Anna Andreou, Aisha Zhantleuova, Elizabeth P. Seward, Michael E. Webb, W. Bruce Turnbull and Bazbek Davletov
Toxins 2026, 18(4), 174; https://doi.org/10.3390/toxins18040174 - 3 Apr 2026
Viewed by 956
Abstract
Botulinum neurotoxin injections are used off-label to treat chronic pain, but their efficacy is limited and paralytic effects restrict clinical utility in these applications. Here, we investigated whether combining the light chain and translocation domains of botulinum neurotoxin A (BoNT/A) with the GM1-binding [...] Read more.
Botulinum neurotoxin injections are used off-label to treat chronic pain, but their efficacy is limited and paralytic effects restrict clinical utility in these applications. Here, we investigated whether combining the light chain and translocation domains of botulinum neurotoxin A (BoNT/A) with the GM1-binding B subunit of cholera toxin would be beneficial in silencing pain-associated sensory neurons. Chimeric ChoBot was assembled via a coiled-coil linking technology and was shown to retain the enzymatic activity of BoNT/A in vitro and in vivo. In cultured dorsal root ganglion neurons, ChoBot cleaved SNAP25 in a calcitonin gene-related peptide (CGRP)-rich subpopulation of sensory neurons, resulting in marked inhibition of CGRP release. ChoBot had a lesser effect on the compound muscle action potentials of the rat gastrocnemius muscle than BoNT/A following subcutaneous injections. In rat models of pain, including chemotherapy-induced peripheral neuropathy, intraplantar administration of ChoBot significantly attenuated mechanical allodynia. Immunohistochemical analysis confirmed SNAP25 cleavage in NF200- and CGRP-expressing sensory fibres in the epidermis following a single injection. ChoBot also mediated SNAP25 cleavage in human neuroblastoma cells in culture. Together, these findings indicate that ChoBot enables a silencing of pain-associated sensory pathways, providing a new strategy for the development of new long-lasting analgesics for chronic pain. Full article
(This article belongs to the Special Issue Botulinum Neurotoxins for the Treatment of Chronic Pain and Headaches)
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13 pages, 1493 KB  
Article
OnabotulinumtoxinA Is an Effective Treatment for Reducing the Interictal Burden in Patients with Chronic Migraine: A Prospective Observational Study
by Alejandro Sánchez-Huertas, Oscar Camejo-Mas, Sebastian Garcia-Roldan, Rocio Alonso-Castillo, Lara Pulido-Fraiz, Andrea Higuera Ruiz de la Hermosa, Leonardo Portocarrero-Sánchez and Javier Díaz-de-Terán
Toxins 2025, 17(9), 463; https://doi.org/10.3390/toxins17090463 - 16 Sep 2025
Cited by 2 | Viewed by 2009
Abstract
Interictal burden (IB), defined as the symptoms and impairments that occur between migraine attacks, including cognitive dysfunction, photophobia, and fatigue, is recognized as a significant determinant of quality of life in patients. A prospective observational study was conducted. Patients diagnosed with chronic migraine [...] Read more.
Interictal burden (IB), defined as the symptoms and impairments that occur between migraine attacks, including cognitive dysfunction, photophobia, and fatigue, is recognized as a significant determinant of quality of life in patients. A prospective observational study was conducted. Patients diagnosed with chronic migraine (CM) and under treatment with OnabotulinumtoxinA (OnabotA) according to the PREEMPT protocol (every 12 weeks) were assessed at baseline and at 3, 6, 9, and 12 months. The primary endpoint was to evaluate the change in the IB measured with the Migraine Interictal Burden Scale (MIBS-4) and in the monthly migraine days (MMD). The secondary endpoint was acute medication use. This single-center study included 150 patients (91.3% female; median age 44 years). MIBS-4 scores were decreased by 29.1% at 3 months (8.47 to 5.97) and by 41.6% at 12 months (to 4.86; p < 0.001). IB-free status was achieved by 16 patients (10.7%). The most disabling baseline symptoms were photophobia (37%), fatigue (20%), and allodynia (18%), which reduced by 52%, 43%, and 39% at 12 months, respectively. MMD were reduced from 18.6 to 8.3 days at 12 months and triptan and analgesic intake decreased by 58.7% and 55.4%. OnabotA significantly reduced both IB and migraine frequency over 12 months, underscoring its relevance in CM management. Full article
(This article belongs to the Special Issue Botulinum Neurotoxins for the Treatment of Chronic Pain and Headaches)
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13 pages, 3351 KB  
Article
Patient Satisfaction with Aesthetic Outcomes Following OnabotulinumtoxinA Treatment for Chronic Migraine: A Cross-Sectional Study
by Magdalena Boczarska-Jedynak, Marta Bott-Karoń, Karol Marschollek, Mariola Antolak, Maciej Świat and Marta Waliszewska-Prosół
Toxins 2025, 17(6), 292; https://doi.org/10.3390/toxins17060292 - 8 Jun 2025
Viewed by 3125
Abstract
OnabotulinumtoxinA (OnaBoNT-A) is approved for chronic migraine prevention and follows the PREEMPT protocol with injections in the glabellar and forehead regions. While aesthetic changes are considered a side effect, their effect on patient satisfaction has not been thoroughly assessed. This study evaluated patient [...] Read more.
OnabotulinumtoxinA (OnaBoNT-A) is approved for chronic migraine prevention and follows the PREEMPT protocol with injections in the glabellar and forehead regions. While aesthetic changes are considered a side effect, their effect on patient satisfaction has not been thoroughly assessed. This study evaluated patient satisfaction with facial aesthetic outcomes after repeated OnaBoNT-A treatment for chronic migraine. Conducted at specialist headache centers, it included adult patients with chronic migraine who had received at least three OnaBoNT-A cycles. Participants completed a structured questionnaire on demographics, migraine history, facial wrinkles and age perception, appearance satisfaction, psychological impact, treatment satisfaction, and adverse aesthetic events. A total of 124 patients (92.7% female; median age 42.5 years) participated. OnaBoNT-A reduced wrinkle severity (p < 0.0001). Most patients (74.2%) reported aesthetic improvement post-treatment. The majority of patients (76.7%) declared that treatment met or exceeded expectations. 32% reported looking younger post-treatment, with a median perceived age difference of 5 years. Adverse event frequency was similar to pivotal trial outcomes, mostly mild, with no treatment discontinuations. OnaBoNT-A for chronic migraine, following the PREEMPT protocol, provides significant therapeutic benefits and high patient satisfaction regarding aesthetic outcomes. Although aesthetic side effects were generally mild, they were not uncommon. Full article
(This article belongs to the Special Issue Botulinum Neurotoxins for the Treatment of Chronic Pain and Headaches)
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Review

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15 pages, 264 KB  
Review
Intramuscular Botulinum Toxin for Complex Regional Pain Syndrome: A Narrative Review of Published Cases
by Marc Klee, Nilkolaj la Cour Karottki and Bo Biering-Sørensen
Toxins 2025, 17(7), 350; https://doi.org/10.3390/toxins17070350 - 11 Jul 2025
Cited by 1 | Viewed by 2836
Abstract
Background: Since the 1980s, numerous case reports have explored the use of intramuscular botulinum toxin (BoNT) for Complex Regional Pain Syndrome (CRPS), with significant variation in rationale, dosing, guidance techniques, and outcome measures. This narrative review aims to summarize published evidence on the [...] Read more.
Background: Since the 1980s, numerous case reports have explored the use of intramuscular botulinum toxin (BoNT) for Complex Regional Pain Syndrome (CRPS), with significant variation in rationale, dosing, guidance techniques, and outcome measures. This narrative review aims to summarize published evidence on the use of intramuscular BoNT in patients with CRPS, including studies using earlier terminology such as reflex sympathetic dystrophy (RSD). Given the heterogeneous and largely anecdotal nature of the literature, this review is intended to map the existing landscape rather than conduct a formal analysis. Methods: The PubMed and EMBASE databases were searched in August 2024 using terms related to CRPS and botulinum toxin. Following abstract and full-text screening, 25 publications were included. Results: The included studies span single case reports, case series, and small cohorts, encompassing at least 96 individual CRPS patients treated with intramuscular BoNT. Reported outcomes were heterogeneous, and key treatment parameters—such as toxin type, target muscles, guidance technique, and dosing—were inconsistently reported. Conclusion: The evidence for intramuscular BoNT in CRPS remains limited and heterogeneous, preventing firm conclusions on its efficacy or safety. Its use may be considered in select cases, particularly those with disabling or painful focal dystonia or myofascial pain, but standardized prospective studies are needed to clarify its clinical role. Full article
(This article belongs to the Special Issue Botulinum Neurotoxins for the Treatment of Chronic Pain and Headaches)
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