Special Issue "Botulinum Toxin for Neuropathic Pain Treatment"

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

Deadline for manuscript submissions: closed (30 June 2019).

Special Issue Editor

Dr. Antonella Giannantoni
E-Mail Website
Guest Editor
Department of Medical and Surgical Sciences and Neurosciences, Functional and Surgical Urology Unit, University of Siena, 53100 Siena, Italy
Interests: functional urology; female urology; neuro-urology; oncological urology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Collegues,

Botulinum neurotoxin (BoNT), derived from Clostridium botulinum, has been used worldwide for the treatment of neurologic disorders, such as dystonia or spasticity, and for cosmetic purposes. The neurotoxin has eight antigenically different serotypes, and its main mechanism of action is the inhibition of acetylcholine release at presynaptic nerve terminals, with a resulting reduction of muscle fiber activity.

In recent times, the therapeutic use of BoNT, and particularly of BoNT/A, has expanded to cover different clinical conditions characterized by neuropathic pain (NP), such as chronic migraine, lower back pain, myofascial pain, trigeminal neuropathy, temporo-mandibular joint disorders, osteoarthritis, pelvic pain, and bladder painful syndrome.

NP, which is pain caused by a lesion or a disease of the somatosensory system, affects 6–8% of the general population and exerts a great impact on patients’ quality of life. Despite its high prevalence, NP is still difficult to diagnose and treat, as it is not a unique disease but a syndrome covering a wide spectrum of different pathologies with complex clinical presentations and multiple signs and symptoms. The pathophysiology of NP involves both the peripheral and the central nervous systems and includes changes in the excitability of peripheral nerves and dorsal root ganglions (peripheral sensitization), changes in spinal cord neurons, the descending pain-controlling systems, and abnormal brain plasticity (central sensitization).

Although BoNT/A action on NP is still mainly considered to be of peripheral origin, recent findings showed that the neurotoxin is axonally transported to central sensory regions and suggested that its antinociceptive action is centrally mediated. Yet, the process by which BoNT/A is able to induce pain relief is not clear, and many additional questions remain to be answered on the mechanism of BoNT/A antinociceptive action at both peripheral and central levels and on the effectiveness of the neurotoxin in the treatment of different pain syndromes. Studies addressing these questions are welcomed.

Prof. Dr. Antonella Giannantoni
Guest Editor

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Keywords

  • Botulinum toxin
  • neuropathic pain
  • C-fibers
  • chronic pain syndromes
  • hyperalgesia
  • allodynia
  • substance P
  • glutamate
  • calcitonin gene-related peptide

Published Papers (7 papers)

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Research

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Article
Plasma Levels of Oxidative Stress Markers, before and after BoNT/A Treatment, in Chronic Migraine
Toxins 2019, 11(10), 608; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins11100608 - 19 Oct 2019
Cited by 6 | Viewed by 1181
Abstract
The pathophysiological mechanisms of migraine transformation are debated. Modifications of plasma oxidative stress biomarkers have been described in chronic migraine. OnabotulintoxinA (BoNT/A) treatment, approved for chronic migraine prophylaxis, possibly reduces pain neurotransmitters release and oxidative stress products. Aims of our study were to [...] Read more.
The pathophysiological mechanisms of migraine transformation are debated. Modifications of plasma oxidative stress biomarkers have been described in chronic migraine. OnabotulintoxinA (BoNT/A) treatment, approved for chronic migraine prophylaxis, possibly reduces pain neurotransmitters release and oxidative stress products. Aims of our study were to investigate differences in the levels of selected plasmatic oxidative stress biomarkers (Advanced Oxidation Protein Products (AOPP), Ferric Reducing Antioxidant Power (FRAP), Thiolic Groups (SH)) comparing chronic migraineurs (CM) and healthy controls (HC). We also explored possible clinical and biochemical modifications in the CM group after six months of treatment with BoNT/A. At the baseline, we found higher values of AOPP (p < 0.001), and lower values of SH (p < 0.001) and FRAP (p = 0.005) in the CM group. At the six-month follow-up we found a reduction of AOPP (p < 0.001) and an increase of FRAP (p < 0.001) and SH (p = 0.023) within the CM group. BoNT/A treatment improved migraine symptoms in the CM group. We confirmed previous reports of imbalanced antioxidant mechanisms in chronic migraine showing lower antioxidant capacities in patients than controls. BoNT/A improved the levels of plasma oxidative stress biomarkers and confirmed its role as an effective prophylactic treatment for CM. Other studies should investigate the potential antioxidant properties of BoNT/A treatment. Full article
(This article belongs to the Special Issue Botulinum Toxin for Neuropathic Pain Treatment)
Article
A Prospective Observational Cohort Study on Pharmacological Habitus, Headache-Related Disability and Psychological Profile in Patients with Chronic Migraine Undergoing OnabotulinumtoxinA Prophylactic Treatment
Toxins 2019, 11(9), 504; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins11090504 - 29 Aug 2019
Cited by 6 | Viewed by 1731
Abstract
Chronic Migraine (CM) is a disabling neurologic condition with a severe impact on functioning and quality of life. Successful therapeutic management of patients with CM is complex, and differences in therapeutic response could be attributable to genetically determined factors, sensitivity to pharmacological treatment, [...] Read more.
Chronic Migraine (CM) is a disabling neurologic condition with a severe impact on functioning and quality of life. Successful therapeutic management of patients with CM is complex, and differences in therapeutic response could be attributable to genetically determined factors, sensitivity to pharmacological treatment, psychosocial and relational factors affecting the patient’s compliance and approach on the therapeutic treatment. The aim of this prospective observational study was to explore self-efficacy, coping strategies, psychological distress and headache-related disability in a cohort of 40 patients with CM (mean age: 46.73; standard deviation 13.75) treated with OnabotulinumtoxinA and the relationship between these clinical and psychological aspects and acute medication consumption during OnabotulinumtoxinA prophylactic treatment. Patients presented an overall significant reduction in the Headache Index (HI) (p < 0.001), HI with severe intensity (p = 0.009), and total analgesic consumption (p = 0.003) after the prophylactic treatment. These results are in line with the literature. Despite this, higher nonsteroidal anti-inflammatory drugs consumption was associated with higher psychological distress, higher HI with severe and moderate intensity, and worse quality of life. Conversely, triptans consumption was correlated with HI of mild intensity, and problem-focused coping strategies. To conclude, the psychological profile, and in particular, the psychological distress and specific coping strategies might influence the self-management of acute medication. Full article
(This article belongs to the Special Issue Botulinum Toxin for Neuropathic Pain Treatment)
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Article
OnabotulinumtoxinA Reduces Temporal Pain Processing at Spinal Level in Patients with Lower Limb Spasticity
Toxins 2019, 11(6), 359; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins11060359 - 20 Jun 2019
Cited by 1 | Viewed by 1282
Abstract
Spasticity is a muscle tone disorder associated with different neurological conditions. Spasticity could be associated with pain, high disability, poor functional recovery, and reduced quality of life. Botulinum neurotoxin type A (BoNT-A) is considered a first-line treatment for spasticity and, more recently, it [...] Read more.
Spasticity is a muscle tone disorder associated with different neurological conditions. Spasticity could be associated with pain, high disability, poor functional recovery, and reduced quality of life. Botulinum neurotoxin type A (BoNT-A) is considered a first-line treatment for spasticity and, more recently, it also represents a therapeutic option for various chronic pain conditions. In this open label study, we aim to evaluate the effect of the BoNT-A on the spinal nociception in patients affected by spasticity of the lower limbs with associated pain with predominantly neuropathic features. Ten patients with stroke, 10 with multiple sclerosis and 5 with spinal cord injury were enrolled in the study. They were tested with clinical scales (neuropathic pain scale inventory (NPSI), numerical rating scale (NRS), modified Ashworth scale (MAS) and with the nociceptive withdrawal reflex at lower limbs to explore the spinal temporal summation threshold at baseline and 30 day after BoNT-A injection. OnabotulinumtoxinA (50 to 200 units per site) was injected in the lower limb muscles according to the distribution of spasticity. No significant differences were found at baseline for neurophysiological features across groups. After the BoNT-A injection, we recorded a significant reduction in MAS and NRS scores. Regarding the neurophysiological parameters, we described a significant increase in the temporal summation threshold after the BoNT-A injection. Our data supports the hypothesis that peripherally injected OnabotulinumtoxinA modulates the excitability of spinal cord nociceptive pathways. This activity may take place irrespective of the effect of the drug on spasticity. Full article
(This article belongs to the Special Issue Botulinum Toxin for Neuropathic Pain Treatment)
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Review

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Review
The Use of Botulinum Toxin for the Treatment of Chronic Joint Pain: Clinical and Experimental Evidence
Toxins 2020, 12(5), 314; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12050314 - 10 May 2020
Cited by 5 | Viewed by 1278
Abstract
Chronic osteoarthritis pain is an increasing worldwide problem. Treatment for osteoarthritis pain is generally inadequate or fraught with potential toxicities. Botulinum toxins (BoNTs) are potent inhibitors of neuropeptide release. Paralytic toxicity is due to inhibition at the neuromuscular junction, and this effect has [...] Read more.
Chronic osteoarthritis pain is an increasing worldwide problem. Treatment for osteoarthritis pain is generally inadequate or fraught with potential toxicities. Botulinum toxins (BoNTs) are potent inhibitors of neuropeptide release. Paralytic toxicity is due to inhibition at the neuromuscular junction, and this effect has been utilized for treatments of painful dystonias. Pain relief following BoNT muscle injection has been noted to be more significant than muscle weakness and hypothesized to occur because of the inhibition of peripheral neuropeptide release and reduction of peripheral sensitization. Because of this observation, BoNT has been studied as an intra-articular (IA) analgesic for chronic joint pain. In clinical trials, BoNT appears to be effective for nociceptive joint pain. No toxicity has been reported. In preclinical models of joint pain, BoNT is similarly effective. Examination of the dorsal root ganglion (DRG) and the central nervous system has shown that catalytically active BoNT is retrogradely transported by neurons and then transcytosed to afferent synapses in the brain. This suggests that pain relief may also be due to the central effects of the drug. In summary, BoNT appears to be safe and effective for the treatment of chronic joint pain. The long-term effects of IA BoNT are still being determined. Full article
(This article belongs to the Special Issue Botulinum Toxin for Neuropathic Pain Treatment)
Review
Botulinum Neurotoxin A Intravesical Injections in Interstitial Cystitis/Bladder Painful Syndrome: A Systematic Review with Meta-Analysis
Toxins 2019, 11(9), 510; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins11090510 - 30 Aug 2019
Cited by 5 | Viewed by 1845
Abstract
Botulinum neurotoxin A (BoNT/A) appears to be one of the best intravesical treatments for interstitial cystitis/bladder painful syndrome (IC/BPS). We aimed to point out what the evidence is regarding the effects of BoNT/A intravesically injected in patients with IC/BPS. We performed a systematic [...] Read more.
Botulinum neurotoxin A (BoNT/A) appears to be one of the best intravesical treatments for interstitial cystitis/bladder painful syndrome (IC/BPS). We aimed to point out what the evidence is regarding the effects of BoNT/A intravesically injected in patients with IC/BPS. We performed a systematic review of all randomized controlled trials (RCTs) assessing BoNT/A for IC/BPS by using Medline, EMBASE, CINAHL, CENTRAL and MetaRegister of Controlled Trials. Standardized mean differences (SMD) were extracted from the available trials and combined in a meta-analysis applying a random effect model, including heterogeneity of effects. Twelve trials were identified. Significant benefits from BoNT/A injections were detected in: Interstitial Cystitis Symptom Index and Problem Index (ICSI, ICPI) (small to medium effect size: SMD = –0.302; p = 0.007 and –0.430, p = 0.004, respectively); Visual Analog Scale (VAS) for pain and day-time urinary frequency (medium effect size: SMD = –0.576, p < 0.0001 and –0.546, p = 0.013, respectively). A great effect size was detected for post-void residual volume (PVR, SMD = 0.728; p =0.002) although no clinically relevant in most cases. Great heterogeneity was observed in treatments’ methodologies and symptoms assessment. Overall, BoNT/A intravesical injections significantly improve some of the most relevant symptoms affecting IC/BPS patients. Full article
(This article belongs to the Special Issue Botulinum Toxin for Neuropathic Pain Treatment)
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Review
Botulinum Toxin a Valuable Prophylactic Agent for Migraines and a Possible Future Option for the Prevention of Hormonal Variations-Triggered Migraines
Toxins 2019, 11(8), 465; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins11080465 - 08 Aug 2019
Cited by 4 | Viewed by 2589
Abstract
Background: In 1989, Botulinum toxin (BoNT) was accepted by the FDA for the management of some ophthalmic disorders. Although it was initially considered a lethal toxin, in recent times, Botulinum toxin A (BoNT-A), which is the more used serotype, has expanded to cover [...] Read more.
Background: In 1989, Botulinum toxin (BoNT) was accepted by the FDA for the management of some ophthalmic disorders. Although it was initially considered a lethal toxin, in recent times, Botulinum toxin A (BoNT-A), which is the more used serotype, has expanded to cover different clinical conditions, primarily characterized by neuropathic pain, including migraines and headaches. Evidence suggests that migraines are influenced by hormonal factors, particularly by estrogen levels, but very few studies have investigated the prevalence and management strategies for migraines according to the hormonal status. The effects of several therapeutic regimens on migraines have been investigated, but the medications used varied widely in proven efficacies and mechanisms of action. BoNT-A is increasingly used in the management of migraine and several placebo-controlled trials of episodic and chronic migraine are currently underway. This paper is a review of the recently published data concerning the administration of BoNT-A in the prevention of chronic migraines. Considering the lack of population-based studies about the effectiveness of BoNT-A in the alleviation of premenstrual and perimenopausal migraines, this study proposes a new perspective of the therapeutic approach of migraine syndrome associated with menopausal transition and the premenstrual period. Methods: We selected the reviewed papers from CrossRef, PubMed, Medline, and GoogleScholar, and a total of 21 studies met our inclusion criteria. Results: To date, no specific preventive measures have been recommended for menopausal women with migraines. BoNT-A often reduces the frequency and intensity of migraine attacks per month; the treatment is well tolerated and does not exhibit a significantly higher rate of treatment-related side effects. No population-based studies were conducted in order to highlight the role of BoNT-A in menopause-related migraines, neither in menstrual migraines. Conclusion: There is a need for further research in order to quantify the real burden of menstrual and perimenopausal migraines and to clarify if BoNT-A could be used in the treatment of refractory postmenopausal and premenstrual migraines. Full article
(This article belongs to the Special Issue Botulinum Toxin for Neuropathic Pain Treatment)
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Review
Mechanisms of Botulinum Toxin Type A Action on Pain
Toxins 2019, 11(8), 459; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins11080459 - 05 Aug 2019
Cited by 38 | Viewed by 4829
Abstract
Already a well-established treatment for different autonomic and movement disorders, the use of botulinum toxin type A (BoNT/A) in pain conditions is now continuously expanding. Currently, the only approved use of BoNT/A in relation to pain is the treatment of chronic migraines. However, [...] Read more.
Already a well-established treatment for different autonomic and movement disorders, the use of botulinum toxin type A (BoNT/A) in pain conditions is now continuously expanding. Currently, the only approved use of BoNT/A in relation to pain is the treatment of chronic migraines. However, controlled clinical studies show promising results in neuropathic and other chronic pain disorders. In comparison with other conventional and non-conventional analgesic drugs, the greatest advantages of BoNT/A use are its sustained effect after a single application and its safety. Its efficacy in certain therapy-resistant pain conditions is of special importance. Novel results in recent years has led to a better understanding of its actions, although further experimental and clinical research is warranted. Here, we summarize the effects contributing to these advantageous properties of BoNT/A in pain therapy, specific actions along the nociceptive pathway, consequences of its central activities, the molecular mechanisms of actions in neurons, and general pharmacokinetic parameters. Full article
(This article belongs to the Special Issue Botulinum Toxin for Neuropathic Pain Treatment)
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