Botulinum Toxin Type A as a Therapeutic Agent against Headache and Related Disorders (original) (raw)
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Botulinum Neurotoxin for Pain Management: Insights from Animal Models
2010
The action of botulinum neurotoxins (BoNTs) at the neuromuscular junction has been extensively investigated and knowledge gained in this field laid the foundation for the use of BoNTs in human pathologies characterized by excessive muscle contractions. Although much more is known about the action of BoNTs on the peripheral system, growing evidence has demonstrated several effects also at the central level. Pain conditions, with special regard to neuropathic and intractable pain, are some of the pathological states that have been recently treated with BoNTs with beneficial effects. The knowledge of the action and potentiality of BoNTs utilization against pain, with emphasis for its possible use in modulation and alleviation of chronic pain, still represents an outstanding challenge for experimental research. This review highlights recent findings on the effects of BoNTs in animal pain models.
The role of botulinum toxin in management of pain: an evidence-based review
Current Opinion in Anaesthesiology, 2010
Purpose of review In the present review we discuss the role of botulinum neurotoxins (BoNTs) in the management of different pain conditions, with evidence-based data on the toxins' efficacy on pain and its mechanisms. Recent findings Experimental in-vitro studies have reported promising results of a novel recombinant chimera of BoNT A and E that inhibits the calcitonin gene-related peptide exocytosis from brainstem sensory neurons. Animal studies in neuropathic pain rat models have reported an analgesic effect of BoNT A given after the neuropathic procedure and a bilateral antinociceptive effect to the unilateral noxious stimuli. There is a growing body of evidence that BoNTs are effective in myofascial pain syndrome, neuropathic pain, and joint pain. The pre-existing evidence that BoNTs are ineffective in migraine or other headache disorders has not yet been challenged. In other pain syndromes, studies published in the last review year have not contributed significantly in either demonstrating or invalidating the research that has so far proved inconclusive. Summary The role of BoNTs in management of pain is not yet well established. Larger studies in neuropathic pain, joint pain, and myofascial pain syndrome are needed to fully ascertain the role for BoNT therapy in those areas.
Botulinum toxins: Mechanisms of action, antinociception and clinical applications
Toxicology, 2013
Botulinum toxin (BoNT) is a potent neurotoxin that is produced by the gram-positive, spore-forming, anaerobic bacterium, Clostridum botulinum. There are 7 known immunologically distinct serotypes of BoNT: types A, B, C1, D, E, F, and G. Clostridum neurotoxins are produced as a single inactive polypeptide chain of 150 kDa, which is cleaved by tissue proteinases into an active di-chain molecule: a heavy chain (H) of ∼100 kDa and a light chain (L) of ∼50 kDa held together by a single disulfide bond. Each serotype demonstrates its own varied mechanisms of action and duration of effect. The heavy chain of each BoNT serotype binds to its specific neuronal ecto-acceptor, whereby, membrane translocation and endocytosis by intracellular synaptic vesicles occurs. The light chain acts to cleave SNAP-25, which inhibits synaptic exocytosis, and therefore, disables neural transmission. The action of BoNT to block the release of acetylcholine botulinum toxin at the neuromuscular junction is best understood, however, most experts acknowledge that this effect alone appears inadequate to explain the entirety of the neurotoxin's apparent analgesic activity. Consequently, scientific and clinical evidence has emerged that suggests multiple antinociceptive mechanisms for botulinum toxins in a variety of painful disorders, including: chronic musculoskeletal, neurological, pelvic, perineal, osteoarticular, and some headache conditions.
The long-term efficacy and safety of botulinum toxin in refractory chronic tension-type headache
The Journal of Headache and Pain, 2007
Local chemodenervation with botulinum toxin (BoNT) injections to relax abnormally contracting muscles has been shown to be an effective and well-tolerated treatment in a variety of movement disorders and other neurological and non-neurological disorders. Despite almost 30 years of therapeutic use, there are only few studies of patients treated with BoNT injections over long period of time. These published data clearly support the conclusion that BoNT not only provides safe and effective symptomatic relief of dystonia but also long-term benefit and possibly even favorably modifying the natural history of this disease. The adverse events associated with chronic, periodic exposure to BoNT injections are generally minor and self-limiting. With the chronic use of BoNT and an expanding list of therapeutic indications, there is a need to carefully examine the existing data on the long-term efficacy and safety of BoNT. In this review we will highlight some of the aspects of long-term effects of BoNT, including efficacy, safety, and immunogenicity.
Neurology: Clinical Practice
This article is presented as a companion to the American Academy of Neurology guideline update on the use of botulinum neurotoxin (BoNT) for the treatment of blepharospasm, cervical dystonia, adult spasticity, and headache. Whereas the guideline update provides clarity on the efficacy of different BoNT-branded preparations for the 4 listed indications, this companion piece identifies ambiguities in the evidence for efficacy among various brand names for a given clinical indication, their dosing equivalencies, as well as different clinical indications. This article provides guidance and background information to reduce obstacles for third party payment, especially when uncertainties exist and levels of evidence are lower. Neurol Clin Pract 2016;6:281-286 T he first American Academy of Neurology (AAN) guideline on the use of botulinum toxin (BoNT), published in 2008, focused predominantly on the pharmacology and immunology of the toxin. 1-3 The guideline also reviewed a variety of clinical indications, with recommendations of efficacy based on the toxin as a whole. Furthermore, there was insufficient evidence to recommend the use of BoNT for chronic migraine. Since then, there has been more evidence on the efficacy of different brand formulations for different indications as well greater understanding of the differences in pharmacology and immunology between the toxin A and B serotypes and branded formulations. However, there are
Botulinum toxin A, brain and pain
Progress in Neurobiology, 2014
Botulinum neurotoxin type A (BoNT/A) is one of the most potent toxins known and a potential biological threat. At the same time, it is among the most widely used therapeutic proteins used yearly by millions of people, especially for cosmetic purposes. Currently, its clinical use for treatment of certain types of pain is increasing, and its long-term effectiveness represents a special clinical value. Efficacy of BoNT/A in different types of pain has been found in numerous clinical trials and case reports, as well as in animal pain models. However, sites and mechanisms of BoNT/A actions involved in nociception are a matter of controversy. In analogy with well known neuroparalytic effects in peripheral cholinergic synapses, presently dominant opinion is that BoNT/A exerts pain reduction by inhibiting peripheral neurotransmitter/inflammatory mediator release from sensory nerves. On the other hand, growing number of behavioral and immunohistochemical studies demonstrated the requirement of axonal transport for BoNT/A's antinociceptive action. In addition, toxin's enzymatic activity in central sensory regions was clearly identified after its peripheral application. Apart from general pharmacology, this review summarizes the clinical and experimental evidence for BoNT/A antinociceptive activity and compares the data in favor of peripheral versus central site and mechanism of action. Based on literature review and published results from our laboratory we propose that the hypothesis of peripheral site of BoNT/A action is not sufficient to explain the experimental data collected up to now. Keywords: botulinum toxin type A; pain; axonal transport; sensory nervous system, synaptosomal-associated protein of 25 kDa Highlights:-BoNT/A is therapeutically useful in certain chronic pain conditions and migraine 3. 3 BoNT/A activity is not restricted to inhibition of SNAP-25-mediated acetylcholine release 3.3.1 Effect on neurotransmitters other than acetylcholine 3.3.2 Preferential effect on excitatory vs. inhibitory neurons. 3.3.3 Activity outside of synaptic active zone. 3.3.4 Effects on cell types other than neurons. 3.3.5 Additional actions of BoNT/A mediated by SNAP-25 3.3.6 Possible additional targets of BoNT/A action other than SNAP-25 4. ANTINOCICEPTIVE ACTION OF BONT/A 4.1 Clinical evidence of BoNT/A's antinociceptive activity 4.1.1 Early clinical observations 4.1.2 Present clinical experience 4.2 Preclinical studies 4.2.1 Ex vivo and in vitro studies 4.2.2 In vivo models 4.3 Peculiar properties of BoNT/A antinociceptive activity 5. PERIPHERAL OR CENTRAL MECHANISM OF BONT/A'S ANTINOCICEPTIVE ACTIVITY 5.1 Peripheral theory of BoNT/A's antinociceptive action 5.2 Dissociation of BoNT/A antinociceptive activity and peripheral anti-inflammatory effects 5.3 Effects on bilateral pain: indication of central action of BoNT/A 6. AXONAL TRANSPORT OF BONT/A 6.1 Early studies of BoNT/A axonal transport to CNS 6.2 Behavioral and pharmacological evidence for the necessity of BoNT/A axonal transport for its antinociceptive activity 5 6.3 Neurophysiological evidence for axonal transport of BoNT/A 6.3.1 Studies in humans 6.3.2. Neurophysiological evidence for BoNT/A axonal transport in animals 6.4 Axonal transport of enzymatically active BoNT/A in the CNS and motoneurons 6.5 Immunohistochemical studies of axonal transport of enzymatically active BoNT/A to central nociceptive regions 7. WHAT IS THE MECHANISM OF BONT/A ANTINOCICEPTIVE ACTION IN CNS? POSSIBLE ROLE OF OPIOIDERGIC AND GABA-ERGIC NEUROTRANSMISSION 8. CONCLUDING OVERVIEW 8.1 Central vs. peripheral action of BoNT/A 8.2 Is there any predictive value of preclinical research and discoveries about central mechanism of BoNT/A action? 8.3 What we do not know about BoNT/A and CNS? 9. CONCLUSION
Neurotherapeutics, 2020
With a prevalence of 15%, migraine is the most common neurological disorder and among the most disabling diseases, taking into account years lived with disability. Current oral medications for migraine show variable effects and are frequently associated with intolerable side effects, leading to the dissatisfaction of both patients and doctors. Injectable therapeutics, which include calcitonin gene-related peptide-targeting monoclonal antibodies and botulinum neurotoxin A (BoNT/A), provide a new paradigm for treatment of chronic migraine but are effective only in approximately 50% of subjects. Here, we investigated a novel engineered botulinum molecule with markedly reduced muscle paralyzing properties which could be beneficial for the treatment of migraine. This stapled botulinum molecule with duplicated binding domain-binary toxin-AA (BiTox/AA)-cleaves synaptosomal-associated protein 25 with a similar efficacy to BoNT/A in neurons; however, the paralyzing effect of BiTox/ AA was 100 times less when compared to native BoNT/A following muscle injection. The performance of BiTox/AA was evaluated in cellular and animal models of migraine. BiTox/AA inhibited electrical nerve fiber activity in rat meningeal preparations while, in the trigeminovascular model, BiTox/AA raised electrical and mechanical stimulation thresholds in Aδ-and Cfiber nociceptors. In the rat glyceryl trinitrate (GTN) model, BiTox/AA proved effective in inhibiting GTN-induced hyperalgesia in the orofacial formalin test. We conclude that the engineered botulinum molecule provides a useful prototype for designing advanced future therapeutics for an improved efficacy in the treatment of migraine.
Clinical Uses of Botulinum Neurotoxins: Current Indications, Limitations and Future Developments
Botulinum neurotoxins (BoNTs) cause flaccid paralysis by interfering with vesicle fusion and neurotransmitter release in the neuronal cells. BoNTs are the most widely used therapeutic proteins. BoNT/A was approved by the U.S. FDA to treat strabismus, blepharospam, and hemificial spasm as early as 1989 and then for treatment of cervical dystonia, glabellar facial lines, axillary hyperhidrosis, chronic migraine and for cosmetic use. Due to its high efficacy, longevity of action and satisfactory safety profile, it has been used empirically in a variety of ophthalmological, gastrointestinal, urological, orthopedic, dermatological, secretory, and painful disorders. Currently available BoNT therapies are limited to neuronal indications with the requirement of periodic injections resulting in immune-resistance for some indications. Recent understanding of the structure-function relationship of BoNTs prompted the engineering of novel BoNTs to extend therapeutic interventions in non-neuronal systems and to overcome the immune-resistance issue. Much research still needs to be done to improve and extend the medical uses of BoNTs.