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Botulinum toxin treatment of pain syndromes –an evidence based review
Abstract
This review evaluates the existing level of evidence for efficacy of BoNTs in different pain syndromes using the recommended efficacy criteria from the Assessment and Therapeutic Subcommittee of the American Academy of Neurology. There is a level A evidence (effective) for BoNT therapy in post-herpetic neuralgia, trigeminal neuralgia, and posttraumatic neuralgia. There is a level B evidence (probably effective) for diabetic neuropathy, plantar fasciitis, piriformis syndrome, pain associated with total knee arthroplasty, male pelvic pain syndrome, chronic low back pain, male pelvic pain, and neuropathic pain secondary to traumatic spinal cord injury. BoNTs are possibly effective (Level C -one class II study) for female pelvic pain, painful knee osteoarthritis, post-operative pain in children with cerebral palsy after adductor release surgery, anterior knee pain with vastus lateralis imbalance. There is a level B evidence (one class I study) that BoNT treatment is probably ineffective in carpal tunnel syndrome. For myofascial pain syndrome, the level of evidence is U (undetermined) due to contradicting results. More high quality (Class I) studies and studies with different types of BoNTs are needed for better understanding of the role of BoNTs in pain syndromes.
... Se caracteriza por un dolor de moderado a severo 5 , pudiendo ser continuo o en ocasiones difuso; en raras ocasiones, el dolor traspasa la línea media y de tipo quemante 9 , punzante, pudiendo cursar con alodinia, hiperalgesia, hiperestesia o disestesia 10 . Por lo general, no presenta un gatillante ni un periodo de latencia y es refractario, similar a la neuralgia de trigémino 5 . ...
... En la forma periférica, el daño al sistema nervioso periférico provoca irritación de la terminación del nervio periférico y acumulación de agentes nociceptivos (péptido relacionado con el gen de calcitonina, sustancia P, glutamato, bradiquinina). La acumulación de moduladores del dolor, más la inflamación local, reduce el umbral sensorial de las terminaciones nerviosas periféricas a los estímulos nociceptivos (sensibilización periférica) 10 . La sensibilización periférica incrementa las señales nociceptivas en la médula espinal (sensibilización central). ...
... inyecciones a lo largo del recorrido del nervio trigémino[3][4][5][6][7][8][9][10][11][12][13][14][15] . En estudio de la dilución se realiza en 4cc de solución salina por 100 U de OnaBoNT-A 10 . ...
La toxina botulínica A (BoNT-A) es una potente neurotoxina producida por Clostridium botulinum. Se utiliza ampliamente en la medicina y en el campo cosmético, ya que tiene un efecto analgésico. Este efecto se logra mediante la inhibición de neurotransmisores y neuropéptidos involucrados en los mecanismos de inflamación y dolor. La BoNT-A ha demostrando ser eficaz para el tratamiento de diversas condiciones, como migraña crónica, cefaleas primarias, neuropatía diabética, neuralgia post herpética y síndromes dolorosos, como neuralgia de trigémino, neuralgia postraumática. Recientemente, la Clasificación de la Sociedad Internacional de Cefaleas (IHS, por sus siglas en inglés) ha adoptado el término “dolorneuropático trigeminal postraumático” (PTTN). Este tipo de dolor neuropático se define como aquel causado por una lesión o enfermedad del sistema somatosensorial. Se caracteriza por un dolor difuso que persiste sin una causa o enfermedad obvia. El patrón de dolor asociado es de tipo sordo, con una sensación de quemazón.
... Most often, such pain is described by patients as burning, burning. Additionally, allodynia, hyperalgesia, hyperesthesia, or dysaesthesia often coexist (6). ...
... According to the efficacy criteria established by the American Academy of Neurology, botulinum toxin effectively treats post-herpetic, trigeminal, and post-traumatic neuralgia (level A of evidence of efficacy). In addition, BTA is also expected to be effective in the treatment of diabetic neuropathy, chronic lumbar spine pain, male pelvic pain syndrome, carpal tunnel syndrome, plantar fasciitis, knee replacement pain, post-traumatic neuropathic pain (evidence level B efficacy), and female pelvic pain syndrome, knee pain caused by osteoporosis (evidence of efficacy level C) (6). ...
... Studies in cell cultures and animals show that BTA can affect pain transmitters in the peripheral and central nervous systems (6). In cell culture studies, the administration of botulinum toxin type A to neurons inhibits the release of calcitonin gene-related peptide (CGRP), glutamate, and other pain transmitters from nerve endings dorsal root ganglia of sensory fibers. ...
... Analgesia was first observed as a side effect concomitant to muscle relaxation after BoNT application [17,18]. BoNT-A provides analgesic effects in pain disorders such as chronic migraine [19], trigeminal neuralgia [20], peripheral neuropathic pain [21][22][23], and other pain syndromes [24,25]. The analgesic effect produced by BoNT appears to be multifactorial, by blocking the release of pain-related neurotransmitters [16,26], by blocking the release of excitatory neurotransmitters in the dorsal root ganglions after being retrogradely transported in peripheral administration [27], and potentially, by indirect desensitization of peripheral nociceptors [24]. ...
... BoNT-A provides analgesic effects in pain disorders such as chronic migraine [19], trigeminal neuralgia [20], peripheral neuropathic pain [21][22][23], and other pain syndromes [24,25]. The analgesic effect produced by BoNT appears to be multifactorial, by blocking the release of pain-related neurotransmitters [16,26], by blocking the release of excitatory neurotransmitters in the dorsal root ganglions after being retrogradely transported in peripheral administration [27], and potentially, by indirect desensitization of peripheral nociceptors [24]. ...
Osteoarthritis (OA) is the most prevalent rheumatologic disease and a leading cause of years lived with disability worldwide. There are no disease-modifying drugs available to treat it. This study aimed to evaluate the effect of a single dose of 100U botulinum neurotoxin-A (BoNT-A) in patients with early knee OA. We designed a single-arm preliminary clinical trial in patients diagnosed with knee OA (KOA) grades I and II. 45 Patients received a single dose of 100U IncobotulinumtoxinA in the retro-patellar bursa and received nutritional and physical rehabilitation indications. Patients were evaluated at baseline and at days 5, 30, 60, and 90 after injection. The primary outcome was the reduction in pain using the visual analog scale (VAS). Knee function was evaluated using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). We assessed secondary adverse effects and measured muscular strength in every consultation. Descriptive endpoint summaries and a generalized linear random-effect model were used to evaluate changes in each follow-up time compared to baseline. IncobotulinumtoxinA treatment significantly (p < 0.001) reduced pain in all treated patients at day 90 compared to day 0. Patients showed a significant reduction in total WOMAC score (p < 0.001), from a mean baseline of 44.6 (95% CI; 41.4, 47.8) to 4.4 at day 90 (95% CI; 0.2, 0.3). Our results show that IncobotulinumtoxinA applied in the retro-patellar bursa is a safe and effective treatment for pain in patients with early-stage KOA, offering a potential alternative for symptomatic control in KOA.
... The pathophysiology of CRPS involves peripheral sensitisation driven by neurogenic inflammation as well as central sensitisation (6). Botulinum toxin type A holds promise in mitigating neurogenic inflammation by suppressing nociceptive neuropeptides and may also possess the capacity to inhibit central sensitisation (7). Furthermore, BTX-A injections have been employed for pain alleviation in various central and peripheral neuropathic pain conditions (8,9). ...
... Previous empirical evidence was primarily confined to isolated case studies employing proximal BTX-A injections for individuals afflicted with CRPS linked to myofascial pain syndrome (MFPS) (13,14). However, a recent comprehensive study involving 20 patients experiencing refractory CRPS, who underwent BTX-A injections, exhibited a noteworthy reduction in pain scores (7). Furthermore, a recent meta-analysis of 25 randomised controlled trials (RCTs) concluded that BTX-A e xhibited efficacy in alleviating pain across a spectrum of conditions, encompassing both muscle-related conditions such as spasticity and dystonia as well as non-muscle-based pain disorders, including CRPS and diabetic neuropathy. ...
... Ботулинотерапия. Ботулинический токсин типа А (БТА) предотвращает экзоцитоз возбуждающих нейротрансмиттеров периферических и сенсорных нейронов путем расщепления белков SNARE (soluble NSF attachment receptor) и ингибирования их действия [100]. Это приводит к блокаде высвобождения ацетилхолина в пресинаптическом нервно-мышечном соединении и, таким образом, вызывает паралич мышцы [101]. ...
... Исследования показали, что БТА служит для ингибирования высвобождения вещества P из культивируемых эмбриональных нейронов ганглия дорсального корня. Это также уменьшает высвобождение CGRP из нейронов культуры тройничных ганглиев [100]. Предполагается, что инъекции БТА аналогичным образом ингибируют высвобождение этих нейропептидов in vivo, а также снижают уровень лактата в интересующей сокращающейся мышце, что приводит к ингибированию высвобождения сенсибилизирующих медиаторов [102]. ...
Currently, back pain ranks fourth among the causes of disability of the population. Lumbar pain and pain in the lower back are the most common among the pain syndromes. Tunnel neuropathies of the pelvic girdle including piriformis syndrome are among the particular manifestations of this pathology. The purpose of this article was to summarize modern ideas about the etiology and pathogenesis, diagnosis and treatment of piriformis syndrome.
... BoNT can inhibit not only the release of Ach but also other neurotransmitters [32]. For several types of neuropathic pain such as trigeminal, posttraumatic, or postherpetic neuralgia, significant analgesic effects have been observed after administration of botulinum toxin A (BoNT/A) [165,201,202]. It is speculated that BoNT/A exerts its therapeutic effect by inhibiting the process of the secretion of some pain mediators (substance P, glutamate, and calcitonin-gene-related protein (CGRP)) and other pain transmitters released from the nerve terminals and dorsal root ganglions (DRGs) and trigeminal sensory neurons [165,[203][204][205]. ...
... For several types of neuropathic pain such as trigeminal, posttraumatic, or postherpetic neuralgia, significant analgesic effects have been observed after administration of botulinum toxin A (BoNT/A) [165,201,202]. It is speculated that BoNT/A exerts its therapeutic effect by inhibiting the process of the secretion of some pain mediators (substance P, glutamate, and calcitonin-gene-related protein (CGRP)) and other pain transmitters released from the nerve terminals and dorsal root ganglions (DRGs) and trigeminal sensory neurons [165,[203][204][205]. There is evidence that after peripheral administration of BoNT/A, the antinociceptive action is not primarily mediated by the direct prevention of central CGRP release. ...
Neurotoxins generally inhibit or promote the release of neurotransmitters or bind to receptors that are located in the pre- or post-synaptic membranes, thereby affecting physiological functions of synapses and affecting biological processes. With more and more research on the toxins of various origins, many neurotoxins are now widely used in clinical treatment and have demonstrated good therapeutic outcomes. This review summarizes the structural properties and potential pharmacological effects of neurotoxins acting on different components of the synapse, as well as their important clinical applications, thus could be a useful reference for researchers and clinicians in the study of neurotoxins.
... Botulinum toxin type A (BoNT/A) has been demonstrated to be effective in improving pain in many different neuropathic pain syndromes refractory to conventional treatment [4] even though chronic migraine pain is the only approved indication in such contexts [5]; in other cases of neuropathic pain, BoNT/A is suggested as a third-line therapy [6]. ...
... During 2016 and 2017, she performed physiotherapy cycles without significant improvement, and, in the last months of 2017, she was treated with two anesthetic brachial plexus blocks with partial control of the pain that lasted until the end of 2019; unfortunately, these blocks triggered a seizure immediately and the patient refused to perform the procedure again. In the first months of 2020, the pain worsened progressively, and we decided to treat the patient with subcutaneous injections of botulinum toxin, considering the evidence of its efficacy in neuropathic pain [4]. ...
We treated a 51-year-old woman with refractory Complex Regional Pain Syndrome type I (CRPS-I) involving her left hand and forearm with subcutaneous injections of BoNT/A. The injections were performed every 3 months, with a total of six treatments. Each treatment was able to effectively improve pain and motor impairment; however, the duration of the effect was limited to only a few months. BoNT/A could improve patients’ quality of life with CRPS; however, extensive clinical studies are needed to determine its role in clinical practice.
... In addition, peripherally injected BoNT-A exerts beneficial actions in different chronic pain states, like chronic migraine [4,5]. Research on BoNT-Aʹs analgesic properties remains a focus of the broader scientific community due to its lasting efficacy in treatment-resistant chronic pain (level A evidence for trigeminal, post-herpetic, and post traumatic neuralgia, level B evidence for diabetic neuropathy, plantar fasciitis, piriformis syndrome, pain associated with total knee arthroplasty, male pelvic pain syndrome, chronic low back pain, and neuropathic pain secondary to traumatic spinal cord injury) [6]. Based on in vitro data and ex vivo studies suggesting that the toxin peripheral injection is associated with reduced peripheral neurotransmitter release and nerve terminal ion channel activity, it was believed that its action was limited to the site of application in the periphery [7]. ...
Botulinum toxin type A (BoNT-A) induces a bilateral analgesic effect following unilateral injection in rodent bilateral or mirror pain models. This occurs either by indirect plasticity-related actions, or by the toxin’s direct central action in bilateral spinal circuits. Herein, we aimed to resolve this question by assessing the role of trans-synaptic toxin traffic in a bilateral inflammatory pain model. The analgesic effect of the toxin was examined in rats pre-treated with unilateral intraplantar BoNT-A (7 U/kg) and subsequently challenged with bilateral carrageenan-evoked hind-paw inflammation (2%, 50 µL/paw, 6 days post BoNT-A). Specific neutralizing antitoxin injected into the lumbar intrathecal space (2 IU, 24 h post BoNT-A), aimed at preventing the spinal trans-synaptic traffic of BoNT-A, abolished its bilateral analgesic effect. The toxin trans-synaptic effect was associated with reduced c-Fos neuronal activation and BoNT-A-mediated cleavage of synaptosomal-associated protein 25 (SNAP-25) in the bilateral dorsal horn. Here, we showed that, in bilaterally occurring pain, BoNT-A exerts a direct contralateral analgesic action extending beyond the level of the dorsal root ganglion sensory neuron that directly links the hindlimb injection site to the primary sensory region. This points to the crucial role of the toxin’s central trans-synaptic traffic, and its direct action at propriospinal nociceptive circuits in its pain-relieving efficacy.
... In the clinic, chronic migraine treatment remains the only pain-related indication approved for the use of BoNT 20,21 . Furthermore, based on the outcome of multiple clinical trials, level A evidence for analgesic efficacy of BoNT exists in postherpetic neuralgia, posttraumatic neuralgia and trigeminal neuralgia, while level B evidence, suggesting probable efficacy, exists in diabetic neuropathy, plantar fasciitis, piriformis syndrome, chronic low back pain and several other pain conditions 22 . ...
Previously, abobotulinumtoxinA (aboBoNT-A) injected intraoperatively resulted in effective, but delayed post-surgical analgesia in pigs. Here, we explore the efficacy of preemptively administered aboBoNT-A in intact animals on pain and associated behaviors following a full-skin-muscle incision and retraction surgery on the lower back. AboBoNT-A (200 U/animal) or saline, distributed across ten points, were injected around anticipated incision 15, 5, or 1 day before surgery via ID route (part A) or 15 days before surgery via ID, intramuscular (IM) or subcutaneous (SC) routes (part B). We assessed mechanical sensitivity (withdrawal force; WF), distress behavior score (DBS), and latency to approach the investigator before and after surgery for 7 days.AboBoNT-A, injected ID 15 days before surgery, didn’t alter any baseline behaviors, but resulted in 5-fold increases in WF, 75% reduction in DBS and 70% reduction in approach latencies (all p < 0.01). Injections 5 days before surgery led to similar effects, albeit with a fewer animals reaching thresholds, while those made 1 day before surgery were less effective. SC and IM injections were ineffective. Thus, aboBoNT-A administered ID 15 days before surgery represents the most optimal condition for postoperative analgesia. These findings warrant for clinical investigation of preemptively administered aboBoNT-A in postsurgical pain.
... Los pacientes con NPH desarrollan una mala calidad de vida, debido a los intensos episodios de dolor que afectan el patrón del sueño y aumentan el riesgo de ansiedad y depresión (7). La ineficacia del manejo farmacológico es frecuente, además de que la polifarmacia es un hallazgo común que supone un problema, especialmente en pacientes de edad avanzada, lo que se refleja en el aumento de riesgo de hospitalización y aumento en los días de ausentismo laboral, que aumentan el impacto de costo de la enfermedad (8), lo que hace reconsiderar la costoefectividad de los tratamientos, por lo cual se hace necesario la instauración de manejos más eficaces, con un menor número de interacciones farmacológicas y menos efectos secundarios para el tratamiento de esta patología (9). Estos pacientes podrían beneficiarse de las terapias intervencionistas y, por lo tanto, de la aplicación de toxina botulínica. ...
Introducción: aproximadamente, el 12,5% de los pacientes con herpes zóster (HZ), >50 años, sufren de neuralgia posherpética (NPH) a los tres meses del brote; además, cerca del 50?% de los casos no presentan alivio del dolor con la farmacoterapia, la cual a largo plazo se asocia con efectos adversos, afectando negativamente su calidad de vida, que en estos casos podrían beneficiarse de terapias intervencionistas. Presentación del caso: femenina de 70 años con antecedente de HZ en el año 2013 con compromiso de V1, primera rama derecha (oftálmica) del trigémino, con desarrollo de NPH. La paciente tuvo múltiples manejos orales y aplicaciones subcutáneas de lidocaína con pobre modulación del dolor durante 10 años, que en la escala visual analógica (EVA) del dolor inicial declaró un 10/10. En este tratamiento se aplicó toxina botulínica tipo A (BTX-A) con seguimiento a las cuatro semanas con EVA 0/10 y a las 12 semanas con EVA 2/10, con mejoría del sueño y la calidad de vida. Discusión: los estudios actuales demuestran que la BTX?A tiene una mayor eficacia sobre la lidocaína para la NPH, según puntuaciones EVA a uno, dos y tres meses, lo cual coincide con el presente caso. Además, fue significativamente más eficaz que otras terapias, a excepción de las de tipo intervencionistas combinadas. Finalmente, la BTX?A no se ha asociado con ningún evento adverso grave. Conclusiones: la BTX-A induce a una reducción significativa del dolor (30-50?% de la EVA) durante un máximo de 3-4 meses por ciclo de inyección, lo cual coincide con los resultados de este reporte de caso, lo que apunta a que la aplicación de la BTX-A sea una alternativa terapéutica tolerable, segura y eficaz.
... К этому моменту к нервным окончаниям возвращается способность проводить возбуждение, мышечные сокращения восстанавливаются [20,21]. Ботулиновый токсин А накапливается локально, что позволяет создавать различные концентрации в зоне введения и эффективно лечить пациентов с болезненными мышечными спазмами, такими как фибромиалгия, дисфункция височно-нижнечелюстного сустава, бруксизм и цервикальная дистония [20,22]. В дополнение, помимо анимационной деформации, БТА достоверно снижает частоту формирования капсулярных контрактур [23]. ...
Рак молочной железы (РМЖ) продолжает занимать лидирующие позиции среди злокачественных опухолей у женщин. В современной реконструктивно-пластической хирургии выполнение одномоментных реконструктивных вмешательств с использованием эндопротезов составляет порядка 70-75 % всех реконструкций. При субпекторальной реконструкции частота встречаемости анимационной деформации достигает 76 %. При этом женщины испытывают дискомфорт в повседневной жизни, явления хронической послеоперационой боли. Варианты коррекции анимационной деформации, как правило, предполагают повторные хирургические вмешательства, что тем не менее не гарантирует надёжную коррекцию анимационной деформации, и лишь замена имплантата с установкой нового в препекторальную позицию, что не всегда возможно, радикально решает проблему. Целью настоящего обзора явилось обобщение функциональных и эстетических результатов инъекций ботулотоксина типа А (БТА) в область реконструированной железы, анализ методики, безопасности введения при лечении анимационной деформации. Проведённый обзор литературы показал, что применение ботулотоксина типа А является малоинвазивной, эффективной, однако обратимой альтернативой вариантам хирургического лечения. В подавляющем большинстве случаев введение осуществляли в большую грудную мышцу (в т. ч. интрооперационно) или в широчайшую мышцу спины, чаще в количестве 100 ЕД на одну зону, при этом показана безопасность повышения дозировки вплоть до 250 ЕД. Сообщений о возникновении локальных или системных неблагоприятных реакций выявлено не было. В связи с обратимостью действия рекомендовано выполнять повторные инъекции с интервалом в 3-4 месяца. Субъективный миорелаксирующий эффект наступал не раньше, чем через 3 суток после первой инъекции БТА и совпадал с появлением ощущений облегчения боли. Кроме того, применение БТА статистически значимо снижало потребление наркотических анальгетиков, начиная с 7-14 дня послеоперационного периода. В связи с ограниченным количеством исследований по затронутой тематике требуется дальнейшее наблюдение и изучение рассматриваемых в обзоре вопросов.
... BoNT has demonstrated efficacy in alleviating various types of pain, including neuropathic pain and chronic pain associated with specific conditions. Studies have shown its effectiveness in conditions such as trigeminal neuralgia (TN), post-herpetic neuralgia, painful diabetic neuropathy, central neuropathic pain in multiple sclerosis, pain in traumatic brain injury/spinal cord injury, and post-stroke pain [44]. BoNT injections have also been used to treat pelvic pain, urological pain, and pain associated with cancer, resulting in significant pain reductions and improvements in quality of life in some cases [45,46]. ...
This review discusses the expanding application of botulinum neurotoxin in treating neurological conditions. The article specifically explores novel approaches to using non-paralytic botulinum molecules. These new molecules, such as BiTox or el-iBoNT, offer an alternative for patients who face limitations in using paralytic forms of botulinum neurotoxin due to concerns about muscle function loss. We highlight the research findings that confirm not only the effectiveness of these molecules but also their reduced paralytic effect. We also discuss a potential cause for the diminished paralytic action of these molecules, specifically changes in the spatial parameters of the new botulinum molecules. In summary, this article reviews the current research that enhances our understanding of the application of new botulinum neurotoxins in the context of common conditions and suggests new avenues for developing more efficient molecules.
... Emerging evidence suggests that botulinum toxin A (BTX) may exert notable analgesic effects with minimal side effects in both traumatic and nontraumatic neuropathy, including posttraumatic neuralgia of the trigeminal nerve [77][78][79][80][81]. The inhibition of acetylcholine release by BTX results in the suppression of nerve excitation transmission. ...
Objectives
This scoping review explores the risk and management of traumatic injuries to the inferior alveolar and lingual nerves during mandibular dental procedures. Emphasizing the significance of diagnostic tools, the review amalgamates existing knowledge to offer a comprehensive overview.
Materials and methods
A literature search across PubMed, Embase, and Cochrane Library informed the analysis.
Results
Traumatic injuries often lead to hypo-/anesthesia and neuropathic pain, impacting individuals psychologically and socially. Diagnosis involves thorough anamnesis, clinical-neurological evaluations, and radiographic imaging. Severity varies, allowing for conservative or surgical interventions. Immediate action is recommended for reversible causes, while surgical therapies like decompression, readaptation, or reconstruction yield favorable outcomes. Conservative management, utilizing topical anesthesia, capsaicin, and systemic medications (tricyclic antidepressants, antipsychotics, and serotonin-norepinephrine-reuptake-inhibitors), proves effective for neuropathic pain.
Conclusions
Traumatic nerve injuries, though common in dental surgery, often go unrecorded. Despite lacking a definitive diagnostic gold standard, a meticulous examination of the injury and subsequent impairments is crucial.
Clinical relevance
Tailoring treatment to each case's characteristics is essential, recognizing the absence of a universal solution. This approach aims to optimize outcomes, restore functionality, and improve the quality of life for affected individuals.
Graphical abstract
... There is new evidence showing that botulinum toxin may alter the pain cascade and improve nociceptive and neuropathic pain. Multiple injections along the incisional pain site are recommended [17]. ...
Purpose of Review
Breast cancer is currently the most prevalent cancer diagnosed globally, and there is a significant gap in the availability of effective first-line treatment options. In addition to a cancer diagnosis, breast cancer patients face additional pain and morbidity after treatment. Radiation fibrosis, muscle spasms, muscle pain, neuropathy, and limited shoulder function are all potential side effects of breast cancer treatment and breast reconstruction. Post-mastectomy pain syndrome affects 25–60% of people after breast surgery. The current review moves forward to explain interventional pain management options that can be used to supplement conservative measures (physical therapy, medication, topical ointments) to help these patients.
Recent Findings
There are many new interventional procedures to treat chest wall pain, neuropathic pain, and spasticity after breast surgery. Currently, the most commonly performed procedures are botulinum toxin injections, serratus anterior plane blocks, intercostobrachial nerve blocks, thoracic paravertebral nerve blocks, pectoralis nerve blocks, and erector spinae nerve blocks.
Summary
Utilizing one of these interventional procedures, along with physical therapy and pharmacologic interventions, can help manage post-mastectomy pain syndrome in the millions of breast cancer patients diagnosed and treated every year.
... [52] In limb spasticity, patients often reported improved pain, and from there onabotulinumtoxinA was assessed in orthopedics and was evaluated for the treatment of osteoarthritis, shoulder spasms, and plantar fasciitis. [53,54] Clinicians observed a decrease in muscle bulk after onabot-ulinumtoxinA injections and began administering it for masseter shaping; [55] this became popular in aesthetics, particularly in Asia, with reports from South Korea and Taiwan. [56][57][58] OnabotulinumtoxinA has also been investigated for calf muscle shaping. ...
Clinical use of onabotulinumtoxinA evolved based on strategic, hypothesis-driven applications, as well as serendipitous observations by physicians and patients. The success of onabotulinumtoxinA in blepharospasm and strabismus led to its study in other head and neck dystonias, followed by limb dystonia, tremor, and spasticity. The aesthetic use of onabotulinumtoxinA followed initial reports from patients of improved facial lines after injections for facial dystonias and hemifacial spasm. Although patients with dystonias and spasticity regularly reported that their local pain improved after injections, onabotulinumtoxinA was not systematically explored for chronic migraine until patients began reporting headache improvements following aesthetic injections. Clinicians began assessing onabotulinumtoxinA for facial sweating and hyperhidrosis based on its inhibition of acetylcholine from sympathetic cholinergic nerves. Yet another line of research grew out of injections for laryngeal dystonia, whereby clinicians began to explore other sphincters in the gastrointestinal tract and eventually to treatment of pelvic sphincters; many of these sphincters are innervated by autonomic nerves. Additional investigations in other autonomically mediated conditions were conducted, including overactive bladder and neurogenic detrusor overactivity, achalasia, obesity, and postoperative atrial fibrillation. The study of onabotulinumtoxinA for depression also grew out of the cosmetic experience and the observation that relaxing facial muscle contractions associated with negative emotions may improve mood. For approved indications, the safety profile of onabotulinumtoxinA has been demonstrated in the formal development programs and post-marketing reports. Over time, evidence has accumulated suggesting clinical manifestations of systemic effects, albeit uncommon, particularly with high doses and in vulnerable populations. Although onabotulinumtoxinA is approved for approximately 26 indications across multiple local regions, there are 15 primary indication uses that have been approved in most regions, including the United States, Europe, South America, and Asia. This review describes many uses for which AbbVie has not sought and/or received regulatory approval and are mentioned for historical context only.
... This resulted in chemical denervation of the muscles, decreasing the muscular spasms. Injection of BTX has been widely used for treating patients with painful muscle spasms such as fibromyalgia, temporomandibular joint dysfunction, and cervical dystonia [17][18][19]. Reducing abnormal pectoralis major muscle activity in the setting of breast surgeries should maintain the desired cosmetic outcomes while preventing functional impairment. Whereas many published studies revealed the usability and safety of BTX injection for reducing abnormal muscle activity, the functional and cosmetic results in breast surgeries deserved further assessment [20][21][22]. ...
Background:
Breast surgeries aim to restore the natural appearance of the breasts with acceptable functional and cosmetic outcomes. However, these surgical procedures may be associated with considerable adverse events. The present systematic review and meta-analysis was designed to reveal the functional and aesthetic outcomes of botulinum toxins (BTX) injection in patients subjected to breast surgeries.
Methods:
A literature review was performed up to 21 September 2022. All clinical studies included patients older than 18 years old and treated with BTX injection for breast surgeries were included.
Results:
The present study included 12 articles, encompassing 496 patients. The average dosage of BTX injection ranged from 20 to 100 units. Injecting BTX significantly reduced the mean post-operative opioid analgesics usage (SMD -1.577; 95% -2.087, -1.067; P < 0.001) and the risk of severe animation deformity (RR 12.37; 95% 1.76, 86.66; P = 0.01). There was a statistically significant higher mean expansion volume per visit in the BTX injection group (SMD 1.166; 95% 0.313, 2.018; P = 0.007). There was no statistically significant impact of BTX injection on the risk of surgical site infection (RR 0.59; 95% 0.15, 2.34; P = 0.45) and seroma (RR 0.51; 95% 0.03, 10.15; P = 0.66).
Conclusions:
The present study revealed the potential benefits of BTX injection in breast surgeries. This included reduced post-operative analgesics, as well as the risk of severe animation deformity. This was accomplished with increased expansion volume per visit and a similar risk of BTX injection-related complications.
Level of evidence iii:
This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
... BoNT/A has also been demonstrated to be effective in neuropathic pain and neuralgias, with a level A of evidence in trigeminal neuralgia, post-herpetic neuralgia, and posttraumatic neuralgia [20]. Hereby, we report our experience in treating the patients with ATN, who addressed our headache outpatient clinic for an alternative relief, with BoNT/A. ...
Auriculotemporal neuralgia is a rare pain disorder in which anesthetic nerve blockade is usually effective but not always resolutive. Botulinum toxin type A has proven to be effective in treating neuropathic pain, and patients with auriculotemporal neuralgia could also benefit from this treatment. We described nine patients with auriculotemporal neuralgia treated with botulinum toxin type A in the territory of auriculotemporal nerve innervation. We compared the basal NRS and Penn facial pain scale scores with those obtained 1 month after BoNT/A injections. Both Penn facial pain scale (96.67 ± 24.61 vs. 45.11 ± 36.70, p 0.004; mean reduction 52.57 ± 36.50) and NRS scores (8.11 ± 1.27 vs. 4.22 ± 2.95, p 0.009; mean reduction 3.89 ± 2.52) improved significantly at one month after treatment. The mean duration of the effect of BoNT/A on pain was 95.00 ± 53.03 days and no adverse effects were reported.
... Today, BoNT-A is licensed for a broad range of indications (that vary depending on the country and the pharmaceutical formulation) including temporary improvement of dynamic facial lines, treatment of muscle hyperactivity disorders (spasticity, dystonia), hyperhidrosis, and prophylaxis of headaches in adults with chronic migraine (Dressler, 2013;Fonfria et al., 2018;Heckmann et al., 2001;Khenioui et al., 2016;Lacković 2021). In addition to chronic migraine, BoNT-A's efficacy is reported in other chronic pain conditions such as postherpetic neuralgia, trigeminal neuralgia, posttraumatic neuralgia, and chronic lateral epicondylitis (Safarpour and Jabbari, 2018;Lacković 2021). Also, the effect of direct BoNT-A injections (onabotulinumtoxinA [onaBoNT-A]) into the joints has been investigated in patients with knee, shoulder, or ankle pain due to osteoarthritis (Boon et al., 2010;Cinone et al., 2018;Khenioui et al., 2016;Singh, 2010). ...
In vivo studies of botulinum neurotoxin type A (BoNT-A) enabled characterization of its activity in the nociceptive sensory system separate from its preferred action in motor and autonomic nerve terminals. However, in the recent rodent studies of arthritic pain which employed high intra-articular (i.a.) doses (expressed as a total number of units (U) per animal or U/kg), possible systemic effects have not been conclusively excluded. Herein we assessed the effect of two pharmaceutical preparations, abobotulinumtoxinA (aboBoNT-A, 10, 20, and 40 U/kg corresponding to 0.05, 0.11, and 0.22 ng/kg neurotoxin) and onabotulinumtoxinA (onaBoNT-A, 10 and 20 U/kg corresponding to 0.09 and 0.18 ng/kg, respectively) injected into the rat knee, on safety-relevant readouts: digit abduction, motor performance and weight gain during 14 days post-treatment. The i. a. toxin produced dose-dependent impairment of the toe spreading reflex and rotarod performance, which was moderate and transient after 10 U/kg onaBoNT-A and ≤20 U/kg aboBoNT-A doses, and severe and long-lasting (examined up to 14 days) after ≥20 U/kg of onaBoNT-A and 40 U/kg aboBoNT-A. In addition, lower toxin doses prevented the normal weight gain compared to controls, while higher doses induced marked weight loss (≥20 U/kg of onaBoNT-A and 40 U/kg aboBoNT-A). Commonly employed BoNT-A formulations, depending on the doses, cause local relaxation of the surrounding muscles and systemic adverse effects in rats. Thus, to evade possible toxin unwanted local or systemic spread, careful dosing and motor testing should be mandatory in preclinical behavioral studies, irrespective of the sites and doses of toxin application.
... Nowadays, in addition to the only approved indications in chronic migraine as pain treatment, the BT-A has been reported to be effective in several neuropathic conditions, such as trigeminal, posttraumatic, or postherpetic neuralgia. However, there is still not sufficient scientific basis to obtain the indication of use of BT-A in these conditions [17]. ...
Neuropathic pain has different causes including surgery, trauma, viral infections, cancer, vascular malformations, alcoholism, neurological conditions such as multiple sclerosis, and metabolic conditions such as diabetes. Although there are various medical treatments for chronic neuropathic pain, these treatments may have limited or weak evidence, as well as interventional treatments, which have short-term efficacy and therefore require repeated interventions over time. Botulinum toxin type-A (BT-A) has been used for its analgesic effects in different pain situations. There are several potential mechanisms of action of BT-A, which are currently being researched. We report a series of three cases where ultrasound-guided intraneural infiltration with BT-A was administered as compassionate use for successful treatment of persistent neuropathic pain. This method may be effective for patients with persistent neuropathic pain and provide long-lasting effects. More studies, including randomized and controlled trials, are required to confirm the effectiveness of the treatment. Until more evidence arrives, intraneural injection of BT-A can be considered when conventional treatment has failed.
... Botulinum toxin injections have also been shown to have utility in treating severe incisional pain with neuropathic symptoms, which is a common occurrence after breast surgery [18]. This is due to emerging evidence that it also may alter the pain cascade and improve nociceptive and neuropathic pain as well [19]. ...
Purpose of Review
Breast cancer is a major cause of morbidity in the USA. Patients often experience poor self-image, pain, and reduced shoulder function, all of which have significant effects on their quality of life. Management of post-mastectomy pain syndrome is multimodal, often including physical therapy, pharmacological therapies, modalities, and interventional treatments. However, this review seeks to explore the interventional side of management.Recent FindingsPost-breast surgery pain syndrome, otherwise known as post-mastectomy pain syndrome, is a broad category of conditions that often develop after radiation and breast surgery. The variety of interventional procedures to treat neuropathic and musculoskeletal chest wall and axillary pain is constantly evolving. The most commonly performed procedures include botulinum toxin injections and the following nerve blocks: serratus anterior, intercostobrachial nerve, thoracic paravertebral nerves, pectoralis (Pecs I and II), and the erector spinae.SummaryWith a multimodal approach, including the prudent use of the interventions, the skilled clinician can make a significant impact in reducing the suffering endured by millions of patients after breast cancer treatments.
... Several studies have reported the positive effects of BoNT-A in pain syndromes [6], such as neuropathic pain [7], chronic migraine [8,9], trigeminal neuralgia [10], chronic back pain [11], chronic pelvic pain [12], and chronic myofascial pain in TMD patients [13]. Considering its use for TMD management, our/a previous study [13] has shown reduction in patient-reported pain and pain sensitivity, demonstrating BoNT-A's positive effect for this condition. ...
This study assessed the long-term effects of botulinum toxin type A (BoNT-A) in subjective pain, pain sensibility, and muscle thickness in persistent myofascial temporomandibular-disorder pain (MFP-TMD) patients. Fourteen female subjects with persistent MFP received BoNT-A treatment with different doses (10U-25U for temporalis muscle and 30U-75U for masseter muscle). The treatment was injected bilaterally in the masseter and anterior temporalis muscles in a single session. Clinical measurements included: self-perceived pain (VAS), pain sensibility (PPT), and muscles thickness (ultrasonography). Follow-up occurred 1, 3, 6, and 72 months after treatment for VAS and PPT and 1, 3, and 72 months for ultrasonography. For statistical analysis, the Friedman test with the Bonferroni test for multiple comparisons as a post hoc test was used for non-parametric repeated measures comparisons among the evaluation times. A 5% probability level was considered significant in all tests. VAS values presented a significant decrease throughout the study (p < 0.05). Regarding PPT values, a significant increase was found when comparing baseline data with post-treatment follow-ups (p < 0.05), and even though a significant decrease was found in muscle thickness when baseline values were compared with the 1- and 3-months assessments, no differences were found when compared with the 72 months follow-up (p > 0.05). A single injection of BoNT-A presents long-term effects in reducing pain in persistent MFP-TMD patients, and a reversibility of adverse effects on masticatory-muscle thickness.
... There is good evidence for use the use of Botulinum toxin in treating specific chronic neuropathic pain conditions through reduction in hyperalgesia (23). As botulinum toxin type A already has a good safety profile in children for the treatment of spasticity, this is an interesting area of development for the paediatric patient. ...
A child in pain needs not only appropriate medical treatment, but specific attention to psychosocial, cultural, and spiritual issues in order to allow meaningful exploration of wider fears or concerns. Management requires a collaborative, multimodal approach; optimal use of non-pharmacological strategies, targeted analgesic pharmacotherapy, and if necessary, specific interventional therapies. Although managing pain is only one aspect of providing palliative care for children, however, it is a core task. The experience of severe pain demands an individual’s whole attention, leaving little chance of addressing wider psychosocial or existential concerns while it remains uncontrolled. Difficult pain is a highly prevalent symptom among children with life-limiting conditions (LLC). It is complex, usually multifactorial and multifaceted. It is encountered in every dimension; the physical perception and experience of pain will be dictated by the existential and psychosocial context in which it occurs for the individual child.
Neuropathic pain is caused by abnormal processing of signals in the peripheral and central nervous systems. It is characterized by pain occurring without external stimulation or long after the injury has passed. Typically, it is chronic, with patients describing it as burning, stinging, stabbing, or tingling. Causes include diabetes, herpes zoster, surgery, stroke, multiple sclerosis, tumors, and injuries. Despite significant advances in neuropathic pain research in recent years, therapeutic options remain limited and often insufficiently effective. Symptomatic therapy for neuropathic pain is based on the use of drugs from four basic groups: antidepressants, anticonvulsants, local analgesics, and opioids. In addition to pharmacological methods, non-pharmacological interventions are also used in the treatment of neuropathic pain. A combination of these methods with pharmacological therapy often yields the best results.
Driven by the clinical success of botulinum toxin serotype A (BoNT/A) and the need for improved chronic pain management, researchers attempted to develop re-designed botulinum toxin (BoNT)-based molecules as novel analgesics. Various recombinant protein expression strategies including retargeted binding domains, and chimeric toxins combining different serotypes were tested to improve BoNT/A therapeutic safety margin and expand its efficacy. The aim of this review is to re-evaluate the current design strategies for recombinant BoNT-based molecules for pain treatment, compares their analgesic profile against the native BoNT/A, as well as to discuss the main strengths and potential weaknesses of reported approaches.
Background
Injections of botulinum toxin type A (BoNT‐A) have been proposed as an additional treatment modality for patients suffering chronic temporomandibular disorder (TMD)‐related myofascial pain (MFP). BoNT‐A impairs muscle function, along with its analgesic effect, and a minimal effective dose should be used. The objective of this randomized placebo‐controlled crossover study was to evaluate the clinical benefit of a moderate dose (50 U) of BoNT‐A.
Methods
Sixty‐six subjects were randomized into two groups, one which received BoNT‐A first and a second which received a saline solution (SS) first. Follow‐ups were performed 2, 11, and 16 weeks after the injections. Diagnostic criteria for temporomandibular disorders (DC/TMD) diagnostic algorithms were used to evaluate characteristic pain intensity (CPI) and pain‐related disability based on the Graded Chronic Pain Scale (GCPS). Electromyographic and bite force were also evaluated.
Results
The within‐group analysis showed a significant improvement in pain intensity and pain‐related disability after BoNT‐A ( p < 0.001, p = 0.005, p = 0.011) and SS ( p = 0.003, p = 0.005, p = 0.046) injections up to week 16. The between‐group analysis of pain‐related variables revealed no differences between groups at any time. Nonetheless, BoNT‐A, but not SS, caused a significant decline in muscle performance. The number needed to treat (NNT) regarding a clinically significant pain reduction (≥30%) was 6.3, 57.0, and 19.0 at 2, 11, and 16‐week follow‐ups favoring BoNT‐A.
Conclusions
Injections of 50 U of BoNT‐A might improve MFP symptoms, but the specific effect of the drug on pain compared to the placebo is not obvious.
According to the latest data from the National Multiple Sclerosis Society (2019) nearly one million people live in US with this disease annually. The disease process destroys the nerve fibers in the spinal cord and brain myelin substance resulting in motor and sensory problems. Injection of botulinum toxins into the stiff muscles of patients with multiple sclerosis reduces the muscle tone and improves muscle function. In patients with bladder dysfunction, injection of botulinum toxins into the wall of the bladder decreases abnormal urges to urinate and regulates bladder function. Involuntary and painful muscle spasms in MS patients, can be subdued by injection of botulinum toxin into the affected muscles.
Over the past 20 years, researchers and clinicians have found different potential indications for the use of botulinum toxin therapy in dentistry. The areas of interest are management of pain in temporomandibular disorder, pain after fracture of jawbone, local persistent pain at the site of tooth extraction, teeth grinding, angular cheilitis and burning mouth syndrome as well as improvement of gummy smile and management of protruded tongue.
Emerging literature supports that local injection of botulinum toxins can help local pain in animals. In dogs, botulinum toxin injections have been studied for treatment of painful joints (osteoarthritis) and pain after breast removal (mastectomy) for malignant breast cancer. In horses, botulinum toxin injections have been used to improve pain resulting from bone degeneration in animal’s hoofs leading to soft tissue damage (laminitis and synovitis). This chapter reviews the potential of botulinum toxin therapy for alleviation of local pain in canine and equine species.
Animal studies have shown that local injection of botulinum toxins improves pain behavior via blocking the release of pain transmitters and modulators. In human, carefully designed studies comparing the effect of local injection of botulinum toxins with placebo (salt water) have demonstrated efficacy of toxin injection in relieving the pain of chronic osteoarthritis, local pain of tennis elbow, chronic pain after knee surgery and knee pain related to tightness of lateral thigh muscles.
Background
Botulinum toxin type A (BTX-A) is a potential treatment for cancer pain. This study aimed to analyze the effectiveness and safety of BTX-A in the treatment of pain after cancer treatment.
Patients and methods
Systematic searches of PubMed, Cochrane Library, and Embase databases were conducted. Randomized controlled trials evaluating the efficacy and safety of BTX-A compared with either placebo or active treatment in patients with pain after cancer treatment were included. The outcomes included pain intensity, quality of life, and adverse events.
Results
This systematic review included four studies of which 2 were included in the meta-analysis. Compared with a placebo, BTX-A injection in patients with pain after cancer treatment had a clinically meaningful reduction in self-reported pain post-treatment (mean difference=−1.79 [95% confidence interval (CI), −2.14 to −1.43], P ＜0.00001, I² =0%).
Conclusion
This systematic review and meta-analysis demonstrated that BTX-A is safe and effective for pain relief in patients with pain after cancer treatment.
Plantar fasciitis (PF) is the most common cause of chronic heel pain, predominantly impacting those who perform heavy footwork, are avid runners or lare ong-distance walkers. Overuse injury leads to repetitive microtears of the plantar fascia near the calcaneus, irritating pain fibers and producing secondary inflammation. Patients typically have intense heel pain, described as aching, jabbing or burning. Pain usually starts with the first few steps in the morning and is reproduced by palpation of the median tubercle of the calcaneum and with dorsiflexion of the toes.
Conventional treatments such as ice, heel cup orthoses, deep-tissue massage and night splints, periods of immobilization and stretching/strengthening exercise programs can reduce pain satisfactorily. Persistent discomfort may respond to treatments such as ultrasound, iontophoresis and phonophoresis. More severe and recalcitrant cases require extracorporeal shock wave therapy (ECSWT) or local corticosteroid injections. When medical approaches fail, surgery is advocated but can only offer modest results.
This chapter reviews pertinent studies to date on the application of botulinum neurotoxin to plantar fasciitis, and discusses injection technique and dosing, including the WRAMC–Yale technique for injecting the soleus muscle, along with the plantar fascia. Clear anatomical illustrations are provided.
Botulinum toxin has been used for decades in the treatment of a variety of painful diseases. Botulinum toxin not only blocks neuromuscular transmission, but also the secretion of neuropeptides, such as substance P, glutamate and calcitonin gene-related peptide (CGRP) and thus inhibits neurogenic inflammation. In addition, it has a modulatory pain-relieving effect via retrograde transport into the central nervous system. In addition to approval for the treatment of dystonia or spasticity, onabotulinum toxin A is also approved for the prophylaxis of chronic migraine if the oral prophylactic migraine medication has had an insufficient effect or has not been tolerated. In addition, botulinum toxin is also recommended in guidelines as a third-line treatment for neuropathic pain, but in Germany this is an off-label application. This article provides an overview of the current clinically relevant areas of application of botulinum toxin in the field of pain medicine.
Chronic pain conditions like genito-pelvic pain penetration disorder and chronic pelvic pain cause significant morbidity in women worldwide and yet are underdiagnosed and undertreated. While the use of botulinum toxin for pain conditions has expanded, there are few randomized controlled studies of botulinum toxin for pelvic pain conditions in women. This paper provides an update on the current status and context for considering botulinum toxin treatment for these conditions to complement and expand currently available approaches. High quality clinical trials to evaluate safety and efficacy and to determine optimal doses and approaches to injection are urgently needed.
We present the case of a 73-year-old man with history of back and left sciatic nerve pain, who came to our hospital centre due to perform a lumbar spine MRI. The MRI scan didn’t reveal compression of the left nerve roots by hernia formations, but collaterally showed a well-defined lesion, with MRI characteristics of adipose tissue, localized in the left piriformis muscle, compatible with a lipoma that displaced the ipsilateral sciatic nerve but did not invade it.
AB toxins are protein virulence factors secreted by many bacterial pathogens, contributing to the pathogenicity of the cognate bacteria. AB toxins consist of two functionally distinct components: the enzymatic “A” component for pathogenicity and the receptor-binding “B” component for toxin delivery. Consistently, unlike other virulence factors such as effectors, AB toxins do not require additional systems to deliver them to the target host cells. Target host cells are located in the infection site and/or located distantly from infected host cells. The first part of this review discusses the structural and functional features of single-peptide and multiprotein AB toxins in the context of host–microbe interactions, using several well-characterized examples. The second part of this review discusses toxin neutralization strategies, as well as applications of AB toxins relevant to developing intervention strategies against diseases.
Hintergrund und Ziele Die chronische Obstipation des Kindesalters präsentiert sich als ein Komplex unterschiedlicher Symptome, welche häufig therapierefraktär sind. Die therapeutische Herangehensweise stellt daher eine Herausforderung dar und beinhaltet zahlreiche Möglichkeiten mit verschiedenen Stellenwerten und Indikationen. Das Ziel dieser Studie ist die Untersuchung des Effekts der Injektion von Botulinumtoxin A in den analen Sphinkterapparat (BiSa). Dadurch soll auch diese Therapiemodalität in das Procedere bei dieser chronischen Erkrankung eingeordnet werden. Methoden 84 Kinder wurden retrospektiv bewertet, welche in der Kinderchirurgie Erlangen im Zeitraum von Januar 2009 bis Dezember 2019 BiSa erhielten. Alle Auswertungen wurden mit 65 Patienten ausgeführt, welche eine mediane Follow-up-Dauer von 21,0 Monaten aufwiesen (Spannweite 1,0-106,1 Monate). Es erfolgten Untersuchungen bezüglich der Krankheitsätiologien (M. Hirschsprung (HD)/funktionelle Obstipation (non-HD)) und bezüglich der klinischen und therapeutischen Daten. BiSa fand in Allgemeinnarkose mit einer üblichen Dosis von 50 IE statt, die meist auf vier Quadranten des Sphinkters aufgeteilt injiziert wurden. Ergebnisse Die Studie beinhaltete 37 männliche und 28 weibliche Patienten mit einem medianen Alter von 3,1 Jahren bei erster BiSa (Spannweite 0,2-18,4 Jahre). 80% der Patienten erhielten ein bis zwei BiSa (n = 52/65). HD-Patienten erhielten signifikant häufiger über zwei BiSa (34%, n = 12/35, maximal bis zu acht BiSa), verglichen mit non-HD-Patienten (3%, n = 1/30, p-Wert 0,002). Wiesen Patienten mehr als eine BiSa auf (42%, n = 27/65), betrug die mediane Zeit zwischen den Injektionen 17,8 Wochen. Insgesamt war BiSa in 60% der Studienkohorte effektiv (n = 39/65), indem es die chronischen Obstipationssymptome reduzierte und zu normaler Stuhlfrequenz und -konsistenz für mindestens vier Wochen führte. Ein an-haltender Effekt war bei 29% (n = 19/65) zu verzeichnen. Es ergaben sich keine signifikanten Zusammenhänge zwischen Alter, Geschlecht oder zugrundeliegender Erkrankung zu Therapieeffektivität. Bezüglich der Applikationshäufigkeit war das Therapieansprechen bei Patienten mit > 2 BiSa mit 92% (n = 12/13) signifikant höher als bei Patienten mit ≤ 2 BiSa (52%, n = 27/52, p-Wert 0,010). Darüber hinaus wurden die Intervalle zwischen BiSa bei < 3-Jährigen signifikant häufiger länger (86%, n = 6/7) als bei ≥ 3-Jährigen (17%, n = 1/6, p-Wert 0,029). Eine Tendenz des besseren Ansprechens konnte bei HD-Patienten beobachtet werden (66%, n = 23/35, verglichen mit 53% der non-HD-Patienten (n = 16/30), p-Wert 0,310)). Neun der 24 HD-Patienten mit Therapieansprechen konnten nach BiSa ohne nachfolgende Operation behandelt werden. Komplikationen blieben auf geringem Niveau. Fäkale Inkontinenz nahm bei Patienten zu, welche diese bereits vor Therapiebeginn zeigten (31%, n = 4/13, verglichen mit 8% der Patienten ohne prätherapeutische Inkontinenz (n = 4/52), p-Wert 0,044). Schlussfolgerung BiSa ist als Therapiemöglichkeit der chronischen Obstipation im Kindesalter in knapp zwei Dritteln der Patienten effektiv. Dabei weist es geringe Nebenwirkungen auf, muss aber für eine andauernde Wirkung wiederholt verabreicht werden. Ein vorgeschlagener Therapiealgorithmus erleichtert eine effiziente Therapie der chronischen Obstipation und empfiehlt BiSa vor allem bei jüngeren Patienten. Zudem sollte der mögliche Vorteil multipler Injektionen bedacht werden.
Chronic pain of the hard and soft tissues of the face and oral cavity is generally known as orofacial pain (OFP). OFP is a major issue in dentistry and an area of therapeutic challenge for practicing dentists. Due to the unique characteristics of this region and the psychosocial and emotional issues affecting individuals with OFP, access to a safe, conservative, and effective treatment is essential, especially considering that the existing pharmacological options have been inefficient in many patients. Disorders causing OFP with relevance to dentistry are discussed under musculoskeletal, neuropathic, and idiopathic subtypes in this chapter. After describing definitions, classifications, epidemiologic data, and conventional treatments on each entity, we examine the current literature on the effectiveness of botulinum neurotoxin (BoNT) in alleviating OFP separately for each disorder and present the applied doses, injection points, and administration routes reported in clinical studies. Despite the limited research on chronic OFP, the preliminary reports of BoNT efficacy are promising and offer the potential to improve pain relief in patients’ refractory to conventional treatments. Further high-quality, large well-designed, double-blind, placebo-controlled clinical trials with long follow-up periods are needed to determine the effectiveness of BoNT in the wide range of disorders causing OFP.
Myofascial pain is one of the most common forms of human pain and a major cause of disability. It is characterized by spontaneous muscle pain and pain induced by pressing the muscle’s trigger points. Treatment of myofascial pain syndrome (MPS) is partially successful with nonpharmacological measures and analgesic agents, but a large number of patients remain unsatisfied. Eleven double-blind, placebo-controlled studies have been published on treatment of myofascial pain with botulinum toxins; some of these studies strongly support the palliative role of botulinum neurotoxins (BoNTs) in myofascial pain syndrome. Successful studies that have used onabotulinumtoxinA and abobutulinumtoxinA for this form of pain emphasize the importance of a flexible rather than a fixed pattern of injection and injecting more than five or all trigger points. Fibromyalgia is a systemic disease, characterized by diffuse muscle pain, fatigue, headaches, mood disorders, sleep disturbance, bowel disorders, and endocrine dysfunction. Due to lack of controlled data, the use of BoNTs for treatment of fibromyalgia is not currently recommended.
Chronic pain is a major issue in many orthopedic disorders. With the discovery of analgesic effects of BoNTs, there is an emerging interest in exploring a potential role for BoNT injections in relieving orthopedic pain. In this chapter, the data on BoNT therapy in four orthopedic disorders are presented—with information on blinded studies provided in more detail. These disorders consist of chronic lateral epicondylitis, painful local arthritis, refractory pain after total knee arthroplasty, and anterior knee pain related to patellofemoral syndrome due to vastus lateralis imbalance. The efficacy levels are defined based on recommendations of the Guideline and Assessment Subcommittee of the American Academy of Neurology. The level of evidence for chronic lateral epicondylitis is B (probably effective) based on one class I and two class II studies; it is level C (possibly effective) for refractory pain after total knee arthroplasty, local painful arthritis, and anterior knee pain related to vastus lateralis imbalance (each with one class II study). While these positive data are encouraging, better designed and more high-quality studies (class I and II) are needed to support the use of botulinum neurotoxin injections in these orthopedic disorders.
Chronic low back pain (cLBP) is the most common cause of medical disability. Treatment of cLBP is complicated due to its diverse etiologies and high rate of undesirable side effects observed with the use of powerful analgesics and their short duration of action. In recent years, our understanding of the pathophysiology of low back pain has improved particularly in regard to the contribution of dorsal root ganglia and pain mediators. In animal models, botulinum neurotoxins (BoNTs) have shown analgesic effects through peripheral and central mechanisms. Five randomized, placebo-controlled (four double-blind and one single-blind) studies have investigated and reported on the effect of BoNT therapy in cLBP. Three of these studies, using the same methodology (injecting erector spinae at five lumbar levels), reported significant improvement of cLBP in patients with no history of surgery and no acute lesions on magnetic resonance imaging. Using the assessment guidelines of the American Academy of Neurology, the level of efficacy for onaA and abobotulinumtoxinA in this form of cLBP (with the aforementioned technique) is C (possibly effective) based on one class II study conducted with each toxin. Further blinded and controlled studies with larger number of patients (preferably multicenter) are needed to prove the efficacy of this technique in chronic low back pain.KeywordsBotulinum toxinBotulinum neurotoxinLow back painChronic low back painOnabotulinumtoxinAbobotulinumtoxinErector spinae
In dogs, botulinum toxin injections have been studied in painful osteoarthritis and pain after mastectomy for malignant breast cancer. In horses, botulinum toxin injections have been used to improve pain of laminitis and synovitis and pain resulting from degeneration of navicular bone in animal’s hoof associated with soft tissue damage. This chapter reviews and discusses the limited literature available for treatment of canine and equine pain disorders.KeywordsBotulinum toxinBotulinum neurotoxinOnabotulinum toxinAAbobotulinum toxinARimabotulinumtoxinBCanine osteoarthritisCanine postmastectomy painEquine laminitisEquine synovitisEquine hoof pain
Plantar fasciitis/fasciopathy (PF) affects two million people in the United States. It is a common problem in runners and those individuals whose work requires heavy footwork. In affected patients, heel pain and foot discomfort interfere with daily functions. Approximately 10% of patients do not respond to conventional treatments, and their condition evolves into a chronic form. Botulinum neurotoxins (BoNTs) alleviate pain by reducing the function of pain transmitters at peripheral and central sensory levels. Four double-blind, placebo-controlled studies, conducted in small cohorts, have investigated the efficacy of BoNT injection in alleviating heel pain and improving foot function in PF. All four studies demonstrated that injection of botulinum toxin-A (onabotulinumtoxin or incobotulinum toxin) decreases heel pain. Three of the four studies showed improvement of foot function as well. Two blinded studies compared the effect of BoNT injection with steroid injection in PF. In one study, BoNT injection was superior to steroids in improvement of heel pain and foot function; also, the results after BoNT injection lasted longer than steroids. Another study, however, found equal efficacy and duration of function when BoNT injections in PF were compared with steroid and anesthetic injections. Using the efficacy criteria of the guideline and development subcommittee of the American Academy of Neurology, the level of BoNT injection efficacy in PF is B (probably effective) based on availability of more than one class II studies.
Chronic low back pain is a debilitating condition with a complex and multifactorial pathophysiology. Botulinum neurotoxins (BoNTs) have strong analgesic effects, as shown in both animal models of pain and in human beings. A randomized, double-blind, placebo-controlled, parallel format study to investigate the efficacy of abobotulinum toxin A (aboA) in chronic low back pain was conducted. The study cohort consisted of 18 patients who received 100 units of aboA into each of the five lumbar extensor spinae muscles unilaterally or bilaterally (total dose 500 to 1000 units), and 19 who received normal saline of the same volume. The level of pain and quality of life were assessed using the visual analogue scale (VAS) and three questionnaires including the Oswestry Low Back Pain Disability Questionnaire (OLBPDQ). Patients’ perception of improvement was recorded via patient global impression of change (PGIC). The primary outcome measure, the proportion of responders with VAS of <4 at 6 weeks, was not met, but the data was significantly in favor of aboA at 4 weeks (p = 0.008). The total Oswestry score representing quality of life improved in the aboA group compared to the placebo group (p = 0.0448). Moreover, significantly more patients reported their low back pain as “much improved” in the abobotulinum toxin A group (0.0293).
“Mirror pain” or mirror-image pain (MP) is pain opposite to the side of injury. Mechanism and frequency in humans are not known. There is no consent on therapy. Here we report that unilaterally injected botulinum toxin type A (BT-A) has bilateral effect in experimental MP, thus deserves to be investigated as therapy for this condition. We examined the localization of BT-A’s bilateral antinociceptive action in MP induced by 3 % carrageenan intramuscular injection in Wistar rats. BT-A was applied peripherally (5 U/kg), into ipsilateral or contralateral hind paw pad (i.pl.) and centrally (1 U/kg), at spinal (intrathecally, i.t.) or supraspinal (intracisternally, i.c.) level. Additionally, we examined the involvement of central opioid and GABAergic systems, as well as the contribution of peripheral capsaicin-sensitive neurons to BT-A’s bilateral antinociceptive effect. Ipsilateral i.pl. and i.t. BT-A reduced the bilateral mechanical sensitivity to von Frey filaments, while contralateral i.pl. and i.c. treatments had no effect on either tested side. Bilateral antinociceptive effect of ipsilateral i.pl. BT-A was prevented by μ-opioid antagonist naloxonazine (1.5 μg/10 μl) and GABAA antagonist bicuculline (1 μg/10 μl) if applied at the spinal level, in contrast to supraspinal application of the same doses. Local treatment of sciatic nerve with 2 % capsaicin 5 days following BT-A i.pl. injection caused desensitization of sciatic capsaicin-sensitive fibers, but did not affect bilateral antinociceptive effect of BT-A and the presence of cleaved SNAP-25 at the spinal cord slices. Present experiments suggest segmental actions of peripheral BT-A at spinal level, which are probably not solely dependent on capsaicin-sensitive neurons.
Current evidence suggests that botulinum neurotoxins (BoNTs) A1 and B1, given locally into peripheral tissues such as skin, muscles, and joints, alter nociceptive processing otherwise initiated by inflammation or nerve injury in animal models and humans. Recent data indicate that such locally delivered BoNTs exert not only local action on sensory afferent terminals but undergo transport to central afferent cell bodies (dorsal root ganglia) and spinal dorsal horn terminals, where they cleave SNAREs and block transmitter release. Increasing evidence supports the possibility of a trans-synaptic movement to alter postsynaptic function in neuronal and possibly non-neuronal (glial) cells. The vast majority of these studies have been conducted on BoNT/A1 and BoNT/B1, the only two pharmaceutically developed variants. However, now over 40 different subtypes of botulinum neurotoxins (BoNTs) have been identified. By combining our existing and rapidly growing understanding of BoNT/A1 and /B1 in altering nociceptive processing with explorations of the specific characteristics of the various toxins from this family, we may be able to discover or design novel, effective, and long-lasting pain therapeutics. This review will focus on our current understanding of the molecular mechanisms whereby BoNTs alter pain processing, and future directions in the development of these agents as pain therapeutics.
Botulinum neurotoxin (BoNT), derived from Clostridium botulinum, has been used therapeutically for focal dystonia, spasticity, and chronic migraine. Its spectrum as a potential treatment for neuropathic pain has grown. Recent opinions on the mechanism behind the antinociceptive effects of BoNT suggest that it inhibits the release of peripheral neurotransmitters and inflammatory mediators from sensory nerves. There is some evidence showing the axonal transport of BoNT, but it remains controversial. The aim of this review is to summarize the experimental and clinical evidence of the antinociceptive effects, mechanisms, and therapeutic applications of BoNT for neuropathic pain conditions, including postherpetic neuralgia, complex regional pain syndrome, and trigeminal neuralgia. The PubMed and OvidSP databases were searched from 1966 to May 2015. We assessed levels of evidence according to the American Academy of Neurology guidelines. Recent studies have suggested that BoNT injection is an effective treatment for postherpetic neuralgia and is likely efficient for trigeminal neuralgia and post-traumatic neuralgia. BoNT could also be effective as a treatment for diabetic neuropathy. It has not been proven to be an effective treatment for occipital neuralgia or complex regional pain syndrome.
Onabotulinumtoxin type A (BoNT-A) has been found to reduce pain in chronic migraine. The aim of the present study was to ask if BoNT-A can interact directly on sensory mechanisms in the trigeminal ganglion (TG) using an organ culture method.
To induce inflammation, rat TGs were incubated for 24 hrs with either the mitogen MEK1/2 inhibitor U0126, BoNT-A or NaCl. After this the TGs were prepared for immunohistochemistry. Sections of the TG were then incubated with primary antibodies against CGRP (neuronal transmitter), iNOS (inflammatory marker), IL-1β (Interleukin 1β), SNAP-25 (synaptic vesicle docking protein) or SV2-A (Botulinum toxin receptor element).
We report that CGRP, iNOS, IL-1β, SNAP-25 and SV2-A were observed in fresh TG with a differential distribution. Interestingly, NaCl organ culture of the TG resulted in enhanced expression of CGRP and SNAP-25 in neurons and iNOS in SGCs. Co-incubation with U0126 or BoNT-A retained the increased expression of SNAP-25, while it decreased the IL-1β immunoreactivity in neurons. The iNOS expression in SGCs returned to levels observed in fresh specimens. Moreover, we observed no alteration SV2-A expression in SGCs. Thus, the overall picture is that both U0126 and BoNT-A have the ability to modify the expression of certain molecules in the TG.
We hypothesize that chronic migraine might be associated with some degree of inflammation in the TG that could involve both neurons and SGCs. It is clinically well recognized that treatment with corticosteroids will reduce the symptoms of chronic migraine; however this remedy is associated with long-term side effects. Understanding the mechanisms involved in the expressional alterations may suggest novel ways to modify the changes and indicate novel therapeutics. The results of the present work illustrate one way by which BoNT-A may modify these expressional alterations.
This study investigated the presence of cell membrane docking proteins synaptosomal-associated protein, 25 and 23 kD (SNAP-25 and SNAP-23) in satellite glial cells (SGCs) of rat trigeminal ganglion; whether cultured SGCs would release glutamate in a time- and calcium-dependent manner following calcium-ionophore ionomycin stimulation; and if botulinum neurotoxin type A (BoNTA), in a dose-dependent manner, could block or decrease vesicular release of glutamate. SGCs were isolated from the trigeminal ganglia (TG) of adult Wistar rats and cultured for 7 days. The presence of SNAPs in TG sections and isolated SGCs were investigated using immunohistochemistry and immunocytochemistry, respectively. SGCs were stimulated with ionomycin (5 μM for 4, 8, 12 and 30 min.) to release glutamate. SGCs were then pre-incubated with BoNTA (24 hrs with 0.1, 1, 10 and 100 pM) to investigate if BoNTA could potentially block ionomycin-stimulated glutamate release. Glutamate concentrations were measured by ELISA. SNAP-25 and SNAP-23 were present in SGCs in TG sections and in cultured SGCs. Ionomycin significantly increased glutamate release from cultured SGCs 30 min. following the treatment (P < 0.001). BoNTA (100 pM) significantly decreased glutamate release (P < 0.01). Results from this study demonstrated that SGCs, when stimulated with ionomycin, released glutamate that was inhibited by BoNTA, possibly through cleavage of SNAP-25 and/or SNAP-23. These novel findings demonstrate the existence of vesicular glutamate release from SGCs, which could potentially play a role in the trigeminal sensory transmission. In addition, interaction of BoNTA with non-neuronal cells at the level of TG suggests a potential analgesic mechanism of action of BoNTA.
© 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.
Background:
In the majority of cases, trigeminal neuralgia (TN) is a unilateral condition with ultra-short stabbing pain located along one or more branches of the trigeminal nerve. Although prophylactic pharmacological treatment is first choise, considering of insufficient effect or unacceptable side effects, neurosurgical treatment or lesion treatment should be considered. In addition to all these procedures mentioned above, one approach has been based on local intradermal and/or submucosal injections of Botulinum Toxin Type A (BTX-A).
Methods:
We conducted a randomized, double-blind, placebo-controlled since November 2012, and adopted local multi-point injection in 84 cases of classical TN with different doses of BTX-A. Eighty four patients were randomized into following groups: placebo (n = 28); BTX-A 25U (n = 27); BTX-A 75U (n = 29). Follow-up visits were conducted every week after the injection, and the overall duration of the study for each patient were 8 weeks to observe the pain severity, efficacy and adverse reactions at endpoint.
Results:
The visual analogue scale (VAS) scores of 25U and 75U groups reduced significantly compared to placebo as early as week 1, and sustained until week 8 throughout the study. There was no significant difference in VAS between 25U and 75U groups throughout the study. The response rates of 25U group (70.4%) and 75U group (86.2%) were significantly higher than placebo group (32.1%) at week 8, and there was no significant difference between 25U and 75U groups. Evaluation of the Patient Global Impression of Change (PGIC) demonstrated that 66.7% (25U group) and 75.9% (75U group) of the patients reported that their pain symptoms were 'much improved' or 'very much improved' versus 32.1% of the placebo group, and there was also no significant difference between 25U and 75U groups. All adverse reactions were graded as mild or moderate.
Conclusions:
BTX-A injection in TN is safe and efficient. It is a useful treatment for refractory TN. Lower dose (25U) and high dose (75U) were similar in efficacy in short-term.
Background
We investigated the long-term effects and safety of botulinum toxin-A (BTX-A) for treating trigeminal neuralgia (TN). We also studied long-term maintenance of this therapeutic effect.
Methods
A visual analog scale (VAS) score, pain attack frequency per day, patient’s overall response to treatment and side effects during 14-month follow-up were evaluated in 88 patients with TN receiving BTX-A. The primary endpoints were pain severity (assessed by VAS) and pain attack frequency per day. The secondary endpoint was the patient’s overall response to treatment, assessed using the Patient Global Impression of Change. The influence of different doses (≤50, 50–100 and ≥100 U) on the therapeutic effect was evaluated.
Results
Treatment was deemed “effective” within 1 month in 81 patients and at 2 months in 88 patients (100%). The shortest period of effective treatment was 3 months, and complete control of pain was observed in a maximum of 46 patients. The therapeutic effect decreased gradually after 3 months, and the prevalence of effective treatment at 14 months was 38.6%, with complete control of pain seen in 22 patients (25%). There was no significant difference in the prevalence of effective treatment between different dose groups at identical time points (p > 0.05). Three patients showed swelling at injection sites and 10 patients showed facial asymmetry, both of which disappeared spontaneously without special treatment.
Conclusion
Local subcutaneous injection of BTX-A for TN treatment has considerable therapeutic effects lasting several months and is safe for this indication. At least one-quarter of patients maintained complete analgesia. The maintenance period of the therapeutic effect may be related to the reduction in the VAS score after the first injection of BTX-A.
Considering the dramatic increasing rate of diabetes and consequently its related complications, most importantly diabetic peripheral neuropathy (DPN), challenges regarding proper treatment of DPN and its effect on the quality-of-life and care of diabetic patients, the aim of this current study is to evaluate the effect of intradermal botulinum toxin type A (BTX-A) injections on pain symptoms of patients with diabetic neuropathic pain.
In this randomized double-blind placebo-controlled clinical trial study, diabetic patients aged <70 years with neuropathic pain in both feet were enrolled. Diabetic neuropathy (DN) in selected patients was diagnosed using DN4 questionnaire and nerve conduction velocity examinations. They randomized in two intervention (BTX-A injection/100 unit, N = 20) and placebo groups (normal saline injection, N = 20). The outcome of injection on diabetic neuropathic pain was assessed using neuropathy pain scale (NPS) and visual analog scale (VAS) score and compared in two studied groups.
There was no significant difference in DN4, NPS and VAS scales of studied population after intervention in the placebo group. Intradermal injection of BTX-A reduced NPS scores for all items except cold sensation (P = 0.05). It reduced DN4 scores for electric shocks, burning, pins and needles and brushing (P < 0.05). According to VAS scale 30% and 0% of patients in intervention and placebo groups have no pain after intervention (P = 0.01).
Intradermal injection of BTX-A is a well-tolerated agent that has a significant effect on DPN pain.
Botulinum toxin type A (BTX-A) has been reported to have analgesic effects independent of its action on muscle tone, mostly by acting on neurogenic inflammatory mediators and controlling the neurotransmitter release of sensory and autonomic nerve terminals that are involved in many chronic painful conditions as chronic intractable trigeminal neuralgia (TN).The aim of our work was evaluating the efficacy, safety, and tolerability of BTX-A for the treatment of intractable idiopathic TN.
This was a randomized, single-blinded, placebo-control study carried out on 20 Egyptian patients with intractable TN. Patients received a one-time subcutaneous administration of BTX-A using "follow the pain" method. The primary efficacy measure was reduction in pain severity on the 10-cm VAS score as well as in paroxysms frequency from the baseline to week 12 (endpoint last observation carried forward [LOCF]). Secondary efficacy measures included QoL assessment and number of acute medications received from baseline to the endpoint.
Pain reduction at the 12-week endpoint was significant in BTX-A group (p<0.0001); VAS scores at endpoint LOCF relative to baseline for BTX-A group showed a decrease of 6.5 compared with a decrease of 0.3 for placebo, also there was a significant decrease in the number of acute medications and an increase in QoL functioning scale.
These results indicate that BTX-A has a direct analgesic effect in patients with TN and can represent a therapeutic option for intractable cases.
In this narrative review, we aim to provide the pathophysiology and diagnostic criteria of the piriformis syndrome (PS), an underdiagnosed cause of buttock and leg pain that can be difficult to treat. Based on existing evidence, frequencies of clinical features are estimated in patients reported to have PS. In view of the increasing popularity of ultrasound for intervention, the ultrasound-guided technique in the treatment of PS is described in detail.
A literature search of the MEDLINE(®) database was performed from January 1980 to December 2012 using the search terms e.g., " piriformis injection", " ultrasound guided piriformis injection", " botulinum toxin", "pain management", and different structures relevant in this review. There was no restriction on language.
A review of the medical literature pertaining to PS revealed that the existence of this entity remains controversial. There is no definitive proof of its existence despite reported series with large numbers of patients.
Piriformis syndrome continues to be a controversial diagnosis for sciatic pain. Electrophysiological testing and nerve blocks play important roles when the diagnosis is uncertain. Injection of local anesthetics, steroids, and botulinum toxin into the piriformis muscle can serve both diagnostic and therapeutic purposes. An ultrasound-guided injection technique offers improved accuracy in locating the piriformis muscle. Optimizing the therapeutic approach requires an interdisciplinary evaluation of treatment.
Background:
The objective of this study was to compare intramuscularly applied botulinum toxin A (BTX-A) in the gastroc-soleus complex with intralesional steroids for the treatment of plantar fasciitis.
Methods:
The patients were randomly divided into 2 groups according to the treatment received. The patients were evaluated over 6 months. The evaluation scores included the Visual Analog Scale (VAS), Maryland Foot and Ankle, Foot and Ankle Disability Index (FADI), and American Orthopaedic Foot and Ankle Society (AOFAS) score. Moreover, patients were instructed to perform plantar fascia stretching exercises over the course of the study. The final number of patients was 36, of whom 19 received BTX-A (10 men and 9 women) and 17 (6 men and 11 women) received steroids.
Results:
When compared to patients who received steroids, the patients who received BTX-A exhibited more rapid and sustained improvement over the duration of the study.
Conclusion:
A combination of BTX-A and plantar fascia stretching exercises yielded better results for the treatment of plantar fasciitis than intralesional steroids.
Level of evidence:
Level I, therapeutic studies.
In recent years a growing debate is about whether botulinum neurotoxins are retrogradely transported from the site of injection. Immunodetection of cleaved SNAP-25 (cl-SNAP-25), the protein of the SNARE complex targeted by botulinum neurotoxin serotype A (BoNT/A), could represent an excellent approach to investigate the mechanism of action on the nociceptive pathways at peripheral and/or central level. After peripheral administration of BoNT/A, we analyzed the expression of cl-SNAP-25, from the hindpaw's nerve endings to the spinal cord, together with the behavioral effects on neuropathic pain. We used the chronic constriction injury of the sciatic nerve in CD1 mice as animal model of neuropathic pain. We evaluated immunostaining of cl-SNAP-25 in the peripheral nerve endings, along the sciatic nerve, in dorsal root ganglia and in spinal dorsal horns after intraplantar injection of saline or BoNT/A, alone or colocalized with either glial fibrillar acidic protein, GFAP, or complement receptor 3/cluster of differentiation 11b, CD11b, or neuronal nuclei, NeuN, depending on the area investigated. Immunofluorescence analysis shows the presence of the cl-SNAP-25 in all tissues examined, from the peripheral endings to the spinal cord, suggesting a retrograde transport of BoNT/A. Moreover, we performed in vitro experiments to ascertain if BoNT/A was able to interact with the proliferative state of Schwann cells (SC). We found that BoNT/A modulates the proliferation of SC and inhibits the acetylcholine release from SC, evidencing a new biological effect of the toxin and further supporting the retrograde transport of the toxin along the nerve and its ability to influence regenerative processes. The present results strongly sustain a combinatorial action at peripheral and central neural levels and encourage the use of BoNT/A for the pathological pain conditions difficult to treat in clinical practice and dramatically impairing patients' quality of life.
Botulinum neurotoxin type A (BoNT/A) is a metalloprotease that blocks synaptic transmission via the cleavage of SNAP-25 (synaptosomal-associated protein of 25 kDa). BoNT/A is successfully used in clinical neurology for the treatment of several neuromuscular pathologies and pain syndromes. Despite its widespread use, relatively little is known on BoNT/A intracellular trafficking in neurons. Using the visual pathway as a model system, here we show that catalytically active BoNT/A is capable of undergoing anterograde axonal transport and transcytosis. Following BoNT/A injection into the rat eye, significant levels of BoNT/A-cleaved SNAP-25 appeared in the retinorecipient layers of the superior colliculus (SC). Anterograde propagation of BoNT/A effects required axonal transport, ruling out a systemic spread of the toxin. Cleaved SNAP-25 was present in presynaptic structures of the tectum, but retinal terminals were devoid of the immunoreactivity, indicative of transcytosis. Experiments based on sequential administration of BoNT/A and BoNT/E showed a persistent catalytic activity of BoNT/A in tectal cells following its injection into the retina. Our findings demonstrate that catalytically active BoNT/A is anterogradely transported from the eye to the SC and transcytosed to tectal synapses. These data are important for a more complete understanding of the mechanisms of action of BoNT/A.
To assess short-term efficacy of single intraarticular botulinum toxin (IA-BoNT/A) injection in patients with chronically painful total knee arthroplasty (TKA) in a randomized, placebo-controlled, triple-blind study.
Patients with chronic TKA pain (pain > 6 on 0-10 scale and > 6 months post-TKA) evaluated in and referred from orthopedic surgery clinics were recruited. The primary outcome, proportion of patients with clinically meaningful decrease of at least 2 points on 0-10 visual analog scale (VAS) for pain, was compared between treatment groups at 2 months using comparison of proportions test and for all efficacy timepoints (2, 3, and 4 months) using generalized estimating equations (GEE). Secondary outcomes of global assessment, function, and quality of life were compared using GEE, duration of pain relief by t-test, and adverse events by chi-square test.
In total, 54 patients with 60 painful TKA were randomized, with main analyses restricted to one TKA per patient (49 TKA in 49 patients). Mean age was 67 years, 84% were men, and mean duration of TKA pain was 4.5 years. A significantly greater proportion of patients (71%) in the IA-BoNT/A group compared to IA-placebo (35%) achieved clinically meaningful reduction in VAS pain at 2 months (p = 0.028) and at all efficacy timepoints (p = 0.019). Duration of meaningful pain relief was significantly greater after IA-BoNT/A, 39.6 days (SD 50.4) compared to IA-placebo, 15.7 days (SD 22.6; p = 0.045). Statistically significantly better scores were seen in IA-BoNT/A vs IA-placebo for all efficacy timepoints for the following outcomes: "very much improved" on physician global assessment of change (p = 0.003); Western Ontario McMaster Osteoarthritis Index physical function (p = 0.026), stiffness (p = 0.004), and total scores (p = 0.024); and Short-Form 36 pain subscale score (p = 0.049). Number of total and serious adverse events was similar between groups, with no patients in either group with new objective motor or sensory deficits during followup.
In this single-center randomized trial, single IA-BoNT/A injection provided clinically meaningful short-term improvements in pain, global assessment, and function in patients with chronic painful TKA. A multicenter trial is needed to confirm these findings.
When using botulinum toxin for the management of lateral epicondylitis, injection at a fixed distance from an anatomic landmark could result in inadequate paralysis of the intended muscle. We assessed the effectiveness of injection of botulinum toxin using precise anatomic measurement in individual patients.
In this randomized placebo-controlled trial, 48 patients with chronic refractory lateral epicondylitis were randomly assigned to receive a single injection of either botulinum toxin (60 units) or placebo (normal saline). The site of injection was chosen as a distance one-third the length of the forearm from the tip of the lateral epicondyle on the course of the posterior interosseus nerve. The primary outcome measure was intensity of pain at rest, measured with the use of a 100-mm visual analogue scale, at baseline and at 4, 8 and 16 weeks after injection.
Compared with the placebo group, the group given botulinum toxin had significant reductions in pain at rest during follow-up (decrease at 4 weeks 14.1 mm, 95% confidence interval [CI] 5.8-22.3; at 8 weeks 11.5 mm, 95% CI 2.0-21.0; at 16 weeks 12.6 mm, 95% CI 7.7-17.8; p = 0.01). As for the secondary outcomes, the intensity of pain during maximum pinch decreased in the botulinum toxin group; there was no difference in pain during maximum grip or in grip strength between the two groups. All but one of the patients in the intervention group experienced weakness in the extension of the third and fourth fingers at week 4 that resolved by week 16. No serious adverse events were reported.
The use of precise anatomic measurement to guide injection of botulinum toxin significantly reduced pain at rest in patients with chronic refractory lateral epicondylitis. However, the transient extensor lag makes this method inappropriate for patients whose job requires finger extension.
This randomised controlled crossover trial examined the efficacy of botulinum toxin type A (BoNT-A) injection, plus an exercise programme, to remediate chronic anterior knee pain (AKP) associated with quadriceps muscle imbalance.
24 individuals with refractory AKP received either BoNT-A (500 U Dysport) or the same volume saline injection to the vastus lateralis (VL) muscle and performed home exercises focusing on re-training the vastus medialis (VM) muscle. All subjects were offered open-label injection at 12 weeks. Knee-related disability (anterior knee pain scale; AKPS) and activity-induced pain (10 cm visual analogue scale) at 12 weeks were the primary outcomes. Peak isometric extensor force was recorded and normalised VL:VM ratios were derived from simultaneous surface electromyography. Self-reported pain and disability measures were collected at six time points to a mean of 20±8 months.
14 subjects received BoNT-A and 10 placebo injection. Improvement at 12 weeks was significantly greater for BoNT-A compared with placebo-injected subjects for the AKPS (p<0.03), pain on kneeling (p<0.004), squatting (p<0.02) and level walking (p<0.04). At week 12, five placebo subjects crossed over to open-label injection. At 24 weeks, 16 of 19 BoNT-A-injected and two of the remaining five placebo-injected subjects were either satisfied or very satisfied with treatment outcomes. Improvements were maintained in 11 of 14 BoNT-A-injected and two of five placebo subjects available at longer-term follow-up.
BoNT-A injection produced a greater reduction in pain and disability than placebo injection in carefully selected patients with chronic AKP related to quadriceps muscle imbalance.
Background:
In addition to inhibition of muscle and glandular hyperactivity, botulinum neurotoxin (BoNT) type A also interferes with pain processing. Previously, in a rat model of paclitaxel-induced polyneuropathy, abobotulinumtoxinA (aboBoNT-A) elicited analgesic effects not only in the injected paw, but also in the contralateral, non-injected paw.
Methods:
Here, we assessed bilateral analgesic effects of unilateral aboBoNT-A in several chronic pain models in Sprague-Dawley rats. Effects of aboBoNT-A on the paw withdrawal threshold in response to mechanical pressure was assessed in models of streptozotocin-induced diabetic polyneuropathy, chronic constriction injury (CCI)-associated mononeuropathy, and bilateral carrageenan-induced inflammatory pain.
Results:
In diabetic polyneuropathy, aboBoNT-A (15, 20 U/kg) reversed hyperalgesia in the toxin-injected and non-injected paws. In unilateral CCI-exposed animals, 20 U/kg aboBoNT-A given ipsilateral to the injury reversed mechanical hyperalgesia, while 30 U/kg aboBoNT-A given contralateral to the injury had no effect. In carrageenan-induced bilateral inflammatory pain, aboBoNT-A (20, 30 U/kg) reversed hyperalgesia in both toxin-injected and non-injected paws.
Discussion:
These results suggest that unilateral administration of aboBoNT-A results in bilateral reduction in mechanical hyperalgesia across neuropathic and inflammatory pain conditions, bilateral activation of sensory neurons being prerequisite for its expression. Future studies involving effects on other sensory modalities as well as those evaluating diffusion and migration of the toxin away from the injection site can shed light on mechanisms of this phenomenon.
Significance:
The results expand evidence on bilateral analgesic effects of aboBoNT-A following unilateral administration across pain modalities, as the phenomenon is seen in more than one model of polyneuropathy as well as in a model of chronic inflammatory pain when the latter is rendered bilateral. The mechanism of bilateral analgesic effects of aboBoNT-A may require activation of the peripheral sensory neurons and involve retrograde axonal transport of the toxin into the spinal cord.
Introduction:
Piriformis syndrome is entrapment of the sciatic nerve by the piriformis muscle.
Methods:
In this article we describe a 56-person randomized, double-blind, controlled study involving physical therapy and incobotulinum toxin A or placebo. Inclusion criteria were 3-SD delay of posterior tibial (PT) or fibular (FN) H-reflexes on flexion, adduction, and internal rotation (FAIR) testing, and normal paraspinal electromyographic findings. Outcome measures included adverse side effects, visual analog scale (VAS) findings, and H-reflex delay on the FAIR test.
Results:
Mean intervention VAS score decreased significantly more compared with placebo at 2, 4, 6, 8, 10, and 12 weeks post-injection (P < 0.0001). FAIR test scores for PT, but not FN, decreased significantly more compared with placebo at 2, 4, 6, and 8 weeks post-injection (PT: P = 0.038, 0.003, 0.003, and 0.046). Adverse effects were minimal. VAS slope and PT FAIR test results varied significantly (P < 0.0001).
Conclusion:
Incobotulinum toxin A chemodenervation may be useful for treating piriformis syndrome as identified by the FAIR test. Muscle Nerve 56: 258-263, 2017.
Objective:
To evaluate the efficacy of a botulinum toxin type A (BoTN-A) in treating trigeminal neuralgia (TN) and postherpetic neuralgia (PHN).
Study design:
Three databases were searched: Medline, Web of Science, and Cochrane Library. The search was restricted to English-language randomized, placebo-controlled trials. Three review authors evaluated the cases for risk of bias.
Results:
Six studies were eligible for inclusion. Pooled results showed a difference in post-treatment pain intensity of -3.009 (95% confidence interval -4.566 to -1.453; P < .001) in favor of BoTN-A compared with placebo in managing TN or PHN. Of the six studies, five had unclear risk of bias, and one showed high risk.
Conclusions:
Although the studies had unclear or high risk of bias, moderate evidence regarding the efficacy of BoTN-A in treating TN and PHN was found. BoTN-A might be an alternative treatment to those patients who are either unable to manage their pain medically or would like adjunct therapy.
Background:
Data from previous studies suggest that botulinum toxin A has analgesic effects against peripheral neuropathic pain, but the quality of the evidence is low. We aimed to assess the safety and efficacy of repeated administrations of botulinum toxin A in patients with neuropathic pain.
Methods:
We did a randomised, double-blind, placebo-controlled trial at two outpatient clinics in France (Clinical Pain Centre, Ambroise Paré Hospital, APHP, Boulogne-Billancourt, and Neurological Centre, Hôpital Dupuytren, Limoges) and one in Brazil (Neurological Department, Hospital das Clínicas da FMUSP, São Paulo). Patients aged 18-85 years with peripheral neuropathic pain were randomly assigned (1:1) by block randomisation, according to a centralised schedule, to receive two subcutaneous administrations of botulinum toxin A (up to 300 units) or placebo, 12 weeks apart. All patients and investigators were masked to treatment assignment. The primary outcome was the efficacy of botulinum toxin A versus placebo, measured as the change from baseline in self-reported mean weekly pain intensity over the course of 24 weeks from the first administration. The primary efficacy analysis was a mixed-model repeated-measures analysis in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT01251211.
Findings:
Between Oct 2, 2010, and Aug 2, 2013, 152 patients were enrolled, of whom 68 were randomly assigned (34 per group), and 66 (37 [56%] men) were included in the primary analysis (34 in the botulinum toxin A group and 32 in the placebo group). Botulinum toxin A reduced pain intensity over 24 weeks compared with placebo (adjusted effect estimate -0·77, 95% CI -0·95 to -0·59; p<0·0001). Pain on injection was the only adverse effect reported, and occurred in 19 (56%) participants in the botulinum toxin A group and 17 (53%) of those in the placebo group (p=1·0). Severe pain was experienced by ten (29%) participants in the botulinum toxin A group and 11 (34%) in the placebo group (p=0·8).
Interpretation:
Two administrations of botulinum toxin A, each of which comprised several injections, have a sustained analgesic effect against peripheral neuropathic pain. Several factors, such as the presence of allodynia and a limited thermal deficit, may be useful in predicting treatment response and should be investigated further.
Funding:
Institut National de la Santé et de la Recherche Médicale (INSERM) and Fondation CNP (France).
Objective:
To evaluate the analgesic effect of botulinum toxin type A (BTX-A) on patients with spinal cord injury-associated neuropathic pain.
Methods:
The effect of BTX-A on 40 patients with spinal cord injury-associated neuropathic pain was investigated using a randomized, double-blind, placebo-controlled design. A one-time subcutaneous BTX-A (200 units) injection was administered to the painful area. Visual analogue scale scores (0-100 mm), the Korean-version of the short-form McGill Pain Questionnaire, and the World Health Organization WHOQOL-BREF quality of life assessment were evaluated prior to treatment and at 4 and 8 weeks after the injection.
Results:
At 4 and 8 weeks after injection, the VAS score for pain was significantly reduced by 18.6 ± 16.8 and 21.3 ± 26.8, respectively, in the BTX-A group, whereas it was reduced by 2.6 ± 14.6 and 0.3 ± 19.5, respectively, in the placebo group. The pain relief was associated with preservation of motor or sensory function below the neurological level of injury. Among the responders in the BTX-A group, 55% and 45% reported pain relief of 20% or greater at 4 and 8 weeks, respectively, after the injection, whereas only 15% and 10% of the responders in the placebo group reported a similar level of pain relief. Improvements in the score for the physical health domain of the WHOQOL-BREF in the BTX-A group showed a marginal trend toward significance (p = 0.0521) at 4 weeks after the injection.
Interpretation:
These results indicate that BTX-A may reduce intractable chronic neuropathic pain in patients with spinal cord injury. This article is protected by copyright. All rights reserved.
Neuropathic pain arises as a direct consequence of a lesion or a disease affecting the somatosensory system. Damage to the somatosensory system leads primarily to sensory loss (negative sensory signs). As with other neurological conditions, positive signs and symptoms may also occur. These include ongoing pain and hyperalgesia. Ongoing pain is due to ongoing neural activity that may arise at the site of neural damage or more rostrally.
Objective:
To develop a scientifically sound and clinically relevant evidence-based guideline for the treatment of painful diabetic neuropathy (PDN).
Methods:
We performed a systematic review of the literature from 1960 to August 2008 and classified the studies according to the American Academy of Neurology classification of evidence scheme for a therapeutic article, and recommendations were linked to the strength of the evidence. The basic question asked was: "What is the efficacy of a given treatment (pharmacologic: anticonvulsants, antidepressants, opioids, others; and nonpharmacologic: electrical stimulation, magnetic field treatment, low-intensity laser treatment, Reiki massage, others) to reduce pain and improve physical function and quality of life (QOL) in patients with PDN?"
Results and recommendations:
Pregabalin is established as effective and should be offered for relief of PDN (Level A). Venlafaxine, duloxetine, amitriptyline, gabapentin, valproate, opioids (morphine sulfate, tramadol, and oxycodone controlled-release), and capsaicin are probably effective and should be considered for treatment of PDN (Level B). Other treatments have less robust evidence or the evidence is negative. Effective treatments for PDN are available, but many have side effects that limit their usefulness, and few studies have sufficient information on treatment effects on function and QOL.
Objective
To evaluate the effect of botulinumneurotoxin type-A (BoNT-A) on chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) refractory to medical therapy.Materials and Methods
From November 2011 to January 2013, 60 men aged ≥18 years with CP/CPPS, NIH-CPSI symptom scale score≥10 and pain subscale score≥8, and refractory to 4 to 6 weeks medical therapy underwent transurethral intraprostatic injection of BoNT-A or normal saline (NS) in a prospective pilot double-blind randomized study. NIH-CPSI total and subscale scores, AUA-SS, VAS and (QoL) scores and frequencies of diurnal and nocturnal urination were evaluated and compared at baseline and 1,3 and 6 months after injection and also were compared between two groups.Results60 consecutive patients were randomized as BoNT-A or placebo group. In BoNT-A group at 1, 3 and 6-month evaluation compared to baseline values, NIH-CPSI total and subscale scores, AUA-SS, VAS and QoL scores along with frequencies of diurnal and nocturnal urinations had significantly improved (p<0.05). In contrast, none of these values showed improvement in placebo group and were statistically different from the values in treatment group. Although the difference between two groups in AUA-SS and frequencies of nocturnal urination was not significant at 1st month follow-up, but repeated measure analysis showed significant improving change of each of these values over entire follow up period in BoNT-A group which the most prominent was related to pain subscale score decreasing 64.76%, 75.63%, and 79.97% at 1,3 and 6 months after treatment compared to baseline followed by VAS score decreasing 62.3%, 72.4% and 82.1%, respectively. Only 2 patients developed mild transient gross hematuria, which were managed conservatively.Conclusions
Transurethral intraprostatic BoNT-A injection may be an effective therapeutic option in CP/CPPS patients by reducing pain and improving QoL.
Background
Botulinum toxin A (Onabot/A) has been shown to have an antinociceptive effect. This might be due to an impairment of sensory nerves not only in the peripheral but also in the central nervous system. In this work, we analysed both systems by studying the effect of intrathecal (i.t.) administration of botulinum toxin A in an animal model of bladder pain and hyperactivity induced by cyclophosphamide (CYP).Methods
Rats were implanted with an i.t. catheter at the L6 segment. Bladder pain was induced by intraperitoneal (i.p.) injection of CYP. Five experimental groups were created: (1) Saline i.p. + i.t.; (2) Onabot/A i.t.; (3) CYP i.p. + saline i.t.; (4) CYP i.p. + Onabot/A i.t. 48 h after CYP; and (5) Onabot/A i.t. 30 days. Mechanical sensitivity was assessed in the abdomen and hindpaws. Motor activity was observed in an open-field arena. Bladder reflex activity was evaluated by cystometry. At the end, bladders and spinal cord were immunoreacted (IR) against cleaved SNAP-25 (cSNAP-25), c-Fos, p-ERK, calcitonin gene-related peptide (CGRP) and GAP43.ResultsThe toxin reduced pain symptoms, bladder hyperactivity, expression of neuronal activation markers and CGRP, typically up-regulated in this inflammatory model. The presence of cSNAP-25 was detected in the spinal cord and bladder fibres from animals treated with Onabot/A. No somatic or visceral motor impairments were observed.Conclusions
Our findings suggest that i.t. Onabot/A has a strong analgesic effect in a model of severe bladder pain. This route of administration can be further explored to treat intractable forms of pain.
To report outcomes of patients with medical and/or surgical refractory trigeminal neuralgia (TN) treated with gamma knife stereotactic radiosurgery (GK SRS).
One hundred and forty-nine patients with 152 cases of TN treated with GK SRS were analyzed. All patients, except one, received a dose of 40Gy to the 50% isodose volume. The Barrow Neurological Institute (BNI) pain intensity score was used to grade pain. Actuarial rates of pain relief were calculated. Multiple factors were analyzed for association with pain relief.
The median follow up was 27 months (4-71 months). Overall 92% of cases achieved a BNI score I-III after GK SRS. Of those who had pain relief after GK SRS, 32% developed pain recurrence defined as a BNI score of IV or V. The actuarial rate of freedom from pain recurrence (BNI scores I-III) of all treated cases at 1, 2 and 3-years was 76%, 69% and 60%, respectively. On univariate analysis age ≥70 was predictive of better pain relief (p=0.046). Type of pain, prior surgery, multiple sclerosis, number of isocenters, treated nerve length, volume and thickness and distance from the root entry zone to the isocenter were not significant for maintaining a BNI score of I-III. Those who achieved a BNI score of I or II were more likely to maintain pain relief compared to those who only achieved a BNI score of III (93% vs 38% at three years, p<0.01). The rate of pain relief of twenty-seven patients who underwent repeat GK SRS was 70% and 62% at 1 and 2 years, respectively. Toxicity after first GK SRS was minimal with 25% of cases experiencing only new or worsening post-treatment numbness.
GK SRS provides acceptable pain relief with limited morbidity in patients with medical and/or surgical refractory TN.
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WEIR-MITCHELL, ET AL,
Gunshot Wounds and Other Injuries of Nerves, 1864 80
Objectives:
Cumulative evidence support a beneficial effect of botulinum toxin A (BTX-A) in postherpetic neuralgia (PHN). We aimed to assess efficacy, safety, and tolerability of BTX-A in the management of PHN, performing a randomized, double-blind, single-dose, placebo-controlled trial.
Methods:
Thirty adults with PHN were randomized either to BTX-A or placebo. Severity of pain was evaluated by patients using a visual analogue scale (VAS) and quality of sleep was assessed using a 5-item questionnaire. Primary outcome was reduction in VAS score, with a greater than 50% reduction being considered clinically significant. Secondary outcomes were reduction in sleep score and maintenance of VAS score after treatment, with over 50% maintenance considered clinically meaningful.
Results:
Thirteen patients from the experimental arm achieved an at least 50% reduction in VAS score, compared with none of the placebo patients (NNT=1.2, 95% CI, 2-1; ARR=0.87, 95% CI, 055-096; P<0.001). BTX-A patients showed significant reduction in VAS pain scores between baseline and week 2, which persisted for a median period of 16 weeks. BTX-A patients showed significant reduction in sleep scores between baseline and week 2, which remained unchanged until 16th week (P<0.001). Treatment was well tolerated.
Discussion:
Data confirm that BTX-A is effective and well tolerated in the treatment of PHN.
Objective:
The literature examining the epidemiology, quality of life burden, cost, and treatment of diabetic peripheral neuropathy pain (DPNP) in U.S. adults was reviewed.
Design:
A comprehensive computerized literature review of DPNP was conducted using MEDLINE and other databases, which were searched from 1995 through August 2004 using the Medical Subject Headings diabetic neuropathies and pain combined with relevant terms. A supplementary MEDLINE search of clinical trials of pharmacological treatments for DPNP was conducted through July 2005.
Results:
The search resulted in 321 articles. Several epidemiological studies assessed diabetic peripheral neuropathy among patients with diabetes and reported prevalence rates of 26-47%. No estimates of DPNP prevalence were reported, although one study (N = 2,405) reported that 26.8% of participants with diabetes experienced either pain or tingling. Randomized clinical trials have been conducted of several medications and classes of medication in patients with DPNP, and the U.S. Food and Drug Administration has approved two drugs for DPNP. Several published studies reported that DPNP impairs quality of life. Estimates of the costs of DPNP in the United States were limited. One study estimated average annual pain medication costs of $1,004 per DPNP patient.
Conclusions:
This review of DPNP identifies gaps in the literature and highlights the need for further study. The establishment of a consistent definition and diagnostic code for DPNP would improve ability to collect data and understand the impact of DPNP on patients and the health care system. Well-designed, prospective studies are needed to better define the epidemiology and public health burden of DPNP.
Botulinum toxin A (BoNT-A) is used as an alternative treatment for chronic orthopedic conditions. This study was conducted to investigate the efficacy and safety of BoNT-A on pain and functional outcome in patients with chronic plantar fasciitis.
In this short-term, randomized, multicenter, double-blind, placebo-controlled study, patients (N=40) were randomized to receive 200 units of BoNT-A (Dysport) or saline placebo. The injection was administered in a fan-shaped manner directly at the calcaneal origin of the plantar fascia. The primary outcome measure was the proportion of responders at week 6 [≥50% decrease from baseline in pain score (visual analog scale) while moving during the previous 48 h). Global assessments were performed by the patient and physician at each visit up to week 18.
More patients in the BoNT-A group achieved a response at week 6 (25% vs. 5% for placebo; P=0.18). Differences between treatments were in favor of BoNT-A on secondary measures of pain, but did not reach statistical significance. In the BoNT-A group, 52.7% (vs. 40% for placebo) assessed their condition as slightly/significantly improved at week 6. At study endpoint (week 18), 63.1% of the BoNT-A group perceived an improvement versus 55% of the placebo group. There was no difference in global assessment between physician and patient. No adverse events related to treatment were noted.
There is a need for larger, prospective, long-term, placebo-controlled studies to fully establish the role of BoNT-A for the treatment of plantar fasciitis.
There is a pressing unmet need for long-acting and effective therapeutics to alleviate symptoms of the varied forms of chronic pain. As many sufferers do not respond satisfactorily to non-addictive anti-nociceptives, a new treatment has emerged using inhibitors for the release of pain mediators from peripheral sensory nerves to give prolonged benefit. This strategy relies on proteolytically inactivating intra-neuronal SNARE (soluble N-ethylmaleimide-sensitive-factor attachment protein receptors) proteins which are essential for regulated exocytosis of transmitters, peptides and other pain signalling molecules. Success has been achieved with botulinum neurotoxin A (BoNT/A) which targets neuronal acceptors via its heavy chain, becomes endocytosed and translocated into the cytosol where the long-lived protease of its light chain potently and specifically cleaves SNAP-25 (synaptosomal-associated protease of Mr=25k). Encouragingly, clinical trials have shown that local injections of BOTOX(®) (BoNT/A complex) reduce chronic migraine symptoms including frequency and intensity for many months. Several serotypes of the neurotoxin moiety alone have been prepared recombinantly using Escherichia coli, which exhibit optimal neuroparalysis. Moreover, an engineered chimera of BoNT/E in which its binding domain was replaced with that from /A efficaciously inhibits the TRPV1 (transient receptor potential vanilloid type 1)-triggered release of CGRP (calcitonin gene-related peptide) from cultured sensory neurons, and suppresses the resultant excitatory effects in brain slices. A longer acting composite toxin, containing the protease of type E attached to BoNT/A, displays prolonged amelioration of pain symptoms in an animal model of inflammatory pain. This provides proof of principle that therapeutically advantageous features of /E (most robust inhibitor of CGRP release) and /A (targeting to sensory neurons and dramatic extension of the longevity of E protease) can be incorporated into a single synergistically active anti-nociceptive.
Recent studies have demonstrated that the botulinum neurotoxins inhibit the release of acetylcholine, glutamate, GABA, and glycine in central nerve system (CNS) neurons. The Na(+) current (I(Na)) is of major interest because it acts as the trigger for many cellular functions such as transmission, secretion, contraction, and sensation. Thus, these observations raise the possibility that A type neurotoxin might also alter the I(Na) of neuronal excitable membrane. To test our idea, we examined the effects of A type neurotoxins on I(Na) of central and peripheral neurons. The neurotoxins in femtomolar to picomolar concentrations produced substantial decreases of the neuronal I(Na), but interestingly the current inhibition was saturated at about maximum 50% level of control I(Na). The inhibitory pattern in the concentration-response curve for the neurotoxins differed from tetrodotoxin (TTX), local anesthetic, and antiepileptic drugs that completely inhibited I(Na) in a concentration-dependent manner. We concluded that A type neurotoxins inhibited membrane Na(+)-channel activity in CNS neurons and that I(Na) of both TTX-sensitive and -insensitive peripheral dorsal ganglion cells were also inhibited similarly to a maximum 40% of the control by the neurotoxins. The results suggest evidently that A2NTX could be also used as a powerful drug in treating epilepsy and several types of pain.
Botulinum toxin type A (Botox) injection has been used to manage pain. However, it remains to be proved whether Botox injection is effective to relieve residual limb pain (RLP) and phantom limb pain (PLP).
Randomized, double-blinded pilot study.
Medical College and an outpatient clinic in Department of Physical Medicine and Rehabilitation.
Amputees (n=14) with intractable RLP and/or PLP who failed in the conventional treatments.
Study amputees were randomized to receive 1 Botox injection versus the combination of Lidocaine and Depomedrol injection. Each patient was evaluated at baseline and every month after the injection for 6 months.
The changes of RLP and PLP as recorded by VAS, and the changes of the pressure pain tolerance as determined by a pressure algometer.
All patients completed the protocol treatment without acute side effects, and monthly assessments of RLP, PLP, and pain tolerance after the treatment. The time trend in the outcomes was modeled as an immediate change owing to the treatment followed by a linear tread afterward. Repeated measures were incorporated using mixed effects modeling. We found that both Botox and Lidocaine/Depomedrol injections resulted in immediate improvements of RLP (Botox: P=0.002; Lidocaine/Depomedrol: P=0.06) and pain tolerance (Botox: P=0.01; Lidocaine/Depomedrol: P=0.07). The treatment effect lasted for 6 months in both groups. The patients who received Botox injection had higher starting pain than those who received Lidocaine/Depomedrol injection (P=0.07). However, there were no statistical differences in RLP and pain tolerance between these 2 groups. In addition, no improvement of PLP was observed after Botox or Lidocaine/Depomedrol injection.
Both Botox and Lidocaine/Depomedrol injections resulted in immediate improvement of RLP (not PLP) and pain tolerance, which lasted for 6 months in amputees who failed in conventional treatments.
To assess the benefits of subcutaneous injection of botulinum toxin A (BTX-A) for the treatment of postherpetic neuralgia (PHN).
We investigated the therapeutic benefits of BTX-A in subjects with PHN in a randomized, double-blind, placebo-controlled study. Sixty subjects with PHN were randomly and evenly distributed into BTX-A, lidocaine, and placebo groups.
After randomization, one of the following solutions was injected subcutaneously in the affected dermatome: 5u/mL BTX-A, 0.5% lidocaine, or 0.9% saline (placebo). Visual analog scale (VAS) pain and sleeping time (hours) were evaluated at the time of pretreatment, day 1, day 7, and 3 months posttreatment. Opioid usage was calculated at day 7 and 3 months posttreatment.
Compared with pretreatment, VAS pain scores decreased at day 7 and 3 months posttreatment in all three groups (P<0.01). However, the VAS pain scores of the BTX-A group decreased more significantly compared with lidocaine and placebo groups at day 7 and 3 months posttreatment (P<0.01). Sleep time (hours) had improved at day 7 and at 3 months compared with pretreatment in all three groups, but the BTX-A group improved more significantly compared with lidocaine and placebo groups (P<0.01). The percent of subjects using opioids posttreatment in the BTX-A group was the lowest (21.1%) compared with the lidocaine (52.6%) and placebo (66.7%) groups (P<0.01).
Subcutaneous administration of BTX-A significantly decreased pain in PHN and reduced opioid use compared with lidocaine and placebo at day 7 and 3 months post-treatment. It also increased subjects' sleep times.
Male chronic pelvic pain syndrome (CPPS) has been the subject of numerous clinical trials, but so far, no uniformly effective treatment has been identified. A commonly reported tender spot in men with CPPS is the bulbospongiosus muscle. A randomized placebo controlled pilot trial of botulinum toxin A (BTX-A) injection into the perineal skeletal musculature for the treatment CPPS was conducted.
Twenty-nine men with CPPS were identified from a urology clinic. Symptom evaluation was performed using a Global Response Assessment (GRA) and the Chronic Prostatitis Symptom Index (CPSI). All subjects were randomized to receive either BTX-A 100 U or normal saline injected into the perineal body and bulbospongiosus muscle.
BTX-A injection was administered in 13 men. At the 1 month follow-up there was a 30% response rate for BTX-A treatment compared with 13% for placebo (p = 0.0002), based on GRA results. Total CPSI score did not reach significance in the BTX-A-treated group, compared with controls. The CPSI pain subdomain score reached statistical significance in the BTX-A patients compared with controls (p = 0.05). The injections were well tolerated. There were no complications from the injections and no patients reported side-effects.
BTX-A injection into the perineal body and bulbospongiosus muscle results in a modest response rate on the GRA compared with placebo for overall symptoms associated with CPPS. The treatment is well tolerated and safe. BTX-A use may enhance polytherapeutic pain management.
Among all the causes of chronic low back pain, myofascial pain syndrome of the spinal stabilizer muscles is one of the most frequent, yet underconsidered sources of pain. The purpose of this prospective, randomized, double-blind, controlled trial was to evaluate the efficacy of type-A botulinum toxin (BTX-A) in relieving myofascial pain in patients experiencing mechanical low back pain due to bilateral myofascial pain syndrome involving the iliopsoas and/or the quadratus lumborum muscles.
Each of the 27 enrolled patients received a bilateral, fluoroscopically guided injection in the affected muscle(s) to randomly deliver BTX-A in one side of the low back and a control drug (randomly constituted by NaCl 0.9% or bupivacaine 0.25%) in the opposite side. To evaluate the effects of treatment on daily life activities and psychologic status, 5 different questionnaires were administered (Hospital Anxiety and Depression scale [HAD-A and HAD-D], Lattinen, Oswestry, and Spielberger State-Trait Anxiety Index).
BTX-A injection did not significantly reduce visual analog scale scores more than treatment with NaCl or bupivacaine in the contralateral side; furthermore, the treatments administered did not result in a significant improvement of patients' daily life activities or psychologic status. Although a trend toward a decrease in postintervention visual analog scale scores could be recognized in all low back sides, this trend was significant only in the sides treated with BTX-A.
BTX-A seems to provide significant postintervention pain relief. However, considering its high cost and the small differences compared with control treatments, its use should be reserved only for patients with pain refractory to other invasive treatments.
The literature currently suggests that voltage-gated sodium channels play a major role in the pathogenesis of neuropathic pain. Alterations in the expression and targeting of specific sodium channels within injured dorsal root ganglia neurons appear to predispose the neurons to abnormal firing properties, allowing for the development of neuropathic pain. Mutations of one particular sodium channel (Na(v)1.7) have been shown to cause inherited neuropathic pain in humans, specifically in erythromelalgia and paroxysmal extreme pain disorder. Inherited erythromelalgia is the first human pain syndrome to be understood at a molecular level, having been linked to gain-of-function mutations of Na(v)1.7. Conversely, a loss-of-function of the Na(v)1.7 channel can produce channelopathy-associated insensitivity to pain. Therefore, the Na(v)1.7 channel may provide a unique target for the pharmacotherapy of pain in humans. In this review article we summarize current knowledge regarding several different disease manifestations arising from changes within the Na(v)1.7 channel.
To evaluate the effectiveness of ultrasonographic guided botulinum toxin type A injections into the plantar fascia to reduce pain and improve gait in patients with unilateral plantar fasciitis.
A randomized double-blind control study.
Fifty patients with chronic unilateral plantar fasciitis were recruited, and divided into experimental and control groups.
Subjects in the experimental group were injected with 50 units botulinum toxin type A, reconstituted with normal saline, into the plantar fascia under ultrasonographic guidance. Follow-up evaluations were made 3 weeks and 3 months after injection. The control group subjects were injected with normal saline under ultrasonographic guidance. Outcome measures included comparing scores from the visual analogue pain scale, changes in thickness of the plantar fascia and fat pad, and gait assessment including the maximal centre of pressure velocity during first step loading response.
Visual analogue pain scale and plantar fascia thickness in the symptomatic foot decreased significantly, as noted at follow-up 3 weeks and 3 months after botulinum toxin type A injections (p < 0.001). However, the fat pad thickness remained unchanged. The centre of pressure velocity during loading response increased 3 months after injection (p < 0.05). Outcome measures of the control group remained unchanged.
Botulinum toxin type A is effective in the treatment of foot pain associated with plantar fasciitis and increases the centre of pressure velocity during loading response without inducing fat pad atrophy.
Here we provide behavioural evidence for an axonal transport and the central origin of the antinociceptive effect of botulinum toxin type A (BTX-A). In rats we investigated the effectiveness of BTX-A on "mirror pain" induced by unilateral repeated intramuscular acidic saline injections (pH 4.0). Since experimental evidence suggest that bilateral pain induced by acidic saline is of central origin, peripheral application of BTX-A should have no effect on this type of pain. However, here we demonstrated that the unilateral subcutaneous BTX-A (5U/kg) application diminished pain on the ipsilateral, and on the contralateral side too. When injected into the proximal part of a distally cut sciatic nerve, BTX-A still reduced pain on the contralateral side. Colchicine, an axonal transport blocker, when injected into the ipsilateral sciatic nerve, prevented the effect of the peripheral BTX-A injection on both sides. Additionally, when BTX-A (1U/kg) was applied intrathecally in the lumbar cerebrospinal fluid, the bilateral hyperalgesia was also reduced. The results demonstrate the necessity of retrograde axonal transport and involvement of the central nervous system for the antinociceptive activity of BTX-A.
Many patients with trigeminal neuropathies suffer severe chronic pain which is inadequately alleviated with centrally-acting drugs. These drugs also possess severe side effects making compliance difficult. One strategy is to develop new treatments without central side effects by targeting peripheral sensory neurons, since sensory neuron excitability and neurotransmitter release increase in chronic pain states. Such treatments may include the highly purified botulinum toxin type A 150 kDa (BoNT/A) which reportedly blocks vesicular neurotransmitter release. We set out to determine if experimental trigeminal neuropathy induced by infraorbital nerve constriction (IoNC) in rats could alter neurotransmitter release from somata of trigeminal sensory neurons and if it could be aften-uated by BoNT/A. Thus, we monitored the secretory activity of acutely dissociated trigeminal ganglion (TRG) neurons from naive and IoNC rats by measuring the fluorescence intensity of the membrane-uptake marker (N-(3-triethylammoniumpropyl)-4-(6-(4-(diethylamino)phenyl)hexatrienyl)pyridinium dibromide (FM4-64). FM4-64 staining showed that neurons possess a pool of recycled vesicles which could be released by high KCl (75 mM) application. BoNT/A pre-treatment of acutely dissociated TRG neurons from naive rats significantly reduced the rate of FM4-64 dye release. Neurons isolated from TRG ipsilateral to IoNC exhibited significantly faster onset of FM4-64 release than neurons contralateral to
We compared the short-term efficacy and safety of intra-articular (IA) botulinum toxin A (BoNT/A) to IA-placebo in patients with chronic, refractory shoulder joint pain. Forty-three shoulder joints in patients with moderate-to-severe shoulder arthritis pain were randomized to receive (1) 100 units IA-BoNT/A + lidocaine or (2) IA-saline + lidocaine. The following outcomes were compared using analysis of covariance: (1) primary: change in pain severity on a visual analog scale at 1 month (VAS, 0 cm to 10 cm); (2) secondary: Shoulder Pain and Disability Index (SPADI) disability subscale, quality of life on short-form (SF)-36 subscales, percent of patients who achieved at least a 30% decrease or a 2-point reduction in VAS pain (clinically meaningful pain relief), and safety. Both BoNT/A (n = 21) and placebo (n = 22) groups were comparable at baseline. At 1 month post-injection, the VAS pain reduction was significantly more in the BoNT/A group versus the placebo group (-2.4 vs -0.8; P-value = 0.014). When comparing BoNT/A with the placebo group at 1 month, it was observed that 5 SF-36 subscale scores improved significantly (P </= 0.035), and the SPADI disability improved more with a trend toward significance (51.5 +/- 4.4 vs 64.9 +/- 3.9; P = 0.083). In addition, clinically meaningful pain relief occurred in 61% versus 36% patients (P = 0.22). The total number of adverse events was similar, which included 50 events in the BoNT/A group versus 46 events in the placebo group. A single injection of BoNT/A produced statistically significant and clinically meaningful pain relief and improvement in quality of life in patients with chronic refractory moderate/severe shoulder arthritis pain at 1 month. These data provide evidence to support the efficacy of this novel neurotoxin therapy that needs to be confirmed in a multicenter, randomized trial.
Diabetic neuropathy is a common complication in diabetes, with patients typically experiencing diverse sensory symptoms including dysesthesias in the feet and usually accompanied by sleep disturbance. There is still no comprehensive understanding of the underlying biologic processes responsible for diabetic neuropathic pain. Thus, the current symptomatic therapy remains unsatisfactory. Recent experimental evidence suggests that botulinum toxin type A (BoNT/A) may not only inhibit the release of acetylcholine at the neuromuscular junctions, but also modulate afferent sensory fiber firing, thereby relieving neuropathic pain.
A double-blind crossover trial of intradermal BoNT/A for diabetic neuropathic pain in 18 patients was conducted to evaluate the effectiveness.
We find significant reduction in visual analog scale (VAS) of pain by 0.83 +/- 1.11 at 1 week, 2.22 +/- 2.24 at 4 weeks, 2.33 +/- 2.56 at 8 weeks, and 2.53 +/- 2.48 at 12 weeks after injection in the BoNT/A group, as compared to the respective findings for a placebo group of 0.39 +/- 1.18, -0.11 +/- 2.04, 0.42 +/- 1.62, and 0.53 +/- 1.57 at the same timepoints (p < 0.05). Within the BoNT/A group, 44.4% of the participants experienced a reduction of VAS >/=3 within 3 months after injection, whereas there was no similar response in the placebo group. At the 4-week postinjection stage, improvement in sleep quality was measured using the Chinese version of the Pittsburgh Sleep Quality Index.
This pilot study found that botulinum toxin type A significantly reduced diabetic neuropathic pain and transiently improved sleep quality. Further large-scaled study is warranted.
