Botulinum Toxin Type A for the Treatment of Neuropathic Pain in Neuro-Rehabilitation

Pain is a natural protective mechanism and has a warning function signaling imminent or actual tissue damage. Neuropathic pain (NP) results from a dysfunction and derangement in the transmission and signal processing along the nervous system and it is a recognized disease in itself. The prevalence of NP is estimated to be between 6.9% and 10% in the general population. This condition can complicate the recovery from stroke, multiple sclerosis, spinal cord lesions, and several neuropathies promoting persistent disability and poor quality of life. Subjects suffering from NP describe it as burning, itching, lancing, and numbness, but hyperalgesia and allodynia represent the most bothersome symptoms. The management of NP is a clinical challenge and several non-pharmacological and pharmacological interventions have been proposed with variable benefits. Botulinum toxin (BTX) as an adjunct to other interventions can be a useful therapeutic tool for the treatment of disabled people. Although BTX-A is predominantly used to reduce spasticity in a neuro-rehabilitation setting, it has been used in several painful conditions including disorders characterized by NP. The underlying pharmacological mechanisms that operate in reducing pain are still unclear and include blocking nociceptor transduction, the reduction of neurogenic inflammation by inhibiting neural substances and neurotransmitters, and the prevention of peripheral and central sensitization. Some neurological disorders requiring rehabilitative intervention can show neuropathic pain resistant to common analgesic treatment. This paper addresses the effect of BTX-A in treating NP that complicates frequent disorders of the central and peripheral nervous system such as spinal cord injury, post-stroke shoulder pain, and painful diabetic neuropathy, which are commonly managed in a rehabilitation setting. Furthermore, BTX-A has an effect in relief pain that may characterize less common neurological disorders including post-traumatic neuralgia, phantom limb, and complex regional pain syndrome with focal dystonia. The use of BTX-A could represent a novel therapeutic strategy in caring for neuropathic pain whenever common pharmacological tools have been ineffective. However, large and well-designed clinical trials are needed to recommend BTX-A use in the relief of neuropathic pain.     

Botulinum Toxin for Neuropathic Pain: A Review of the Literature

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.     

Effects of Botulinum Toxin Type A on Pain among Trigeminal Neuralgia,Myofascial Temporomandibular Disorders,and Oromandibular Dystonia

The differences in analgesic effects of botulinum toxin type A were compared in 28 patients with trigeminal neuralgia, 53 patients with myofascial temporomandibular disorders, and 89 patients with the jaw closing oromandibular dystonia. The patients were treated by injection of botulinum toxin type A into the masseter, temporalis, medial pterygoid, and other muscles based on the symptoms of each patient. The pain severity was evaluated using the visual analog scale, pain frequency, and pain scale of the oromandibular dystonia rating scale. Botulinum toxin injection was performed 1068 times in all patients without significant adverse effects. The visual analog, pain frequency, and pain scales at baseline were reduced (p < 0.001) after two, four, eight, and 12 weeks after the first botulinum toxin therapy and at the endpoint. The effects differed significantly (p < 0.001) among the groups (repeated-measures analysis of variance). The mean improvement (0%, no effect; 100%, complete recovery) at the endpoint was 86.8% for trigeminal neuralgia, 80.8% for myofascial pain, and 75.4% for oromandibular dystonia. Injection of the botulinum toxin can be a highly effective and safe method to treat trigeminal neuralgia, myofascial pain, and oromandibular dystonia.     

Ultrasound-Guided Injection of Botulinum Toxin Type A for Piriformis Muscle Syndrome: A Case Report and Review of the Literature

Piriformis muscle syndrome (PMS) is caused by prolonged or excessive contraction of the piriformis muscle associated with pain in the buttocks, hips, and lower limbs because of the close proximity to the sciatic nerve. Botulinum toxin type A (BoNT-A) reduces muscle hypertonia as well as muscle contracture and pain inhibiting substance P release and other inflammatory factors. BoNT-A injection technique is important considering the difficult access of the needle for deep location, the small size of the muscle, and the proximity to neurovascular structures. Ultrasound guidance is easy to use and painless and several studies describe its use during BoNT-A administration in PMS. In the present review article, we briefly updated current knowledge regarding the BoNT therapy of PMS, describing also a case report in which this syndrome was treated with an ultrasound-guided injection of incobotulinumtoxin A. Pain reduction with an increase of hip articular range of motion in this patient with PMS confirmed the effectiveness of BoNT-A injection for the management of this syndrome.     

Botulinum Toxin Type-A (Botulax®) Treatment in Patients with Intractable Chronic Occipital Neuralgia: A Pilot Study

Intractable chronic occipital neuralgia (ON) is an uncommon type of headache often experienced by patients in outpatient neurological clinics. Among patients unresponsive to oral neuralgia medications, needling or injections with several drugs were suggested alternatives for treating chronic ON. This study aimed to determine the effectiveness and safety of botulinum toxin type-A (BTX-A) injection treatments, where eight patients with unilateral chronic ON received BTX-A injections at the pain sites. The pain relief effect was observed 2 weeks after receiving the injections, gradually showing improvements up to 12 weeks after injection. There were no adverse events or changes from baseline in serologic studies and vital signs in any of the participants. The treatment’s pain-relieving effects were confirmed through regular, 12-week follow-ups, confirming the safety and effectiveness of BTX-A on chronic ON and suggesting that this method is an effective, novel alternative option for chronic ON treatment.     

The Role of Botulinum Toxin Type A in the Clinical Management of Refractory Anterior Knee Pain

Anterior knee pain is a highly prevalent condition affecting largely young to middle aged adults. Symptoms can recur in more than two thirds of cases, often resulting in activity limitation and reduced participation in employment and recreational pursuits. Persistent anterior knee pain is difficult to treat and many individuals eventually consider a surgical intervention. Evidence for long term benefit of most conservative treatments or surgical approaches is currently lacking. Injection of Botulinum toxin type A to the distal region of vastus lateralis muscle causes a short term functional “denervation” which moderates the influence of vastus lateralis muscle on the knee extensor mechanism and increases the relative contribution of the vastus medialis muscle. Initial data suggest that, compared with other interventions for anterior knee pain, Botulinum toxin type A injection, in combination with an active exercise programme, can lead to sustained relief of symptoms, reduced health care utilisation and increased activity participation. The procedure is less invasive than surgical intervention, relatively easy to perform, and is time- and cost-effective. Further studies, including larger randomized placebo-controlled trials, are required to confirm the effectiveness of Botulinum toxin type A injection for anterior knee pain and to elaborate the possible mechanisms underpinning pain and symptom relief.     

A Systematic Review and Meta-Analysis of Efficacy of Botulinum Toxin A for Neuropathic Pain

We performed a systematic review and meta-analysis of randomised controlled trials (RCTs) conducted from January 2005 to June 2021 to update the evidence of Botulinum toxin A (BoNT-A) in neuropathic pain (NP) in addition to quality of life (QOL), mental health, and sleep outcomes. We conducted a Cochrane Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria analysis of RCTs from the following data sources: EMBASE, CINAHL, WHO International Clinical Trial Registry Platform, ClinicalTrials.gov, Cochrane database, Cochrane Clinical Trial Register, Australia New Zealand Clinical Trials Registry, and EU Clinical Trials Register. Meta-analysis of 17 studies showed a mean final VAS reduction in pain in the intervention group of 2.59 units (95% confidence interval: 1.79, 3.38) greater than the mean for the placebo group. The overall mean difference for sleep, Hospital Anxiety and Depression Scale (HADS) anxiety, HADS depression, and QOL mental and physical sub-scales were, respectively, 1.10 (95% CI: −1.71, 3.90), 1.41 (95% CI: −0.61, 3.43), −0.16 (95% CI: −1.95, 1.63), 0.85 (95% CI: −1.85, 3.56), and −0.71 (95% CI: −3.39, 1.97), indicating no significance. BoNT-A is effective for NP; however, small-scale RCTs to date have been limited in evidence. The reasons for this are discussed, and methods for future RCTs are developed to establish BoNT-A as the first-line agent.     

普瑞巴林对带状疱疹后遗神经痛神经阻滞效果的影响

目的 观察普瑞巴林对带状疱疹后遗神经痛神经阻滞效果的影响。方法 将40例患者随机分为对照组(A组)和普瑞巴林组(B组), 两组患者均行神经阻滞, B组加服普瑞巴林。对比观察两组患者用药前后VAS评分、睡眠质量评分(QS)和不良反应。结果 与治疗前比较,两组治疗后第2周～第10周,VAS和QS显著下降(P<0.01)。普瑞巴林组治疗后疼痛VAS评分和睡眠质量评分均显著低于对照组(P<0.05)。 两组不良反应的发生率没有区别。结论 普瑞巴林对带状疱疹后遗神经痛的神经阻滞效果具有明显的增强作用。     

Cost-Effectiveness of Treating Upper Limb Spasticity Due to Stroke with Botulinum Toxin Type A: Results from the Botulinum Toxin for the Upper Limb after Stroke (BoTULS) Trial

Stroke imposes significant burdens on health services and society, and as such there is a growing need to assess the cost-effectiveness of stroke treatment to ensure maximum benefit is derived from limited resources. This study compared the cost-effectiveness of treating post-stroke upper limb spasticity with botulinum toxin type A plus an upper limb therapy programme against the therapy programme alone. Data on resource use and health outcomes were prospectively collected for 333 patients with post-stroke upper limb spasticity taking part in a randomized trial and combined to estimate the incremental cost per quality adjusted life year (QALY) gained of botulinum toxin type A plus therapy relative to therapy alone. The base case incremental cost-effectiveness ratio (ICER) of botulinum toxin type A plus therapy was £93,500 per QALY gained. The probability of botulinum toxin type A plus therapy being cost-effective at the England and Wales cost-effectiveness threshold value of £20,000 per QALY was 0.36. The point estimates of the ICER remained above £20,000 per QALY for a range of sensitivity analyses, and the probability of botulinum toxin type A plus therapy being cost-effective at the threshold value did not exceed 0.39, regardless of the assumptions made.     

High Doses of Botulinum Toxin Type A for the Treatment of Post-Stroke Spasticity: Rationale for a Real Benefit for the Patients

In the past few years, there was a great interest in the use of higher doses of botulinum toxin type A, especially in case of upper and lower limb severe spasticity. To date, only one prospective, non-randomized, single-arm, multicenter, open-label, dose-titration study with the employment of incobotulinum toxin up to 800 U has been published, and the authors investigated safety and tolerability. Other researches showed efficacy in spasticity reduction, but there is a lack of evidence about the reasons to use high doses of botulinum toxin. This short communication highlights the benefits of higher doses for subjects with upper and lower limb spasticity.     

A型肉毒毒素治疗肌张力障碍

A型肉毒毒素因用于高兴奋性肌肉疾病的有效性而倍受神经内科医生的关注,治疗的方法越来越多,治疗的病种不断扩展,被认为是近几年来神经内科领域重要进展之一.本文从A型肉毒毒素历史、药理、方法与剂量、适应证(偏侧面肌痉挛与单纯眼肌痉挛、痉挛性斜颈、Meige综合征、祛皱美容)、毒副作用、禁忌证等几个方面进行综述.     

Pain Relief in Cervical Dystonia with Botulinum Toxin Treatment

Dystonia is a neurological disorder characterized by intermittent or sustained muscle contractions that cause abnormal, usually repetitive, movements and postures. Dystonic movements can be tremulous and twisting and often follow a pattern. They are frequently associated with overflow muscle activation and may be triggered or worsened by voluntary action. Most voluntary muscles can be affected and, in the case of the neck muscles, the condition is referred to as cervical dystonia (CD), the most common form of dystonia. The high incidence of pain distinguishes CD from other focal dystonias and contributes significantly to patient disability and low quality of life. Different degrees of pain in the cervical region are reported by more than 60% of patients, and pain intensity is directly related to disease severity. Botulinum toxin (BoNT) is currently considered the treatment of choice for CD and can lead to an improvement in pain and dystonic symptoms in up to 90% of patients. The results for BoNT/A and BoNT/B are similar. The complex relationship between pain and dystonia has resulted in a large number of studies and more comprehensive assessments of dystonic patients. When planning the application of BoNT, pain should be a key factor in the choice of muscles and doses. In conclusion, BoNT is highly effective in controlling pain, and its analgesic effect is sustained for a long time in most CD patients.     

Multidimensional Effectiveness of Botulinum Toxin in Neuropathic Pain: A Systematic Review of Randomized Clinical Trials

Although botulinum toxin (BoNT) has been suggested as a treatment to counter neuropathic pain, no previous systematic reviews investigated the multidimensional effects of BoNT on pain relief and Health-Related Quality of Life (HR-QoL). The aim of this systematic review is to summarize the current evidence on the effectiveness of BoNT treatment for neuropathic pain, and to characterize its multidimensional effectiveness in order to guide physicians in clinical practice. Five databases were systematically searched up to 4 April 2022, to identify randomized controlled trials satisfying the following criteria: adults suffering from neuropathic pain, BoNT administration, any comparator, multidimensional assessment of pain as primary outcome, HR-QoL, physical function, anxiety and depression, and sleep quality as secondary outcomes. Twelve studies were included. The multidimensional pain scales used were short-form McGill Pain Questionnaire, Neuropathic pain scale, Neuropathic Pain Symptom Inventory, International SCI Pain Basic Data Set, West Haven-Yale Multidimensional Pain Inventory, Brief Pain Inventory, and Douleur Neuropathique 4. These scales highlighted the positive effects of BoNT administration. According to the Jadad scale, all the RCTs included were high-quality studies. BoNT administration might be effectively introduced in the comprehensive management of neuropathic pain. Further research should focus on optimal and cost-effective therapeutic protocols.     

Efficacy of Botulinum Toxin Type-A I in the Improvement of Mandibular Motion and Muscle Sensibility in Myofascial Pain TMD Subjects: A Randomized Controlled Trial

This study assessed the effects of botulinum toxin type A (BoNT-A) in mandibular range of motion and muscle tenderness to palpation in persistent myofascial pain (MFP) patients (ReBEC RBR-2d4vvv). Eighty consecutive female subjects with persistent MFP, were randomly divided into four groups (n = 20): three BoNT-A groups with different doses and a saline solution group (placebo control group). Treatments were injected bilaterally in the masseter and anterior temporalis muscle in a single session. Clinical measurements of mandibular movements included: pain-free opening, maximum unassisted and assisted opening, and right and left lateral excursions. Palpation tests were performed bilaterally in the masseter and temporalis muscle. Follow-up occurred 28 and 180 days after treatment. For the statistical analysis the Mann–Whitney U-test with Bonferroni correction was used for groups comparisons. Regardless of dose, all parameters of mandibular range of motion significantly improved after 180 days in all BoNT-A groups, compared with the control group. Palpation pain over the masseter and temporalis muscles were significantly reduced in all BoNT-A groups regardless of dose, compared with the control group, after 28 and 180 days of treatment. Independent of doses, BoNT-A improved mandibular range of motion and muscle tenderness to palpation in persistent MFP patients.     

A型肉毒毒素治疗带状疱疹后顽固性神经痛20例

目的观察A型肉毒毒素治疗带状疱疹后顽固性神经痛的效果。方法将40例带状疱疹后顽固性神经痛患者随机分为治疗组和对照组各20例，两组均排除其他因素引起的疼痛，均给予抗病毒、营养神经、对症治疗，治疗组给予A型肉毒毒素沿神经走向行全身多点皮下注射，每点注射0.1 mL（含2.5万U）。结果治疗第1天治疗组疼痛积分为（6.9±0.85）分，对照组疼痛积分为（7.8±0.7）分，两组比较差异无显著性;治疗第3，第7，第14和第30天,治疗组疼痛积分均较对照组明显下降，且均差异有显著性（均P＜0.05）。结论 沿神经走向皮下注射A型肉毒毒素可有效治疗带状疱疹后顽固性神经痛，改善患者的精神、食欲和睡眠状态。     

Preliminary Exploration of a New Therapy for Interstitial Cystitis/Bladder Pain Syndrome: Botulinum Toxin A Combined with Sapylin

Interstitial cystitis/bladder pain syndrome (IC/BPS) is an intractable disease without long-term effective therapy. This study aims to evaluate the efficacy and safety of botulinum toxin A (BoNT/A) plus Sapylin, which might modulate the immune response of the bladder in the treatment of IC/BPS patients. We retrospectively investigated the clinical outcomes among 34 patients who accepted repeated Sapylin instillations after 200 U of BoNT/A submucosally injected into bladder walls (Mix group) and 28 patients who received BoNT/A alone (Control group). Each of the bladder walls (left, right, anterior and posterior) was injected six times with 8 U of BoNT/A per injection. The primary outcome measure was the global response assessment. The results showed that at 6 months post-injection, the response rate in the Mix group was remarkably higher than that in the Control group (58.8% vs. 28.6%, p < 0.05). The mean effective duration of the responders in the Mix group was apparently better than that in the Control group (27.5 (range 0–89) vs. 4.9 (range 0–11) months, p < 0.05). None of the patients experienced serious adverse events. In conclusion, repeated intravesical instillations of Sapylin after BoNT/A injection can produce significantly better clinical outcomes than BoNT/A alone in IC/PBS patients.     

A型肉毒毒素对三叉神经痛患者心理状况及生活质量的影响

目的 探讨A型肉毒毒素对三叉神经痛患者心理状况以及生活质量的影响.方法 将2014年12月—2015年12月上海市杨浦区市东医院治疗的三叉神经痛患者100例根据不同的治疗方法分为观察组(52例)与对照组(48例).其中观察组接受A型肉毒毒素治疗,对照组接受卡马西平治疗.治疗8周后,观察并比较两组治疗效果及不良反应发生率.结果 治疗前,两组焦虑、抑郁、睡眠干扰、疼痛评分比较差异无统计学意义(P>0.05);治疗后,观察组上述指标较对照组改善更明显(P<0.05),有效率也明显高于对照组(P<0.05),两组不良反应发生率比较差异无统计学意义(P>0.05).结论 A型肉毒毒素治疗三叉神经痛,能显著改善患者心理状况与生活质量,且治疗有效、安全,具有推广价值.     

A型肉毒毒素治疗偏侧面肌痉挛的临床观察

目的探讨A型肉毒毒素治疗偏侧面肌痉挛的临床疗效。方法采用A型肉毒毒素局部多点注射治疗偏侧面肌痉挛142例,对治疗前后的病情随访并进行分级比较。结果症状完全缓解占54%,明显缓解占42%,部分缓解占4%,疗效平均持续约3~6个月,个别持续10个月左右,复发者重复注射仍有效,局部不良反应轻微短暂。结论局部注射A型肉毒毒素是治疗偏侧面肌痉挛一种安全有效且简便易行的手段。     

Effect of Botulinum Toxin Injection and Extracorporeal Shock Wave Therapy on Nerve Regeneration in Rats with Experimentally Induced Sciatic Nerve Injury

This study was designed to compare the roles of botulinum neurotoxin A (BoNT/A) and extracorporeal shock wave therapy (ESWT) in promoting the functional recovery and regeneration of injured peripheral nerves. A total of 45 six-week-old rats with sciatic nerve injury were randomly divided into two experimental groups and one control group. The experimental groups received a single session of intranerve BoNT/A or ESWT immediately after a nerve-crushing injury. The control group was not exposed to any treatment. Differentiation of Schwann cells and axonal sprouting were observed through immunofluorescence staining, ELISA, real-time PCR, and Western blot at 3, 6, and 10 weeks post-nerve injury. For clinical assessment, serial sciatic functional index analysis and electrophysiological studies were performed. A higher expression of GFAP and S100β was detected in injured nerves treated with BoNT/A or ESWT. The levels of GAP43, ATF3, and NF200 associated with axonal regeneration in the experimental groups were also significantly higher than in the control group. The motor functional improvement occurred after 7 weeks of clinical observation following BoNT/A and ESWT. Compared with the control group, the amplitude of the compound muscle action potential in the experimental groups was significantly higher from 6 to 10 weeks. Collectively, these findings indicate that BoNT/A and ESWT similarly induced the activation of Schwann cells with the axonal regeneration of and functional improvement in the injured nerve.