Clinical profile of botulinum toxin A in patients with chronic headaches and cervical dystonia: a prospective, open-label, longitudinal study conducted in a naturalistic clinical practice setting

BACKGROUND AND OBJECTIVES: Some evidence for the efficacy of botulinum toxin A as a preventive treatment for chronic primary headaches has been reported in randomized, controlled clinical studies. This study investigated the clinical profile of botulinum toxin A in a naturalistic clinical practice setting in a population of patients with cervical dystonia associated with chronic headache and a history of migraine. METHODS: This was a prospective, open-label, longitudinal study. Following a prospective run-in period, eligible patients were given three sets of botulinum toxin A injections at 8- to 12-week intervals over a 16- to 24-week period and were monitored for 3 months after the final injections. Efficacy was assessed in terms of headache-related disability (using the Migraine Disability Assessment [MIDAS] questionnaire), pain and emotional function (using the Short Pain Inventory [SPI]), quality of life (QOL, using the Short-Form-36 [SF-36] questionnaire) and patient-assessed headache frequency and severity, and medication use and its effectiveness. Safety was assessed as adverse events. The primary endpoint was the change in MIDAS score from baseline following treatment with botulinum toxin A. RESULTS: Twenty-four patients took part in the study and 17 (71%) completed the study. There were significant improvements in headache-related disability (MIDAS score), pain and emotional function (SPI), QOL (SF-36), headache frequency and medication use following treatment with botulinum toxin A (p < 0.05 for all endpoints). An efficacy response occurred within 8 weeks of treatment initiation and was maintained throughout the study duration. Botulinum toxin A was generally well tolerated. CONCLUSIONS: This study demonstrated that botulinum toxin A is an effective and well tolerated preventive treatment for chronic headache in patients with cervical dystonia and a history of migraine. These results warrant further investigation in a large, randomized, controlled study.     

Botulinum toxin A (Dysport®): in dystonias and focal spasticity

Dysport?, a formulation of botulinum toxin A, blocks acetylcholine release at neuromuscular junctions causing denervation and temporary muscle paralysis. It is used to treat several medical conditions, including dystonias and focal spasticity. Subcutaneous Dysport? was effective in improving functional disability in adults with blepharospasm in a placebo-controlled trial with 16 weeks' follow-up, and in adults with hemifacial spasm in case series. Similarly, intramuscular Dysport? was effective in improving symptoms of cervical dystonia in adults, focal spasticity in adults with post-stroke upper limb spasticity and dynamic equinus spasticity in paediatric patients with cerebral palsy in placebo-controlled trials with up to 20 weeks' follow-up. However, in two 12-week, placebo-controlled trials in adults with focal lower limb spasticity (spastic equinovarus deformity after stroke and hip adductor spasticity associated with multiple sclerosis) intramuscular Dysport? had limited efficacy. Available longer-term data indicated that Dysport? treatment was effective over several treatment cycles in patients with cervical dystonia or upper limb spasticity. Dysport? was generally well tolerated in patients with dystonias or focal spasticity. Most adverse events were mild to moderate and transient.     

Botulinum toxin type A for migraine. First, do no harm

Headache prevention in adults with chronic migraine is based first on oral drug therapy, preferably with propranolol, and on tapering off possible analgesic overuse. Botulinum toxin type A injections in head and neck muscles is now authorised for this purpose in the United Kingdom. It has been used off label for several years. Clinical evaluation in this indication is based on two placebo-controlled double-blind trials with identical designs. A total of 1384 patients underwent two sessions of intramuscular injections of botulinum toxin type A or placebo, 3 months apart, into at least 31 specific sites in the head and neck. Compared to baseline, patients who received botulinum toxin in one trial (but not in the other) experienced a statistically significant reduction in headache frequency at the end of the study, but the results are undermined by methodological issues. Botulinum toxin type A has not been compared with preventive oral therapy. An inherently unreliable indirect comparison suggests that botulinum toxin type A is clearly less effective than oral propranolol. In its other approved indications, botulinum toxin type A has been linked to deaths and muscle paralysis distant from the injection site, leading to swallowing difficulties and respiratory disorders. Some patients enrolled in clinical trials of botulinum toxin type A experienced transient worsening of their migraine and headache (9.3%, versus 5.8% of patients receiving placebo injections), exaggerated paralytic effects, and muscle pain and stiffness. In practice, given its uncertain efficacy, at best only modest, botulinum toxin type A is simply too risky a treatment for migraine. It is better to focus on fine tuning of standard prophylaxis.     

Botulinum toxin type A: Exploring new indications

The use of botulinum toxin has expanded in the last five years to include traditional neurological use against dystonia and spasticity, as well as the emerging use for headache, pain, neuropathy, myofascial pain, joint arthritis, otolaryngology, gastroenterology and genitourinary disorders. This review will focus on these emerging uses of botulinum toxin as reported in recent literature. The exploratory use of botulinum toxin for cervical dystonia, blepharospasm and spasticity in small trials and case reports, has led to its detailed study in larger placebo-controlled clinical trials. Although the use of botulinum toxin for new indications may benefit a specific subset of patients with refractory pain and disability, the reader must realize that this is an emerging area, generally limited by a lack of large, placebo-controlled studies.     

Spasticity associated with cerebral palsy in children: guidelines for the use of botulinum A toxin

Botulinum A toxin produces selective and reversible chemodenervation that can be employed to balance muscle forces across joints in children with cerebral palsy (CP). Currently, there are two commercially available botulinum A toxin formulations (BOTOX) and Dysport). The amount of botulinum A toxin required depends upon the number of muscles that are targeted, and the size of the patient. In order to achieve adequate chemodenervation with botulinum A toxin, the following conditions must be met: (i) a sufficient number of units of toxin must be injected in order to neutralize neuromuscular junction (NMJ) activity; (ii) an appropriate drug volume is required in order to optimize the delivery of the toxin to the NMJs; and (iii) localization of the injecting needle through the fascia of the target muscle is necessary. Localization of the injection may be facilitated by active electromyography, ultrasonography, palpation of the muscle belly, and/or use of anatomic landmarks. Botulinum A toxin injections are indicated for use in pediatric patients with CP to: (i) improve motor function by balancing muscle forces across joints; (ii) improve health-related quality of life by decreasing spasticity and/or decreasing caregiver burden; (iii) decrease pain from spasticity; (iv) enhance self-esteem by diminishing inappropriate motor responses; and (v) provide a presurgical diagnostic tool. Following intramuscular injections of botulinum A toxin, short-term benefits of reduced spasticity are observed in approximately 70-82% of children. The intermediate term (1-2 years) efficacy rate is approximately 50%. The most common deformity treated with toxin injections in pediatric patients with CP is equinus foot deformity. However, efficacy of toxin injections for the management of crouched gait, pelvic flexion contracture, cervical spasticity, seating difficulties, and upper extremity deformity also has been documented. In addition, toxin injections have been shown to manage painful muscle spasticity associated with surgery or application of casts and painful cervical spasticity with or without dystonia. Toxin injections can also be used as a diagnostic tool to determine the appropriateness of other interventions by observing the muscle response to the injection in order to gain additional information for the development of a treatment plan. Botulinum A toxin, when used in appropriate doses, is well tolerated.     

Botulinum toxin type A for treatment of refractory gastroparesis.

PURPOSE: The clinical efficacy and adverse reactions of botulinum toxin type A for refractory gastroparesis are discussed. SUMMARY: Botulinum toxin type A does not have an FDA-labeled indication for the treatment of gastroparesis, but it has been evaluated for this indication in several small case studies and open-label trials. The dose of botulinum toxin type A ranged from 80 to 200 units, injected directly into the pylorus in patients refractory to standard management. One study found both clinical and scintigraphic improvements in patients with diabetic gastroparesis that were maintained for at least six weeks. In another study in patients with diabetic gastroparesis, the agent decreased gastric emptying time and improved nausea, vomiting, and abdominal pain but did not significantly improve patients' overall quality of life. In a study consisting of a chart review, 27 (43%) of 63 patients responded to botulinum toxin type A and 36 patients (57%) did not. Responders had a mean duration of response of 5.1 months. A study in patients with idiopathic gastroparesis found improved gastric emptying and improved symptom scores in most cases. Botulinum toxin type A is contraindicated in patients with infection at the injection site or hypersensitivity to any of the ingredients. There have been rare reports of serious hypersensitivity reactions. Dysphagia is common. CONCLUSION: Botulinum toxin type A may be effective in the management of refractory gastroparesis; however, large, double-blind, placebo-controlled trials are needed to confirm this.     

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.     

Unlabeled uses of botulinum toxins: a review, part 2.

PURPOSE: Efficacy and safety data regarding the unlabeled uses of botulinum toxins are reviewed, and the pharmacology, adverse effects, and characteristics of commercially available botulinum toxins are discussed. SUMMARY: More than 300 articles have been published on the use of botulinum toxins, particularly botulinum toxin type A, to treat conditions characterized by excessive smooth or skeletal muscle spasticity. Botulinum toxins are synthesized by Clostridium botulinum and cause temporary local paralysis of the injected muscle by inhibiting acetylcholine release at the neuromuscular junction. While botulinum toxins have Food and Drug Administration-approved labeling to treat a limited number of spasticity disorders, including cervical dystonia and blepharospasm, the toxins have more than 50 reported therapeutic uses. Among these uses, the most rigorously studied indications include achalasia, essential tremors, palmar hyperhidrosis, chronic anal fissures, headache prophylaxis, and limb spasticity. The main adverse effects of the toxins are pain and erythema at the injection site, although unintended paralysis of muscles adjacent to the site of toxin injection may also occur. CONCLUSION: Clinical studies support the use of botulinum toxins for certain conditions, although more studies are needed to establish the role of the drug relative to conventional therapies and to determine patient predictors of response. Although botulinum toxins are generally well tolerated, a patient-specific risk-benefit assessment should precede any decision to use them for unlabeled indications.     

Unlabeled uses of botulinum toxins: a review, part 1.

PURPOSE: Efficacy and safety data regarding the unlabeled uses of botulinum toxins are reviewed, and the pharmacology, adverse effects, and characteristics of commercially available botulinum toxins are discussed. SUMMARY: More than 300 articles have been published on the use of botulinum toxins, particularly botulinum toxin type A, to treat conditions characterized by excessive smooth or skeletal muscle spasticity. Botulinum toxins are synthesized by Clostridium botulinum and cause temporary local paralysis of the injected muscle by inhibiting acetylcholine release at the neuromuscular junction. While botulinum toxins have Food and Drug Administration-approved labeling to treat a limited number of spasticity disorders, including cervical dystonia and blepharospasm, the toxins have more than 50 reported therapeutic uses. Among these uses, the most rigorously studied indications include achalasia, essential tremors, palmar hyperhidrosis, chronic anal fissures, headache prophylaxis, and limb spasticity. The main adverse effects of the toxins are pain and erythema at the injection site, although unintended paralysis of muscles adjacent to the site of toxin injection may also occur. CONCLUSION: Clinical studies support the use of botulinum toxins for certain conditions, although more studies are needed to establish the role of the drug relative to conventional therapies and to determine patient predictors of response. Although botulinum toxins are generally well tolerated, a patient-specific risk-benefit assessment should precede any decision to use them for unlabeled indications.     

Lack of effficacy of botulinum toxin in chronic anal fissure

BACKGROUND AND AIM: Hypertonicity of internal anal sphincter plays a major role in the persistence of chronic anal fissure. Botulinum toxin could induce internal anal sphincter relaxation without the adverse effects of surgery (long-term faecal incontinence) or topical nitrates (anal burning, headaches, hypotension). METHODS: We conducted a placebo-controlled, randomised, double-blind study to assess the efficacy of a single injection of botulinum toxin in the internal anal sphincter of patients with chronic anal fissure in six ambulatory care clinics. Eligibility criteria included a mean value of post-defecation anal pain >or= 30 mm on a 100 mm visual analogue scale over the week preceding inclusion. Main endpoint was the proportion of patients with symptomatic improvement during the fourth week after inclusion (post-defecation anal pain below 10 mm). RESULTS: Forty-four patients (22 in each group) were included. At inclusion, there was no significant difference between groups on age, sex ratio, pain duration, post-defecation anal pain, analgesic consumption and stool frequency. Ten (45%) and 11 (50%) patients reported symptomatic improvement on the main endpoint (P=0.76) in placebo and botulinum toxin groups, respectively. Ten patients (five in each group) had healed fissure at week 4 and ten patients (five in each group) required surgical treatment between weeks 4 and 12. Similarly, there was no significant difference between groups on other variables between weeks 4 and 12. CONCLUSIONS: The efficacy of a single injection of botulinum toxin in the internal anal sphincter does not differ from that of a placebo in patients with chronic anal fissure.     

Safety profile of iloperidone in the treatment of schizophrenia

The use of botulinum toxin to treat cervical dystonia (CD) has dramatically improved the quality of life of patients with this disabling, often painful disease. Two forms of type A toxin (BOTOX® and Dysport®) and one form of type B toxin (MyoBloc®) are available in some parts of the world to treat patients with CD. The literature supports the efficacy of each in reducing the pain and movement of cervical dystonia. The dosing and side effects vary between the toxins. The potential availability of several forms of toxin will allow physicians to offer further treatment options to patients with CD. However, it is incumbent on the treating physicians to have a working knowledge of the different serotypes, different doses used of each formulation of each serotype, the side effect profile of each product and the potential for anti-body formation for each form of toxin.     

The safety and tolerability of botulinum toxins for the treatment of cervical dystonia

The use of botulinum toxin to treat cervical dystonia (CD) has dramatically improved the quality of life of patients with this disabling, often painful disease. Two forms of type A toxin (BOTOX and Dysport) and one form of type B toxin (MyoBloc) are available in some parts of the world to treat patients with CD. The literature supports the efficacy of each in reducing the pain and movement of cervical dystonia. The dosing and side effects vary between the toxins. The potential availability of several forms of toxin will allow physicians to offer further treatment options to patients with CD. However, it is incumbent on the treating physicians to have a working knowledge of the different serotypes, different doses used of each formulation of each serotype, the side effect profile of each product and the potential for anti-body formation for each form of toxin.     

Xeomin is free from complexing proteins

In contrast to the other botulinum toxin products Xeomin only contains the 150 kD neurotoxin without complexing proteins which have no therapeutic function and don't influence the diffusion of the neurotoxin. In large clinical Phase III studies (blepharospasm and cervical dystonia) Xeomin showed the same efficacy and profile of adverse events as Botox. Whereas competing product must be stored refrigerated, Xeomin is stable for 3 years at room temperature.     

Botulinum toxin type A for the treatment of migraine

Migraine is a common and debilitating disorder that often requires prophylactic therapy, particularly for those migraine patients who meet the diagnostic criteria for chronic daily headache (chronic migraine). Existing prophylactic treatments for migraine are inadequate for many patients due to their modest efficacy and/or systemic side effects. Alternative treatment strategies are needed, particularly in those with chronic migraine. Botulinum toxin type A is a locally injected protein complex that has been investigated as a treatment for episodic migraine and chronic daily headache. A systematic series of controlled trials has led to the identification of a subset of migraineurs with chronic daily headache who obtain demonstrated benefits of botulinum toxin type A over placebo that is maintained with repeated treatments.     

Conversion Ratio between Botox?, Dysport?, and Xeomin? in Clinical Practice

Botulinum neurotoxin has revolutionized the treatment of spasticity and is now administered worldwide. There are currently three leading botulinum neurotoxin type A products available in the Western Hemisphere: onabotulinum toxin-A (ONA) Botox^®, abobotulinum toxin-A (ABO), Dysport^®, and incobotulinum toxin A (INCO, Xeomin^®). Although the efficacies are similar, there is an intense debate regarding the comparability of various preparations. Here we will address the clinical issues of potency and conversion ratios, as well as safety issues such as toxin spread and immunogenicity, to provide guidance for BoNT-A use in clinical practice. INCO was shown to be as effective as ONA with a comparable adverse event profile when a clinical conversion ratio of 1:1 was used. The available clinical and preclinical data suggest that a conversion ratio ABO:ONA of 3:1—or even lower—could be appropriate for treating spasticity, cervical dystonia, and blepharospasm or hemifacial spasm. A higher conversion ratio may lead to an overdosing of ABO. While uncommon, distant spread may occur; however, several factors other than the pharmaceutical preparation are thought to affect spread. Finally, whereas the three products have similar efficacy when properly dosed, ABO has a better cost-efficacy profile.     

Clinical trial: effects of botulinum toxin on levator ani syndrome – a double-blind, placebo-controlled study

Background  Levator ani syndrome is characterized by anorectal discomfort/pain, treatment of which is unsatisfactory. We hypothesized that Botulinum toxin relieves spasm and improves symptoms.
Aim  To perform a randomized, placebo-controlled, crossover study to examine the efficacy and safety of botulinum toxin in patients with levator ani syndrome.
Methods  Twelve patients with levator ani syndrome (≥1 year) received anal intra sphincteric injections of 100 units of botulinum toxin A and placebo at 90-day intervals using EMG guidance. Daily frequency, severity, duration and intensity of pain (VAS) were recorded. Anorectal manometry, balloon expulsion and pudendal nerve latency tests were performed to examine the physiological changes and adverse effects.
Results  Seven patients (male/female = 4/3) completed the study and three had incomplete data, but all 10 underwent in an ITT analysis; two others dropped out. After administration of botulinum toxin, the mean frequency, intensity and duration of pain were unchanged ( P  = 0.31) compared with baseline. The 90-day mean VAS pain score was 6.79 ± 0.27 vs. baseline score of 7.08 ± 0.29 ( P  = 0.25). Anal sphincter pressures, rectal sensory thresholds, pudendal nerve latency and balloon expulsion times were unchanged after drug or placebo administration.
Conclusions  Injection of botulinum toxin into anal sphincter is safe, but it does not improve anorectal pain in levator ani syndrome.     

Botulinum toxin treatment of adult spasticity : a benefit-risk assessment.

Injections of botulinum toxin have revolutionised the treatment of focal spasticity. Before their advent, the medical treatment for focal spasticity involved oral anti-spasticity drugs, which had decidedly non-focal adverse effects, and phenol injections. Phenol injections could be difficult to perform, could cause sensory complications and had effects that were of uncertain duration and magnitude. Furthermore, few neurologists knew how to perform them as they were mostly the province of rehabilitation specialists. Botulinum toxin can produce focal, controllable muscle weakness of predictable duration, without sensory adverse effects.Randomised clinical trials (RCTs) involving patients with spasticity resulting from a variety of diseases (mainly stroke and multiple sclerosis) have clearly shown that botulinum toxin type A (Dysport and Botox) can temporarily (for approximately 3 months) reduce spastic hypertonia in the elbow, wrist and finger flexors of the upper limbs, and the hip adductors and ankle plantar flexors in the lower limbs. The clinical benefits from this reduction of neurological impairment are best shown in the upper limb, with less disability of passive function and reduced caregiver burden. In the lower limbs, there is improved perineal hygiene from hip adductor injections. The benefits of reducing ankle plantar flexor tone are less well established. Pain is also reduced, possibly by mechanisms other than muscle weakness. Improved active function has not yet been clearly demonstrated in RCTs, only in open-label trials. The safety of botulinum toxin-A is impressive, with minimal (mainly local) adverse effects.There are little data on the use of botulinum toxin type B (Myobloc or Neurobloc) in spasticity and the only RCT that has examined this did not show tone reduction; dry mouth appeared to be a very common adverse effect. There are also very little data to allow a benefit-risk comparison of phenol and botulinum toxin injections; each have their clinical and technical advantages and disadvantages, and phenol is much less costly than botulinum toxin.     

Treatment of tension-type headache with botox: a review of the literature

Botulinum toxin has been shown to effectively treat several types of neurological disorders. It has recently been evaluated for the treatment of tension-type headaches in patients who are unable to tolerate or cannot benefit from standard therapies. Most of the open design studies seem to present positive results. However, the randomized, double-blind, placebo-controlled studies present contradictory results for the efficacy of botulinum toxin. Based on these data, further controlled trials of botulinum toxin are needed to evaluate its effects on tension headaches and to determine optimal injection sites, doses, and frequency of treatments.     

A型肉毒毒素治疗Meige's综合征

目的 评估A型肉毒毒素治疗Meige's综合征的疗效.方法 对A型肉毒毒素治疗的30例Meige's综合征患者资料进行回顾性分析.结果 30例Meige's综合征患者注射A型肉毒毒素后25例完全缓解,5例明显缓解,总有效率100%.起效时间注射当天～第3天.疗效维持平均为5个月.重复治疗有效.局部不良反应轻微、短暂、可逆,无全身不良反应及过敏反应.结论 A型肉毒毒素局部注射是治疗Meige's综合征的一种安全、有效、简便、易行的方法.     

The possible adverse effects of intramuscular botulinum toxin injections and their management

In the last two decades or so the intramuscular administration of botulinum toxin type A, and more recently type B, has become an established first line treatment of many neurological and other medical disorders. So far, the toxin has been used mainly by experienced researchers and clinicians with extensive knowledge of its mode of action and potential adverse effects. However, in the foreseeable future it is likely that this treatment will be provided by more medical practitioners and in different clinical settings, especially as the range of its clinical indications increases. Botulinum toxin, in therapeutic doses, is a remarkably safe drug with relatively few adverse effects. The commonest adverse effects are muscle weakness, fatigue, flu-like symptoms, a dry mouth, dizziness and a skin rash. Nonetheless, serious adverse events may occur, albeit rarely, and it is imperative that prescribers of this treatment are thoroughly familiar with its potential risks. The purpose of this article is to review the possible adverse effects of botulinum toxin intramuscular injections, to describe the factors that might predispose to them and to summarise the strategies for their prevention and treatment.