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.     

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.     

Alternative use of botulinum toxin in urology

Botulinum toxin A is used in the treatment of lower urinary tract symptoms due to detrusor sphincter dysynergia and detrusor hyper-reflexia (neurogenic detrusor deficiency). The toxin acts by producing paralysis of muscle tissue and has been shown to be safe and effective in the treatment of conditions caused by increased muscle tonicity and spasticity. Here the literature is reviewed chronologically, the established and emerging indications for the urological use of botulinum toxin evaluated and future applications are also considered.     

Alternative use of botulinum toxin in urology

Botulinum toxin A is used in the treatment of lower urinary tract symptoms due to detrusor sphincter dysynergia and detrusor hyper-reflexia (neurogenic detrusor deficiency). The toxin acts by producing paralysis of muscle tissue and has been shown to be safe and effective in the treatment of conditions caused by increased muscle tonicity and spasticity. Here the literature is reviewed chronologically, the established and emerging indications for the urological use of botulinum toxin evaluated and future applications are also considered.     

Botulinum toxin A treatment of adult upper and lower limb spasticity

This article discusses the treatment of spasticity with botulinum toxin A as a new approach in the neurological rehabilitation of patients after stroke. Clinical studies have been reviewed to provide information about target groups, technical aspects and the advantages and disadvantages of treating spasticity with botulinum toxin A. Open and controlled studies showed that the intramuscular injection of Dysport 500 to 1,500U or Botox 100 to 300U could reversibly relieve upper limb flexor and lower limb extensor spasticity. A reduced muscle tone, pain relief, better hand hygiene and improved walking function were the main benefits. Patients tolerated the treatment well. Activity or, if not possible, electrical stimulation of the injected muscles may enhance the effectiveness of the costly toxin. Serial casting is another option. With respect to the action of botulinum toxin A, it is suggested that the effect of the toxin could be mediated by paresis of both the extrafusal and intrafusal muscle fibres, thereby altering the afferent discharge in the muscle.     

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.     

Electrical Stimulation of Injected Muscles to Boost Botulinum Toxin Effect on Spasticity: Rationale,Systematic Review and State of the Art

Botulinum toxin type A (BoNT-A) represents a first-line treatment for spasticity, a common disabling consequence of many neurological diseases. Electrical stimulation of motor nerve endings has been reported to boost the effect of BoNT-A. To date, a wide range of stimulation protocols has been proposed in the literature. We conducted a systematic review of current literature on the protocols of electrical stimulation to boost the effect of BoNT-A injection in patients with spasticity. A systematic search using the MeSH terms “electric stimulation”, “muscle spasticity” and “botulinum toxins” and strings “electric stimulation [mh] OR electrical stimulation AND muscle spasticity [mh] OR spasticity AND botulinum toxins [mh] OR botulinum toxin type A” was conducted on PubMed, Scopus, PEDro and Cochrane library electronic databases. Full-text articles written in English and published from database inception to March 2021 were included. Data on patient characteristics, electrical stimulation protocols and outcome measures were collected. This systematic review provides a complete overview of current literature on the role of electrical stimulation to boost the effect of BoNT-A injection for spasticity, together with a critical discussion on its rationale based on the neurobiology of BoNT-A uptake.     

Botulinum toxin B: a review of its therapeutic potential in the management of cervical dystonia

Botulinum toxins are well known as the causative agents of human botulism food poisoning. However, in the past two decades they have become an important therapeutic mainstay in the treatment of dystonias including cervical dystonia, a neurological disorder characterised by involuntary contractions of the cervical and/or shoulder muscles. The toxins inhibit acetylcholine release from neuromuscular junctions, producing muscle weakness when injected into dystonic muscles. Data from three double-blind, randomised, placebo-controlled trials demonstrate that botulinum toxin B effectively reduces the severity, disability and pain of cervical dystonia. In two of the trials, mean Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS)-Total score at week 4 (primary efficacy measure) after botulinum toxin B 10 000U was reduced by 11.7 (25%) or 11 (21%) compared with baseline. These changes were significantly greater than those obtained with placebo [4.3 (10%) or 2 (4%)] and were generally similar in patients who were responsive or resistant to botulinum toxin A. Statistically significant benefits compared with placebo were also evident for a range of other efficacy parameters including TWSTRS-Severity, -Pain and -Disability subscales, patient- assessed pain and patient-/physician-assessed global improvement ratings. In another trial, the percentage of patients with botulinum toxin A-resistant or -responsive cervical dystonia who had a > or =20% improvement in the TWSTRS-Total score between baseline and week 4 was significantly higher with botulinum toxin B 2500 to 10 000U (58 to 77%) than with placebo (27%). Overall, botulinum toxin B was generally well tolerated. The most frequently reported treatment-related adverse events were dry mouth and dysphagia. Most adverse events in patients receiving botulinum toxin B were mild or moderate; no serious adverse events or laboratory abnormalities were associated with the use of botulinum toxin B and, where reported, no patients discontinued from any of the clinical trials as a result of adverse events. CONCLUSIONS: Botulinum toxin B has shown clinical efficacy in patients with cervical dystonia at doses up to 10 000U and is generally well tolerated. Its efficacy extends to patients who are resistant to botulinum toxin A. Although the potential for secondary resistance to botulinum toxin B remains unclear, it may occur less than with botulinum toxin A because methods for manufacturing commercially available botulinum toxin B do not include lyophilisation and the product does not require reconstitution before use. As injection with botulinum toxin is generally considered the treatment of choice for patients with cervical dystonia, botulinum toxin B should be considered a potential treatment option in this setting.     

Preventative treatment for migraine and tension-type headaches : do drugs having effects on muscle spasm and tone have a role?

Baclofen, tizanidine and botulinum toxin A, agents used to treat disorders of muscle tone, have been studied as potential preventative treatments for migraine, tension-type headache and other related disorders. The most extensive work has been completed with botulinum toxin A. However, there is still a paucity of well controlled, clinical trials with this agent, and overall there have been conflicting and oftentimes equivocal results: studies of its use in migraine headache have suggested efficacy, whereas those of tension-type headache have not shown significant evidence of efficacy. There were few significant adverse events associated with the use of botulinum toxin A in these trials. The mechanism by which botulinum toxin A may work to prevent headache is not clear. Although changes in muscle tone may play a role in the effect of the drug, central mechanisms such as effects on neuropeptides involved in the pathogenesis of migraine may also be relevant. Further clinical trial work is in progress to help determine optimal administration schedules and choice of injection locations with botulinum toxin A for specific headache disorders. There has been limited study of the use of baclofen, an agent that acts centrally via GABA(A) receptors, in migraine and cluster headache, with only two open trials conducted to date. Both of these studies support the use of baclofen in the preventive treatment of headache.Tizanidine, which may have both a peripheral and a central mechanism in the locus ceruleus in migraine headache, has been studied in several clinical trials. Although the primary mechanism of action of this agent is, like clonidine, as an alpha-adrenoceptor agonist, it has little antihypertensive effect. Open trials of tizanidine have shown it to be useful in chronic headache. One well controlled trial, conducted as a follow-up to an open-label trial in the preventive treatment of chronic daily headache, reported tizanidine as having a statistically significant benefit over placebo. Also of interest is its use in conjunction with a long-acting NSAID to aid in the treatment of rebound headache accompanying the discontinuation of overused acute migraine therapies. In conclusion, though limited, the studies suggest the efficacy of botulinum toxin A, baclofen and tizanidine in primary headache disorders.     

Review article The use of botulinum toxin in the alimentary tract

New and future indications for the treatment of disorders of the alimentary tract using local injections of botulinum toxin are reviewed. Clinical experience shows that overactive smooth muscle sphincters may be weakened to treat disorders such as achalasia or chronic anal fissure. By contrast, injections placed into the sphincter of Oddi have proven less effective for post-cholecystectomy pain syndrome. Experimental evidence suggests that food intake may be reduced by weakening the distal stomach with botulinum toxin. This approach may possibly lead to the treatment of obesity. There are some new possible indications for the use of botulinum toxin on the alimentary tract, and infantile hypertrophic pyloric stenosis seems to be the most promising new development.     

Botulinum toxin for the management of bladder dysfunction

This review highlights a recent innovation in the medical treatment of detrusor overactivity (DO). Anticholinergics are usually the gold standard to treat bladder overactivity. Adverse effects and lack of efficacy are the two main causes for considering alternative treatments. Until recently, invasive surgery (mainly bladder augmentation) was the only available treatment option for patients with intractable DO. This article considers botulinum toxin type A (BTX-A) injection as an alternative treatment to surgery in patients with DO who do not respond to anticholinergic therapy. To identify papers for inclusion in this review, we searched PubMed with the keywords 'botulinum toxin', 'overactive bladder', 'urinary incontinence' and 'neurogenic bladder' for the years 2000-5. Review articles were not included. Abstracts were cited only if they contained important new information. Experimental animal studies and articles or book chapters related to the use of botulinum toxin for other indications (such as achalasia and cervical dystonia) were analysed with regard to the mechanisms of action of botulinum toxin.From this review, it appears that BTX-A injection into the detrusor muscle is a very effective method for treating urinary incontinence secondary to neurogenic detrusor overactivity (NDO), as well as urinary incontinence due to idiopathic overactive bladder (IDO). In both conditions, the duration of effect seems to be at least 6 months. Overall success rates seem to be similar in both patient populations. For NDO, only one evidence-based medicine level 1 study is available, whereas for IDO, only evidence-based medicine level 3 or 4 studies have been published. Particularly in this latter indication, injection technique and outcome parameters vary from study to study and need to be standardised. Without randomised controlled studies aimed at comparing different techniques and dosages, it remains difficult to decide what technique is optimal for treating patients with IDO who are not willing to perform clean intermittent self-catheterisation (CISC). Therefore, studies that compare different dosages and techniques with the risk of needing CISC in regard to the duration of the effect are mandatory. As more studies of repeated injections have been published, it appears that, at least at medium follow-up, the toxin remains as effective as after the first injection, and there is no evidence of change in bladder compliance or detrusor fibrosis. However, long-term observational studies are necessary to assess these last points. Finally, the commonly reported dose appears to be well tolerated, since few adverse effects have been reported.     

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.     

Drugs used to treat spasticity

Spasticity is a common and disabling symptom for many patients with upper motor neuron dysfunction. It results from interruption of inhibitory descending spinal motor pathways, and although the pathophysiology of spasticity is poorly understood, the final common pathway is overactivity of the alpha motor neuron. Therapy for spasticity is symptomatic with the aim of increasing functional capacity and relieving discomfort. Any approach to treatment should be multidisciplinary, including physical therapy, and possibly surgery, as well as pharmacotherapy. It is important that treatment be tailored to the individual patient, and that both patient and care giver have realistic expectations. Pharmacotherapy is generally initiated at low dosages and then gradually increased in an attempt to avoid adverse effects. Optimal therapy is the lowest effective dosage. Baclofen, diazepam, tizanidine and dantrolene are currently approved for use in patients with spasticity. In addition, clonidine (usually as combination therapy), gabapentin and botulinum toxin have shown efficacy, however, more studies are required to confirm their place in therapy. Intrathecal baclofen, via a surgically implanted pump and reservoir, may provide relief in patients with refractory severe spasticity.     

Potential of Botulinum toxin A to treat upper extremity spasticity in children with cerebral palsy

Abstract

Botulinum toxin type A has been used extensively to treat spasticity in children with cerebral palsy. Although the effectiveness of the toxin in the lower limbs is well established, its effectiveness in upper limbs has not been proved yet. Many studies published so far report conflicting results in terms of spasticity, function, activity and participation improvement. The scope of this review is to present the evidence from published studies, focusing on the effectiveness and the safety of botulinum toxin A.     

The role of botulinum toxin in neurourology

Botulinum toxin is a presynaptic neuromuscular blocking agent that induces a selective and reversible muscle weakness of up to several months when injected intramuscularly in minute quantities. Different medical disciplines have applied the toxin to treat mainly muscular hypercontraction. For neurourologically impaired patients, the reported successful treatment of neurogenic detrusor overactivity and detrusor sphincter dyssynergia with botulinum-A toxin is a promising alternative option to conservative medication or surgery. This review of the literature presents current indications, techniques for and results of the use of botulinum toxin in neurourologically impaired patients and aims to give an insight into this new therapeutic option.     

Effect of Botulinum Toxin Injection on the Progression of Hip Dislocation in Patients with Spastic Cerebral Palsy: A Pilot Study

Hip adductor spasticity is a contributing factor to hip dislocation in patients with cerebral palsy (CP). We hypothesized that botulinum toxin injected into the hip adductor muscles would reduce spasticity and help prevent hip dislocation. Twenty patients with bilateral spastic CP aged 2 to 10 years with gross motor function classification system level IV or V were included. Botulinum toxin was injected into the hip adductor muscles at baseline and at 6-month follow-up. Muscle tone was measured with an eight-channel surface electromyography (EMG) recorder. A hip X-ray was performed, and Reimer’s hip migration index (MI) was measured. The Wilcoxon signed-rank test was used to compare the surface EMG values of the hip muscles at baseline and follow-up. The mean root mean square surface EMG value of the hip adductor muscles was significantly reduced at 1, 2, 3, and 7 months after the first injection, up to approximately 53% of the baseline. The 1-year progression of the hip MI was −0.04%. Repeated sessions of botulinum toxin injections at the hip adductor muscles significantly reduced muscle tone and hip displacement. A botulinum toxin injection may be used as an adjunctive treatment in the prevention of hip dislocation.     

Gynecological indications for the use of botulinum toxin in women with chronic pelvic pain

Chronic pelvic pain in women is a common symptom with a wide variety of etiologies that demand accurate diagnosis and appropriate treatment if pain reduction is to be effected. Superficial conditions such as provoked vestibulodynia and problems affecting deeper structures such as pelvic floor muscle spasm are difficult to treat and can have significant impacts on quality of life for the sufferer.Apart from daily pain, symptoms such as painful intercourse (dyspareunia), painful bowel motions (dyschesia) and exacerbation of period pain (dysmenorrhea) are commonly reported by patients. For inflammatory conditions, and in areas where muscle spasm is thought to contribute to pain, botulinum toxins (BoNT) are used with considerable success.For gynecological indications, there are limited data, in the form of case reports and small series, to indicate that BoNT used in the vulva may have a benefit for 3-6 months after injection of 20-40 U of BOTOX^®; for women with provoked vestibulodynia. Re-treatment is reported to be successful and side effects are limited. Controlled studies are essential to further explore this indication.For pelvic floor muscle spasm, a greater number of women have been studied and a double blind, randomized controlled study has reported a significant reduction in pelvic floor pressures with significant pain reduction for some types of pelvic pain compared to baseline. There were no differences in pain compared to the control group who had physical therapy as an intervention. Physical therapy could be used as a non-invasive first line treatment, with BoNT injections reserved for those who are refractory to treatment.In summary, BoNT treatment for a variety of gynecological indications seems successful with limited side effects, although there are minimal data, particularly in superficial vulval conditions. To allow recommendation for wider utilization of this treatment, it is essential that more research is performed to add further evidence to our current knowledge.     

电刺激定位引导埋线治疗脑瘫患儿小腿三头肌痉挛的疗效观察

目的观察电刺激定位引导埋线治疗脑瘫患儿小腿三头肌痉挛的疗效。方法将18例脑瘫患儿随机分为电刺激定位引导埋线组（埋线组）和电刺激定位引导A型肉毒毒素（BTX．A）注射组（肉毒素组）,观察治疗1月后患儿的踝背屈曲度、综合痉挛量表CSS评分、改良Ashworth法评分。结果肉毒素和埋线治疗1月后患儿踝背屈曲度、综合痉挛量表CSS评分、改良Ashworth法评分均有明显改善（P〈0．05）,埋线组对患儿踝背屈曲度的改善弱于肉毒素组（P〈0．05）,但综合痉挛量表CSS评分、改良Ashworth法评分与肉毒素组比较差异无统计意义（P〉0．05）。结论电刺激定位引导埋线治疗脑瘫患儿小腿三头肌痉挛有较好的临床疗效。