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.     

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 therapy for pain and inflammatory disorders: mechanisms and therapeutic effects

Botulinum toxin (BTX) injections are a well-recognised therapeutic modality for the treatment of regional involuntary muscle disorders and recently BTX has been used for treatment of pain and inflammatory disorders. The primary purpose of this review is to discuss the mechanism of action of therapeutic BTX in light of both the traditional understanding of BTX pharmacological effects as well as new observations. The review will deal with clinical observations and relevant animal experimentation. The data and hypotheses presented are not only relevant to botulinum toxin technology but will certainly prove important in the basic mechanisms of some of the diseases where botulinum toxin has been successfully applied. BTX used clinically comprises botulinum neurotoxin (BoNT) complexed with non-toxic proteins. The non-toxic components of the BTX complexes stabilise the labile BoNT during purification and formulation as a therapeutic. The complex proteins may also have unrecognised clinical significance such as slowing diffusion in tissues or imparting stability. The mechanisms of BTX formulations acting on SNARE proteins are briefly reviewed providing a basis for BTX clinical applications. The potential for design of improved botulinum toxins and formulations is addressed.     

Gastrointestinal smooth muscles and sphincters spasms: treatment with botulinum neurotoxin

More than fifty years following the discovery that botulinum neurotoxins inhibit neuromuscular transmission, these powerful poisons have become drugs with many indications. First used to treat strabismus, local injections of botulinum neurotoxin are now considered a safe and efficacious treatment for neurological and non-neurological conditions. One of the most recent achievements in the field is the observation that botulinum neurotoxin is a treatment for diseases of the gastrointestinal tract. Botulinum neurotoxin is not only potent in blocking skeletal neuromuscular transmission, but also block cholinergic nerve endings in the autonomic nervous system. The capability to inhibit contraction of smooth muscles of the gastrointestinal tract was first suggested based on in vitro observations and later demonstrated in vivo; it has also been shown that botulinum neurotoxin does not block non adrenergic non cholinergic responses mediated by nitric oxide. This has further promoted the interest to use botulinum neurotoxin as a treatment for overactive smooth muscles and sphincters, such as the lower esophageal sphincter to treat esophageal achalasia, or the internal anal sphincter to treat anal fissure. Information on the anatomical and functional organization of innervation of the gastrointestinal tract is a prerequisite to understand many features of botulinum neurotoxin action on the gut and the effects of injections placed into specific sphincters. This review presents current data on the use of botulinum neurotoxin to treat diseases of the gastrointestinal tract and summarizes recent knowledge on the pathogenesis of disorders of the gut due to a dysfunction of the enteric nervous system.     

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.     

Pharmaceutical,Biological, and Clinical Properties of Botulinum Neurotoxin Type A Products

Botulinum neurotoxin injections are a valuable treatment modality for many therapeutic indications and have revolutionized the field of aesthetic medicine so that they are the leading cosmetic procedure performed worldwide. Studies show that onabotulinumtoxinA, abobotulinumtoxinA, and incobotulinumtoxinA are comparable in terms of clinical efficacy. Differences between the products relate to the botulinum neurotoxin complexes, specific biological potency, and their immunogenicity. Protein complex size and molecular weight have no effect on biological activity, stability, distribution, or side effect profile. Complexing proteins and inactive toxin (toxoid) content increase the risk of neutralizing antibody formation, which can cause secondary treatment failure, particularly in chronic disorders that require frequent injections and long-term treatment. These attributes could lead to differences in therapeutic outcomes, and, given the widespread aesthetic use of these three neurotoxin products, physicians should be aware of how they differ to ensure their safe and effective use.     

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.     

Treatment of focal dystonias with botulinum neurotoxin

This is a review on the use of injections of botulinum toxin for the treatment of focal dystonias. Disorders covered include cranial dystonia, cervical dystonia, spasmodic dysphonia, and focal hand dystonia. Considered are clinical aspects, alternative treatment strategies and principles of use of botulinum toxin injections.     

Botulinum toxin type A and dynamic equinus in children with cerebral palsy: new indication. Better than repeat casts

(1) Botox degrees , a product based on type A botulinum toxin, has received a new licensed indication in the local treatment of dynamic equinus in children with spasticity due to cerebral palsy. (2) Three placebo-controlled trials show that intramuscular injections of type A botulinum toxin reduce spastic equinus and substantially improve walking for at least 3 months. Two small trials, each involving 20 children, show no difference in effects between type A botulinum toxin and successive stretching casts. (3) In this setting the risk of adverse effects is smaller with type A botulinum toxin than with stretching casts. (4) Treatment with type A botulinum toxin is costly.     

Botulinum toxin A for the Treatment of Overactive Bladder

The standard treatment for overactive bladder starts with patient education and behavior therapies, followed by antimuscarinic agents. For patients with urgency urinary incontinence refractory to antimuscarinic therapy, currently both American Urological Association (AUA) and European Association of Urology (EAU) guidelines suggested that intravesical injection of botulinum toxin A should be offered. The mechanism of botulinum toxin A includes inhibition of vesicular release of neurotransmitters and the axonal expression of capsaicin and purinergic receptors in the suburothelium, as well as attenuation of central sensitization. Multiple randomized, placebo-controlled trials demonstrated that botulinum toxin A to be an effective treatment for patients with refractory idiopathic or neurogenic detrusor overactivity. The urinary incontinence episodes, maximum cystometric capacity, and maximum detrusor pressure were improved greater by botulinum toxin A compared to placebo. The adverse effects of botulinum toxin A, such as urinary retention and urinary tract infection, were primarily localized to the lower urinary tract. Therefore, botulinum toxin A offers an effective treatment option for patients with refractory overactive bladder.     

Tetanus: Pathophysiology,Treatment, and the Possibility of Using Botulinum Toxin against Tetanus-Induced Rigidity and Spasms

Tetanus toxin, the product of Clostridium tetani, is the cause of tetanus symptoms. Tetanus toxin is taken up into terminals of lower motor neurons and transported axonally to the spinal cord and/or brainstem. Here the toxin moves trans-synaptically into inhibitory nerve terminals, where vesicular release of inhibitory neurotransmitters becomes blocked, leading to disinhibition of lower motor neurons. Muscle rigidity and spasms ensue, often manifesting as trismus/lockjaw, dysphagia, opistotonus, or rigidity and spasms of respiratory, laryngeal, and abdominal muscles, which may cause respiratory failure. Botulinum toxin, in contrast, largely remains in lower motor neuron terminals, inhibiting acetylcholine release and muscle activity. Therefore, botulinum toxin may reduce tetanus symptoms. Trismus may be treated with botulinum toxin injections into the masseter and temporalis muscles. This should probably be done early in the course of tetanus to reduce the risk of pulmonary aspiration, involuntary tongue biting, anorexia and dental caries. Other muscle groups are also amenable to botulinum toxin treatment. Six tetanus patients have been successfully treated with botulinum toxin A. This review discusses the use of botulinum toxin for tetanus in the context of the pathophysiology, symptomatology, and medical treatment of Clostridium tetani infection.     

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 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.     

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.     

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.     

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.     

Botulinum Toxin in the Treatment of Headache

Botulinum toxin type A has been used in the treatment of chronic migraine for over a decade and has become established as a well-tolerated option for the preventive therapy of chronic migraine. Ongoing research is gradually shedding light on its mechanism of action in migraine prevention. Given that its mechanism of action is quite different from that of the new monoclonal antibodies directed against calcitonin gene-related peptide (CGRP) or its receptor, it is unlikely to be displaced to any major extent by them. Both will likely remain as important tools for patients with chronic migraine and the clinicians assisting them. New types of botulinum toxin selective for sensory pain neurons may well be discovered or produced by recombinant DNA techniques in the coming decade, and this may greatly enhance its therapeutic usefulness. This review summarizes the evolution of botulinum toxin use in headache management over the past several decades and its role in the preventive treatment of chronic migraine and other headache disorders.     

Outlet type constipation in Parkinson's disease: results of botulinum toxin treatment

BACKGROUND: Constipation is one of the most common autonomic dysfunctions observed in Parkinson's disease. AIM: To investigate the efficacy of injections of botulinum toxin in improving rectal emptying in these patients. METHODS: Eighteen Parkinson's disease patients with outlet constipation were included in the study. The patients were treated with type A botulinum toxin, injected into two sites on either side of the puborectalis muscle under ultrasonographic guidance. RESULTS: Symptomatic improvement was noted in 10 patients, at 2 months evaluation. In these subjects, anorectal manometry demonstrated decreased tone during straining from 96.2 +/- 17.1 to 45.9 +/- 16.2 mmHg at 1 month evaluation (P = 0.00001) and to 56.1 +/- 10.7 mmHg at 2 months (P = 0.00001). Pressure during straining was lower than resting anal pressure at the same times in all patients. Defecography after the treatment showed improvement in anorectal angle during straining, which increased from 99.1 +/- 8.4 degrees to 121.7 +/- 12.7 degrees (P = 0.00001) at 2 months. CONCLUSIONS: Botulinum toxin injections may be a useful treatment for Parkinson's disease patients affected by outlet-obstruction constipation. The treatment is safe and simple. However, because the effects of the toxin wear off within 3 months of administration, repeated injections could be necessary to maintain the clinical improvement.