Unlabeled Uses
The unlabeled use of botulinum toxins, particularly type A, has been evaluated for the treatment of numerous disorders. These include achalasia, anismus, back pain, benign prostatic hyperplasia, cerebral palsy, chronic anal fissure, delayed gastric emptying, dysphonia, epilepsy, epiphora, esotropia, essential tremor, eye lift, facial myokemia, fibromyalgia, flushing, Grey's syndrome, headache, hyperhidrosis, lateral canthal wrinkles ("crow's feet"), musculoskeletal pain syndromes, pancreatitis, Parkinson's disease, poststroke spasticity, puborectalis syndrome, rhinitis, sialorrhea, tardive dyskinesia, tennis elbow, Tourette's syndrome, urinary incontinence, vaginismus, and writer's cramp.[8] After evaluating the medical literature, we identified the seven unlabeled indications that were supported by the greatest number of randomized clinical trials: (1) esophageal achalasia, (2) essential tremor, (3) palmar hyperhidrosis, (4) headache, (5) chronic anal fissure, (6) pediatric spastic cerebral palsy, and (7) poststroke upper- and lower-limb spasticity. The efficacy and safety of botulinum toxins for these indications are reviewed.
Esophageal achalasia is a motility disorder in which incomplete relaxation of the lower esophageal sphincter (LES) and the absence of esophageal peristalsis lead to dysphagia, regurgitation, chest pain, and, in severe cases, megaesophagus.[9] Primary (idiopathic) achalasia is caused by a generalized loss of neurons. Secondary achalasia may arise from Chagas' disease, Parkinson's disease, and malignancies. Invasive therapies, such as pneumatic balloon dilation and myotomy, are effective but carry the risk for serious esophageal damage (i.e., perforation or stricture). Pharmacologic therapies include calcium-channel blockers and long-acting nitrates, which offer only a short-term benefit and may have undesirable generalized adverse effects. Botulinum toxin lowers the resting pressure of the LES by inhibiting the release of acetylcholine from nerve terminals in the LES.[10,11]
In a double-blind, placebo-controlled study, 21 patients were randomized to receive either 80 units of botulinum toxin type A or placebo.[12] At one week postinjection, the treatment group had a significant mean decrease in symptom score from baseline, as well as a significantly greater mean reduction in LES pressure (-33% versus -12%) and a greater mean increase in LES opening widths (204% versus -14%) relative to placebo (p = 0.02 for both measures). In an open-label extension of the study, placebo nonresponders (n = 10) were also treated with botulinum toxin A. The overall response rate was 90% (19 patients) at one week. After six months, 14 patients (74%) were still in remission. Within two months of the initial injection, 3 patients had symptom recurrence and required retreatment. Adverse effects reported included mild transient chest pain and heartburn.
In another placebo-controlled study of 24 patients with achalasia secondary to Chagas' disease, 100 units of botulinum toxin A injected into the LES significantly improved dysphagia scores from baseline at 180 days postinjection (12.5 ± 3.2 pretreatment versus 6.2 ± 4.7 posttreatment) (p = 0.03).[13] The clinical score of dysphagia was based on frequency and severity of symptoms, with higher scores indicating more severe symptoms. Baseline LES pressure and esophageal emptying time also improved among the treatment group, but these differences did not reach statistical significance. Patients who responded to the treatment tended to have earlier stages of the disease than did nonresponders. Seven of 12 (58%) treated patients maintained the response for six months. Only one case of mild transient thoracic pain was reported as an adverse effect of treatment.
Several studies have compared botulinum toxin A with pneumatic dilation for the treatment of achalasia. In one study, 42 patients were randomized to receive 100 units of botulinum toxin A or undergo pneumatic dilation.[14] Patients who did not respond to either treatment within one month were retreated with their respective interventions. At one year, more patients in the pneumatic dilation group were in symptomatic remission (14/20) compared with those in the botulinum toxin group (7/22) (p = 0.02). Although both treatments reduced symptom scores, only pneumatic dilation recipients had significant improvements in LES pressure, esophageal emptying time, and esophageal diameter from baseline over 12 months. Esophageal perforation occurred in two patients who underwent pneumatic dilation. Similar results were seen in a study of 40 patients with achalasia treated with either 200 units of botulinum toxin A (Dysport) or pneumatic dilation.[15] The cumulative remission rate at one year was higher in the pneumatic dilation group compared with the botulinum toxin group (100% versus 60%, respectively) (p < 0.01). No significant complications were seen in either treatment group. Another small study (n = 16) showed similar reductions in LES pressure and improved esophageal retention time for both 100 units of botulinum toxin A- and pneumatic dilation-treated groups at one month.[16] However, seven of the eight botulinum toxin A recipients required retreatment due to recurrent dysphagia at one year.
One long-term randomized study has demonstrated equal efficacy between botulinum toxin A and pneumatic dilation. In that study, 31 patients were randomized to receive a single botulinum toxin A injection (80 units) or undergo pneumatic dilation.[17] Although a higher percent-age of patients undergoing pneumatic dilation were asymptomatic at four months than those treated with botulinum toxin A (89% versus 36%, respectively), there were no significant differences in symptom scores or reductions in LES pressure among successfully treated patients at one year. Patients successfully treated with botulinum toxin A maintained a treatment response for a mean of 14.8 months (range, 2-24 months).
Administration of 400 units of botulinum toxin A (Dysport) before pneumatic dilation resulted in longer remission times compared with pneumatic dilation alone in a study of 24 patients (25.6 months versus 12.6 months, respectively) (p < 0.01).[18] Remission time was defined as a decrease of >50% in symptom score from baseline. Both treatment groups had significant reductions in symptom score from baseline at 1 month; however, the magnitude of the decrease was greater in the group that received both botulinum toxin A and pneumatic dilation (76% decrease from baseline; p < 0.001) than for those treated with pneumatic dilation alone (53% decrease; p < 0.01).
Botulinum toxin A has also been compared with surgery for the treatment of achalasia. Laparoscopic cardiomyotomy led to a greater reduction in symptom scores and a higher likelihood of long-term symptom remission of achalasia compared with botulinum toxin A in a randomized study of 80 patients.[19] Both botulinum toxin A (two injections of 8-100 units one month apart into the LES) and laparoscopic cardiomyotomy were associated with significant reductions from baseline in dysphagia and regurgitation symptoms after six months; however, surgical patients had a greater reduction in symptom scores (82%) than did those treated with botulinum toxin A (66% decrease) (p < 0.05). Significantly more botulinum toxin A recipients were also more likely to have symptom recurrence compared with surgical patients after one year (40% versus 13%, respectively) and two years (66% versus 12.5%, respectively) (p < 0.05).
These studies of botulinum toxin A in the treatment of achalasia had small samples (mean, 34 patients per study) and varied in the duration of follow-up (six months to two years), dosage and formulation used, and outcome measures, including the criteria for treatment response. However, their results suggest that botulinum toxin A is more effective than placebo for the treatment of achalasia but is associated with a shorter duration of relief compared with pneumatic dilation or surgical cardiomyotomy. Thus, botulinum toxin A may be an alternative treatment for patients who are not candidates for or who do not desire pneumatic dilation or surgery; however, more studies are needed to determine the characteristics of potential responders to, most effective dose of, and overall role of botulinum toxin A in treating achalasia.
Essential tremor is an autosomal dominant neurologic movement disorder that causes uncontrollable shaking in different parts of the body, most often affecting the hands, head, and voice.[20,21] Treatment includes oral medications (e.g., primidone, ß-blockers, benzodiazepines) that are associated with systemic adverse effects and are often ineffective or surgery (e.g., thalamotomy, deep brain thalamic stimulation) that carries the risk of permanent neurologic deficits and death. Botulinum toxin A has been studied as an alternative therapy for various essential tremors.[22]
In a double-blind study, botulinum toxin A (50 or 100 units) or placebo was injected into wrist flexors and extensors in 133 patients with moderate to severe essential hand tremor.[20] Tremor severity and disability were scored on a scale of 0 to 4 (0 = none, 1 = mild, 2 = moderate, 3 = marked, 4 = severe). At six weeks postinjection, botulinum toxin A recipients had improvements in kinetic tremor score (p = 0.005 for treatment groups versus placebo). Both treatment groups had significant improvements from baseline in postural tremor score at 16 weeks (1.8 ± 0.8 versus 2.2 ± 0.6 for placebo) (p = 0.0001). There was also a significant dose-dependent reduction from baseline in grip strength among botulinum toxin A recipients at 6, 12, and 16 weeks. None of the groups had significant improvements in the ability to perform motor tasks (e.g., handwriting, pouring) or functional activities (e.g., feeding, drinking, hygiene, dressing). Adverse effects included pain at the injection site, paresthesia, and dose-dependent hand weakness (30% in the low-dose group, 70% in the high-dose group).
Botulinum toxin A was also more effective than placebo in reducing the severity of essential hand tremors in a 16-week, double-blind study of 25 patients with moderate to severe symptoms.[21] Patients were randomized to receive either 50 units of botulinum toxin A or placebo injections to the wrist flexors and extensors. Tremor severity was assessed on a scale ranging from 0 (none) to 4 (severe or disabling). Functional severity of tremor was assessed on a scale ranging from 0 (best) to 4 (worst) to assess activities such as feeding, drinking, dressing, writing, working, and fine movements. At one month postinjection, a significantly higher percentage of patients in the treatment group had mild to moderate tremor improvement compared with placebo (75% versus 27%, respectively) (p < 0.05). However, there was no significant improvement in functional score in either group. Mild to moderate finger weakness was the most common adverse effect, occurring in a higher percentage of botulinum toxin A recipients at week 4 relative to placebo (92% versus 0%, respectively). The frequency of this adverse effect decreased to 42% by week 12.
The effects of botulinum toxin A in treating horizontal ("no-no" pattern) head tremor were studied in 10 patients randomized to receive either 200 units of botulinum toxin A or placebo, distributed to target head and neck muscles.[22] After tremor severity had returned to baseline values, the patients crossed over to the opposite group. The interval between treatments ranged from 8 to 24 weeks. Most patients also had associated hand, voice, trunk, and leg tremors. Prestudy tremor medications, including benzodiazepines, propranolol, and primidone, were continued during the study. Tremor amplitude, frequency, and mean displacement were rated using an accelerometer that was affixed to the patient with a plastic headband. Patients were assessed in the sitting position and were asked to turn their head maximally to the right and then to the left. At four weeks postinjection, tremor amplitude, displacement per half cycle, and centimeters traveled were similar between groups. Adverse effects that occurred during botulinum toxin A treatment included neck weakness or soreness, headache, difficulty swallowing, and dizziness.
There are limited data demonstrating the superiority of botulinum toxin A to placebo in reducing the severity of hand tremors. The data also suggest that treatment with botulinum toxin increases the risk of developing focal hand weakness and has minimal effect on functional ability. Further studies are needed to determine the optimal dose and sites of injection to reduce tremor while minimizing adverse effects. Botulinum toxin A does not appear to reduce head tremor, but larger studies are needed to further explore its potential role in the treatment of this condition.
Focal hyperhidrosis refers to chronic, idiopathic excessive sweating that commonly affects the underarms, palms of the hands, soles of the feet, and the face.[23] Focal hyperhidrosis commonly occurs between the ages of 25 and 64 years and affects approximately 3% of the general population.[24] The disorder severely affects patients' emotional, social, and professional quality of life. While the exact cause of focal hyperhidrosis is unknown, conventional therapies include metal-containing antiperspirants, ionto-phoresis, oral anticholinergics, surgical removal of sweat glands, and sympathectomy. Nonsurgical treatments provide only temporary (two to four days) relief and may cause skin irritation. The use of systemic anticholinergics is limited by adverse effects, such as dry mouth and blurry vision. Botulinum toxin A administered intradermally has been used successfully in patients with focal hyperhidrosis by temporarily blocking cholinergic transmission in innervated sweat glands.[25] Although botulinum toxin A has received FDA-approved labeling for the treatment of axillary hyperhidrosis, several randomized clinical trials have also demonstrated the toxin's effectiveness in palmar hyperhidrosis.
There are several methods to assess the severity and extent of hyperhidrosis. Qualitative assessments, such as Minor's starch-iodine test and ninhydrin-stained sheets, temporarily stain the area of excess sweat production. Quantitative evaluation of sweat production may be conducted with gravimetric measurements that require the use of a special sweat-adsorbing paper that is later weighed. Other approaches include quality-of-life and impairment of daily activities measurements, such as the Dermatology Quality of Life Index or the Hyperhidrosis Disease Severity Scale.[26]
In a small double-blind within-group study, 11 patients were randomized to receive subcutaneous injections of botulinum toxin A (Dysport 120 units) to six sites in one palm and placebo in the other palm.[25] The botulinum toxin-treated palms had a significant reduction in mean sweat production from baseline at weeks 3, 8, and 13 (26%, 26%, and 31%, respectively) (p < 0.001). Subjective assessment of sweat production significantly improved by 38% and 40% from baseline in the treated palms at weeks 3 and 13, respectively. There were no significant changes in objective or subjective measures in the placebo-treated palms. Weakened handgrip in the treated palm, lasting two to five weeks after injection, was noted in 3 patients.
In another small within-group study, 19 patients received botulinum toxin A (100 units) intradermal injections to 15 sites in one palm and placebo in the other palm.[27] At 28 days postinjection, the mean reduction in gravimetric measurement of sweat production from baseline in the botulinum toxin-treated palm was significantly greater than in the placebo-injected palm (p = 0.0037). More botulinum toxin-treated palms improved by 2 or more points on the 5-point physician assessment scale (1 = no sweating, 5 = severe sweating) compared with the placebo-treated palms (p = 0.008). Patients also rated sweat production in the botulinum toxin-treated palms as significantly less severe than in the placebo-treated palms (p < 0.001). There was no significant difference in grip strength between palms, although 1 patient did report minor thumb and finger weakness that resolved after two weeks.
The efficacy of botulinum toxin type B in treating bilateral palmar hyperhidrosis was assessed in a placebo-controlled study of 20 patients.[28] Fifteen patients received intradermal injections of botulinum toxin B (5000 units per palm), and 5 received placebo in both palms. Efficacy was determined by two questionnaires and physician assessment of palmar iodine-starch photographs. At 30 days, patients treated with botulinum toxin had significantly lower mean scores on the quality-of-life survey (p = 0.10) and the symptom improvement survey (p = 0.002) relative to the placebo group. There was no significant difference between groups in physician assessment of palmar photographs (p = 0.56). The mean time to return of baseline perspiration levels was 113 days (range, 69-147 days). Adverse effects were common and included transient dry mouth (90%), heartburn (60%), excessively dry hands (60%), muscle weakness (60%), and decreased grip strength (50%).
The evidence from randomized controlled studies of botulinum toxins for palmar hyperhidrosis is limited to three small studies involving a total of 50 patients and supports the use of botulinum toxin A. The results of the study using botulinum toxin B are less convincing because of the relatively imbalanced distribution of patients to the treatment groups and the lack of correlation between physician and patient assessments of efficacy. Larger trials are needed to determine the duration of anhidrotic effect, optimal dose, injection technique, patient acceptability, and the long-term effects of repeated injections, particularly on muscle tone. The treatment is not curative but does offer an alternative to conventional therapies for palmar hyperhidrosis. Studies comparing botulinum toxin A and conventional therapies will also shed light on the cost-effectiveness of botulinum toxins in the treatment of palmar hyperhidrosis.
Migraine headache is generally the most disabling type of primary headache, characterized by dull pain occurring unilaterally or bilaterally that gradually intensifies to throbbing pain that can last up to 72 hours.[29] An aura of neurologic symptoms (e.g., sensitivity to light or sound) precedes migraine headaches in up to 30% of patients. Other symptoms, such as neck pain and muscle tension, may also be associated with migraine headache. Conventional prophylactic agents include propranolol, timolol, sodium divalproex, verapamil, and amitriptyline. The potential role of botulinum toxins for relieving migraine headache symptoms is thought to involve antinociceptive action and muscle relaxation.[30]
Two of three randomized, placebo-controlled studies of botulinum toxin A for the prophylactic treatment of migraine suggest that this toxin may be beneficial in migraine sufferers.[31,32] In the first study, 123 patients with a history of at least two moderate to severe migraine headaches per month were randomized to receive either botulinum toxin A injections (25 or 75 units) or placebo injections across multiple frontal muscle sites.[28] Maximum migraine severity was rated on a scale of 0 to 3, with higher scores indicating increased severity. Patient response to treatment was rated on a 9-point global assessment scale (-4 = very marked worsening, 4 = no signs and symptoms). At three months postinjection, only the lower dose of botulinum toxin A resulted in fewer migraine headaches per month from baseline (-0.98 versus -1.88, respectively; p = 0.042), lower maximum migraine severity ratings from baseline (-0.9 versus -2.12, respectively; p = 0.014), and reduced frequency of migraine-associated vomiting (31% versus 9.5%, respectively; p = 0.012). The rate of adverse effects, including blepharoptosis, diplopia, and weakness at the injection site, was similar to placebo in the low-dose treatment group (24%) but higher than placebo in the high-dose group (50%) (p = 0.017). In the second study, 60 patients with either chronic tension-type headache (n = 46) or migraine headache (n = 14) at least 15 days each month were randomized to receive either botulinum toxin A (200 units divided among individualized sites) or placebo.[29] Botulinum toxin treatment reduced the number of self-recorded headache-free days relative to placebo over 12 weeks (33 ± 23 days versus 24 ± 16 days, respectively; p < 0.07), with a significant difference reached at postinjection weeks 8 to 12 (p < 0.05). Adverse effects, which included mild eyelid ptosis in one patient, did not differ between groups.
In contrast, a third study of 60 patients averaging two to eight migraines with or without aura per month found that botulinum toxin A had no effect on migraine frequency.[33] Patients were randomized to receive 100 units of botulinum toxin A injected into the frontal and neck muscles, 16 units injected into the frontal muscles only, or placebo. At three months postinjection, there was no significant difference between treatment groups in the number of patients with at least a 50% reduction of migraine frequency from baseline. There were also no significant differences between groups with respect to reduction in migraine frequency, duration, intensity, number of acute drugs needed to treat migraine headaches, depression scores, or Headache Disability Inventory scores from baseline to three months postinjection.
Botulinum toxin A has also been used to treat and prevent cervicogenic headaches. Cervicogenic headaches are characterized by chronic head and neck pain that results from musculoskeletal dysfunction in the cervical spine.[34] Physical therapy, nerve block, and epidural analgesia, as well as oral antispasmodics and analgesics, have been used to relieve symptoms. Surgery may be necessary in severe cases of disk or joint injury.
A double-blind, placebo-controlled study assessed the efficacy of botulinum toxin A (100 units) injected into cervical trigger points in 26 patients with chronic headache secondary to a cervical whiplash injury.[35] Subjective pain assessment was based on a visual analog scale that ranged from 0 (no pain) to 10 (worst pain). Objective measures included degrees of neck range of motion (ROM). At one month postinjection, median pain scores were lower in the botulinum toxin group compared with placebo (3.5 versus 4.5, respectively). Only the botulinum toxin-treated patients had a significant improvement from baseline in mean pain scores, declining from 6.5 preinjection to 3.5 postinjection (p < 0.01). Median total degrees of ROM significantly improved from baseline in the treatment group, decreasing from 312º preinjection to 343º postinjection (p < 0.01). No adverse effects were reported. Five (42%) of 12 patients in the placebo group also had a high response rate at week 2, though their pain scores returned to baseline values by week 4.
Tension headache is the most common type of headache, with a lifetime prevalence of 80% in the general population.[36] Pain is usually dull, diffuse, persistent, and mild to moderate in severity. It occurs bilaterally in a hatband distribution around the head but may radiate to other areas, such as the neck and shoulders. Muscle strain in the upper back, head, and neck area may contribute to chronic tension headaches, which occur at least 15 days per month for at least six months. Approximately 3% of the general population have chronic tension headache.[37]
Several randomized, double-blind, placebo-controlled trials of botulinum toxin A for the prevention of chronic tension headache have shown conflicting results. Six placebo-controlled studies involving a total of 276 patients with chronic tension-type headache have demonstrated that botulinum toxin A injected into pericranial muscles is no more effective than placebo in reducing the average number of days with headache, average number of days of analgesic use, or improving the duration of sleep at three months postinjection.[38,39,40,41,42,43] In the largest of these studies, 107 patients were randomized to receive either botulinum toxin A (Dysport 500 units) over various pericranial muscles or placebo.[38] The primary endpoint was the change from baseline in the area under the curve (AUC), calculated as the sum of the product of headache duration and pain intensity per headache episode across the study period. At 12 weeks, there was no significant difference between groups in the change in AUC. Likewise, there were no significant differences in the mean reduction of analgesic use from baseline, mean number of headache-free days, Back Depression Inventory Score, or sleep duration.
Two smaller studies support the use of botulinum toxin A in patients with chronic tension headache. In one double-blind, placebo-controlled, crossover study, 16 patients received injections of botulinum toxin A (40-95 units) into multiple pericranial sites.[44] The primary measures were headache severity scores and muscle tenderness scores. At eight weeks, more patients in the placebo group reported severe pain (56%) than in the botulinum toxin group (0%); 37% of botulinum toxin-treated patients were pain free. Another placebo-controlled study of 37 patients found that botulinum toxin A (100 units) injected into the temporalis or cervical neck muscles improved headache severity at three months, with 13 (59%) of 22 patients in the treatment group having at least a 25% improvement in headache score at month 3, compared with 2 (13%) of 15 patients in the placebo group.[45]
In a comparison study of botulinum toxin A (5-15 units) and methylprednisolone (40 mg with lidocaine) injected bilaterally into headache tenderpoints in 20 patients with chronic or episodic tension headache, botulinum toxin A was shown to be as effective as methylprednisolone but with a longer duration of action.[46] Both groups had improved visual analog scores at 30 days; however, at 60 days, the botulinum toxin-treated group had a greater mean reduction in visual analog scores compared with patients who had received methylprednisolone (p = 0.0003). No adverse effects were reported.
Preliminary evidence suggests that botulinum toxin A is more effective than placebo for reducing pain and frequency of migraine headache for up to three months posttreatment. One of the migraine studies, however, also included patients with chronic tension headache and used a much higher dose of botulinum toxin than the other migraine studies.[32] In addition, the one study that showed no difference between botulinum toxin and placebo more strictly defined treatment response than did the other two studies.[33] More studies are clearly needed to further establish the efficacy of botulinum toxin for migraine headaches. Botulinum toxin A also appears to be more effective than placebo for cervicogenic headache, although the evidence for this is limited to one small study. The majority of evidence from placebo-controlled studies does not support the use of botulinum toxin for chronic tension headache. It is possible that the doses of botulinum toxin used in the studies were too low, particularly when considering that the study among migraine and chronic tension headache sufferers increased the number of headache-free days with a botulinum toxin A dose of 200 units. It is difficult to interpret the results of the comparison study with methylprednisolone, as this study lacked a placebo or control group. Again, inconsistencies in sample size, dosing, and injection sites limit the overall interpretation of the evidence. However, botulinum toxin A may be an appropriate alternative for patients with chronic headaches who are unable to tolerate or whose symptoms are not relieved by conventional therapies.
Dr. Cheng at the Drug Information and Analysis Service, University of California at San Francisco, 521 Parnassus Avenue, C-152, Box 0622, San Francisco, CA 94143-0622 ( chengc@pharmacy.ucsf.edu ).
Am J Health Syst Pharm. 2005;63(2):145-152. © 2005 American Society of Health-System Pharmacists
Cite this: Unlabeled Uses of Botulinum Toxins: A Review, Part 1 - Medscape - Jan 15, 2005.
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