Pooled Analysis of the Safety of Botulinum Toxin Type A in the Treatment of Poststroke Spasticity Catherine C. Turkel, PharmD, MBA, Beta Bowen, MS, Jingyu Liu, PhD, Mitchell F. Brin, MD ABSTRACT. Turkel CC, Bowen B, Liu J, Brin MF. Pooled analysis of the safety of botulinum toxin type A in the treatment of poststroke spasticity. Arch Phys Med Rehabil 2006;87:786-92. Objective: To examine the safety of botulinum toxin type A (BTX-A). Design: Analysis of pooled data of 9 double-blind, placebocontrolled studies of patients with spasticity after stroke. Setting: University hospitals and specialty rehabilitation centers in the United States. Participants: A total of 482 patients with upper-limb spasticity and 310 with lower-limb spasticity (overall mean age, 58y; 60% men). Intervention: Treatment with BTX-A (n⫽534; 1–3 treatments; mean dose, 231U) or placebo (n⫽258). Main Outcome Measure: Adverse events. Results: Most patients (69%) received only 1 treatment with BTX-A. Patients were followed for a mean of 17.8 weeks (range, 0.1– 44.7wk) after each treatment. A total of 352 (65.9%) patients in the BTX-A group and 163 (63.2%) in the placebo group reported at least 1 adverse event (P⫽.475). The most frequent adverse events reported by patients (⬎5% but ⬍10% in either group) were respiratory infection, seizures, incoordination, and injection site pain, none of which occurred at a significantly higher rate in the BTX-A group (all P⬎.05). The majority of adverse events were rated as mild or moderate in severity. Only nausea was reported at a significantly higher rate in the BTX-A group (12/534 [2.2%]) than the placebo group (0/258) (P⫽.011); in contrast, injection site pain, chest pain, and allergic reaction were reported significantly more frequently in the placebo group. Conclusions: BTX-A has an acceptable safety profile for treatment of patients with focal spasticity following stroke, a population in which adverse events and comorbidities are common. Key Words: Botulinum toxin type A; Cerebrovascular accident; Muscle spasticity; Rehabilitation. © 2006 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation
From Allergan Inc, Irvine, CA (Turkel, Bowen, Liu, Brin); and University of California, Irvine, CA (Brin). Presented in part to the American Academy of Physical Medicine and Rehabilitation, October 2004, Phoenix, AZ, and the Basic and Therapeutic Aspects of Botulinum and Tetanus Toxins, June 2005, Denver, CO. Supported by Allergan Inc. A commercial party having a direct financial interest in the results of the research supporting this article has conferred or will confer a financial benefit upon the authors. Turkel, Bowen, Liu, and Brin are employees of Allergan, which manufactures the drug used in this study, and all own Allergan stock and/or stock options. Reprint requests to Catherine C. Turkel, PharmD, MBA, Clinical Development, Allergan Inc, 2525 Dupont Dr, Irvine, CA 92612, e-mail: [email protected]
Allergan.com. 0003-9993/06/8706-10487$32.00/0 doi:10.1016/j.apmr.2006.02.015
Arch Phys Med Rehabil Vol 87, June 2006
TROKE IS A FREQUENT and often debilitating event that S may result in symptoms of upper motoneuron syndrome (eg, paralysis, spasticity), in addition to cognitive and other deficits, which can significantly interfere with the ability to perform daily activities,1-3 and reduce quality of life (QOL).4-7 Spasticity occurs in approximately 16% of patients as a sequela of stroke.8 Although spasticity can be useful for certain patients,9,10 it is frequently associated with pain, functional limitations (eg, hygiene, dressing, gait, transfers), abnormal limb postures, and contractures.3,11,12 The treatment of poststroke spasticity is typically multimodal, involving physical and occupational therapies in combination with splinting/casting, oral medications, or local chemodenervation agents.10,13 Over the past 15 years, a number of studies have investigated local injections of botulinum toxin for the treatment of focal poststroke spasticity.14-22 Today, botulinum toxin type A (BTX-A) is regarded as an effective treatment option in the management of focal poststroke spasticity that has the potential to reduce pain and discomfort for patients, enhance the benefits of physical therapy, reduce caregiver burden, avoid pressure ulcers, increase independence in self-care, and improve QOL for appropriately selected patients.23 In the treatment of poststroke spasticity, patients treated with BTX-A report mostly transient, local side effects such as injection site pain and local muscular weakness,15,18,24-26 although several controlled trials have not found any differences in the rate of specific adverse events with BTX-A as compared with placebo.20,27 With the growing use and study of this treatment, a wide range of data is now available to further consider the safety profile in large patient populations. Such safety considerations are especially important in poststroke patients due to the concomitant use of multiple medications28 and prevalence of serious comorbidities such as cardiovascular disease, hypertension, and diabetes in this population.29,30 This study reports on the pooled safety data in a large group of poststroke patients with upper- and/or lower-limb spasticity who participated in Allergan’s registration program of doubleblind, placebo-controlled trials of BTX-A (Botox). Because these trials were all conducted as part of Allergan’s registration program, they were all subject to the same general adverse event reporting requirements, including the documentation of all events even if they seemed (to the investigator) unrelated to treatment. The same methodology used for adverse event reporting in these trials provides a basis for analyzing them as a group, to further examine the safety of BTX-A. This analysis is of interest because a large database may permit the detection of rarer adverse events that are not always evident in smaller trials. METHODS Trial Selection This analysis included randomized, double-blind, placebocontrolled trials of BTX-A for the treatment of poststroke spasticity that were conducted as part of Allergan’s registration program.
SAFETY OF BOTULINUM TOXIN TYPE A, Turkel
Description of Patients in the Trials All 9 studies pooled for this analysis included patients who were at least 6 weeks poststroke. Six of the studies evaluated treatment of patients with upper-limb spasticity and 3 evaluated treatment of patients with lower-limb spasticity. These studies covered a broad spectrum of patients with spasticity and associated comorbidity, including patients who met specific disability, spasticity, and pulmonary spirometry inclusion criteria. Eight of the studies required that the limb to be injected show a minimum score on the Ashworth Scale (regular, modified, or expanded version) of 2 or 3 (moderate or severe) at the relevant flexor muscles.31-33 In 1 of the upper-limb studies, patients were required to have a score of moderate or severe for at least 1 domain of hygiene, dressing, pain, or limb posture on the 4-point Disability Assessment Scale.20 In 2 of the studies, patients were required to have baseline scores on the relevant pulmonary spirometry tests (forced expiratory volume at 1 second [FEV1], forced vital capacity [FVC]) that were at least 65% of the predicted value for their ages. In a third study, baseline FEV1 was required to be at least 50% of the predicted value for the patients’ ages. Two of the 3 lower-limb studies required that patients be ambulatory, either with or without assistive devices. Persons with significant neuromuscular diseases, such as myasthenia gravis, Eaton-Lambert syndrome, or amyotrophic lateral sclerosis, were excluded from all of the studies, as were women who were pregnant or breast-feeding.34 Patients with fixed contractures or previous surgery on the limb to be treated were also excluded from most studies. Many of the studies also excluded patients who had profound atrophy of the muscles to be injected, previous injections of phenol or surgery in the study limb, previous botulinum toxin treatment and concurrent treatment with intrathecal baclofen, aminoglycoside antibiotics, or agents that interfere with neuromuscular transmission.34 Patients in all studies but 1 were required to be naïve to treatment with any botulinum toxin (table 1). All studies were conducted in accordance with the Declaration of Helsinki. Studies were approved by institutional review boards at all sites and all patients provided informed consent. Trial Design This analysis is based on pooled data from 9 double-blind, placebo-controlled studies in which patients with poststroke spasticity received 1 to 3 treatments with BTX-A (Botox). Patients were assigned to fixed dosages in all 6 of the upper-limb studies and 1 of the lower-limb studies, and were assigned to fixed dosage ranges in 2 of the lower-limb studies (see table 1). In 5 of the studies (3 upper-limb, 2 lower-limb), patients received 1 treatment with BTX-A, and in 3 of the studies (2 upper-limb, 1 lower-limb), patients received up to 2 treatments with BTX-A separated by at least 12 weeks. In 1 upper-limb study, patients were permitted to receive up to 3 treatments with BTX-A, separated by at least 12 weeks. Follow-up visits were conducted every 2 to 6 weeks in the various studies (see table 1), and adverse events were documented at each visit. Pre- and posttreatment laboratory safety tests were performed in 4 studies: in 3 studies, the full panel of results was available for analysis and in the other, predetermined analysis specified capturing only values that were reported as abnormal. In 2 of the upper-limb and 1 of the lower-limb studies, pulmonary spirometry tests were conducted as part of the study protocol. In these studies, pulmonary spirometry tests consisted of FEV1 and FVC, and 1 of the studies also included maximum inspiratory pressure (PImax). In 2 of the studies, a decrease of 15% or more on either the FEV1 or FVC was documented as an
adverse event, as required by the study protocol, regardless of any additional clinical symptoms related to pulmonary function or lack thereof. In the third study, there was no specific a priori criterion for documenting decreased pulmonary function scores; however, changes from baseline for all pulmonary spirometry tests were analyzed. Statistical Analyses of the Pooled Studies Data pertaining to patient demographics, medical history, concurrent drug usage, BTX-A doses, duration of follow-up, and adverse events (overall and those reported as treatmentrelated by investigators) were pooled and summarized with summary statistics. Adverse event and demographic data from all patients treated with BTX-A in the 9 studies were pooled and compared against data from all patients treated with placebo using Fisher exact tests (individual and overall adverse events) or Pearson chi-square tests (demographic data). Statistical significance was set at P equal to or less than .05. RESULTS Patient Disposition A total of 792 patients were enrolled in the 9 studies and all were included in the present analysis, comprising 534 patients who received at least 1 treatment with BTX-A and 258 who received placebo. Of the total patients, 482 patients were treated for upper-limb spasticity and 310 for lower-limb spasticity. More than 90% of patients in each group completed the studies (BTX-A, 498/534 [93.3%]; placebo, 239/258 [92.6%]). Twelve patients (1.5% overall; 10 [1.9%] treated with BTX-A) discontinued the studies due to adverse events, with only 1 deemed related to treatment by the investigators (arm muscle weakness). Three (0.6%) patients treated with BTX-A and 2 (0.8%) patients treated with placebo discontinued due to lack of efficacy. Five patients discontinued for personal reasons, 7 were unable to continue, 1 was lost to follow-up, and 25 discontinued for other reasons, such as missed visits, patient moved, and transportation issues. Patient Demographics Patients were an average of 58 years old, with the majority between 40 and 64 years of age (table 2). Approximately 60% were men and more than 80% were white (see table 2). None of these variables differed significantly between the BTX-A and placebo groups. Based on medical histories, nearly half of the patients had cardiovascular disorders (BTX-A, 47.0%; placebo, 42.6%), systemic hypertension (BTX-A, 44.2%; placebo, 52.3%), and/or neurologic disorders other than stroke (BTX-A, 41.9%; placebo, 52.3%). Many patients also had gastrointestinal disorders (BTX-A, 15.9%; placebo, 18.2%), abnormal physical findings (BTX-A, 15.9%; placebo, 11.6%), and/or musculoskeletal disorders (BTX-A, 15.5%; placebo, 19.8%). Nearly all patients were taking at least 1 concomitant medication during the study (BTX-A, 93.7%; placebo, 96.7%). Classes of drugs used by at least 20% of patients in either group were angiotensin-converting enzyme inhibitors (BTX-A, 27.5%; placebo, 26.4%), other centrally acting agents (mostly baclofen; BTX-A, 21.2%; placebo, 15.5%), platelet aggregation inhibitors (excluding heparin; BTX-A, 43.1%; placebo, 44.2%), and selective serotonin reuptake inhibitors (BTX-A, 19.5%; placebo, 22.9%). Extent of Exposure and Follow-Up The overall mean BTX-A doses at the first and second treatments, respectively, were 231U (range, 59 – 400U) and Arch Phys Med Rehabil Vol 87, June 2006
Arch Phys Med Rehabil Vol 87, June 2006
Table 1: Study Design, Dosages, Muscles Injected, and Duration for the Individual Randomized, Placebo-Controlled Trials in Adult Poststroke Spasticity Patients Design
Upper-limb studies One treatment: 1 of 3 BTX-A doses or placebo
Muscles Injected (dose range per muscle)
200, 220, 240*
200, 220, 240*
Flexors carpi radialis (50U) and ulnaris (50U), flexors digitorum profundus (50U) and sublimus (50U), and if needed, adductor pollicis (20U), and/or flexor pollicis longus (20U) Same muscles as above, dose per muscle at physician’s discretion 2–6 muscles and dose per muscle at physician’s discretion Biceps brachii (50–200U), flexors carpi radialis (15–60U), and ulnaris (10–40U) Biceps brachii (50–200U), flexors carpi radialis (15–60U) and ulnaris (10–-40U), flexors digitorum profundus (7.5–30U), and sublimus (7.5–30U) Same as above
75, 150, 300
90, 180, 360
One treatment: 1 of 3 BTX doses or placebo Lower-limb studies One treatment: 1 of 2 BTX-A doses or placebo
90, 180, 360
Up to 2 treatments: 1 of 2 BTX-A doses or placebo
One treatment: 1 of 2 BTX-A doses or placebo
1.8–3.3U/kg low-dose group; 3.6–5.5U/kg high-dose group‡ 1.8–3.3U/kg low-dose group; 3.6–5.6U/kg high-dose group§
Posterior tibialis (70–100U), soleus (80–125U), flexor digitorum longus (50– 75U), or medial gastrocnemius (50–75U) Gastrocnemius (80–320U); 2nd injection into anterior (40–80U) or posterior tibialis (40– 80U) Gastrocnemius (80–320U) and, if necessary, anterior (40–80U) or posterior tibialis (40– 80U)
Maximum Follow-Up (wk)
36; 1wk after 2nd and 3rd treatments
24; 1wk after 2nd treatment 12
*The total dose depended on whether 0, 1, or 2 thumb flexors were injected in addition to wrist and finger flexors. † Patients in this study were not naive to BTX treatment, but must not have had BTX therapy within 4 months prior to enrollment. ‡ Patients received approximately 2U/kg (low dose) or 4U/kg (high dose) into gastrocnemius muscle (low dose, 80 –160U; high dose, 160 –320U). Patients who received a second injection received the same dose into the gastrocnemius muscle and approximately 1U/kg into the anterior or posterior tibialis muscle (both dosage groups). § Patients received approximately 2U/kg (low dose) or 4U/kg (high dose) into gastrocnemius muscle and approximately 1U/kg into the anterior or posterior tibialis muscle (both dosage groups) if they had spasticity of the tibialis muscle. 㛳 Data presented as part of a pooled analysis.
SAFETY OF BOTULINUM TOXIN TYPE A, Turkel
Two treatments: 1 of 3 BTX-A doses or placebo Up to 2 treatments: 1 of 2 BTX-A doses or placebo† One treatment: 1 of 3 BTX-A doses or placebo One to 3 treatments: 1 of 3 BTX-A doses or placebo
N (BTX-A/ Placebo)
SAFETY OF BOTULINUM TOXIN TYPE A, Turkel Table 2: Patient Demographics Characteristic
Age (y) Mean ⫾ SD Range Age group, n (%) 18 to ⬍40 40 to ⬍65 65 to ⬍75 ⱖ75 Sex, n (%) Male Female Race, n (%) White Black Asian Hispanic Other
45 (8.4) 320 (59.9) 117 (21.9) 52 (9.7)
22 (8.5) 146 (56.6) 67 (26.0) 23 (8.9)
326 (61.0) 208 (39.0)
151 (58.5) 107 (41.5)
462 (86.5) 45 (8.4) 11 (2.1) 9 (1.7) 7 (1.3)
211 (81.8) 30 (11.6) 7 (2.7) 8 (3.1) 2 (0.8)
Abbreviation: SD, standard deviation.
243U (range, 15– 400U). The total dose was divided and administered in at least 3 muscles (see table 1). Patients were followed for a mean of 17.8 weeks (range, 0.1– 44.7wk), during which 177 of 534 (33.1%) patients treated with BTX-A received at least 2 injections and 7 (1.3%) received 3 injections. Safety Of the 792 patients, 515 (65%) reported at least 1 adverse event, including 352 (65.9%) patients in the BTX-A group and 163 (63.2%) in the placebo group (P⫽.475). Patient-reported adverse events. The most frequent adverse events (⬎5% in either group) reported by patients were respiratory infection, seizures, incoordination, and injection site pain—all of which were reported by less than 10% of patients in each group and none of which were reported at a significantly higher rate in the BTX-A group than the placebo group (table 3). The frequency of seizures reported in this analysis represents the summation of adverse events reported in the various trials as convulsions (BTX-A, 4.1%; placebo, 3.1%), grand mal convulsions (BTX-A and placebo, both ⬍1%), and seizures (BTX-A, 2.1%; placebo, 3.1%), none of which differed significantly between BTX-A and placebo groups (Pⱖ.457). Within each of these terms, each patient was counted only once. These data include 2 patients (1 BTX-A, 1 placebo) for each of whom seizure events with 2 different terms were reported. The only individual adverse event in this analysis that was reported at a significantly higher rate in the BTX-A group (12/534 [2.2%]) than placebo group was nausea (0/258) (P⫽.011). Adverse events reported at a significantly higher rate in the placebo group than BTX-A group included injection site pain (BTX-A, 13/534 [2.4%]; placebo, 14/258 [5.4%]; P⫽.037), chest pain (BTX-A, 2/534 [0.4%]; placebo, 5/258 [1.9%]; P⫽.040), and allergic reaction (BTX-A, 1/534 [0.2%]; placebo, 4/258 [1.6%]; P⫽.041). We classified adverse events as serious if the patient outcome was fatal, life-threatening, resulted in hospitalization (initial or prolonged), disability, congenital anomaly, or if intervention to prevent permanent impairment or damage was required. The most frequently reported serious adverse events were seizure (BTX-A, 12/534 [2.2%]; placebo, 7/258 [2.7%];
P⫽.805; not all seizures were classified as serious—see table 3 for total numbers of seizures) and cerebrovascular accident (BTX-A, 6/534 [1.1%]; placebo, 1/258 [0.4%]; P⫽.437), which did not differ statistically between groups and are not unexpected events in poststroke patients. Three patients died either during the studies or within 30 days of study completion (n⫽1, gastrointestinal hemorrhage with subsequent cardiac arrest; n⫽2, myocardial infarction); these patients had all been treated with BTX-A, but all of the deaths were deemed by the investigator as unrelated to the study medication. One of the deaths occurred 53 days after the first BTX-A injection, and the others occurred 38 and 65 days after a second BTX-A injection. A total of 136 of 534 (25.5%) patients in the BTX-A group and 63 of 258 (24.4%) in the placebo group reported adverse events that the investigator deemed treatment-related. The most frequent adverse events reported by patients that were deemed treatment-related by investigators were injection site pain, peripheral edema, and hypertonia (all ⬍5% in each group) (see table 3). Of the total adverse events reported, most were mild or moderate in maximum severity for both groups (BTX-A, 288/ 352 [81.8%]; placebo, 129/163 [79.1%]; P⫽.471). The percentage of patients with severe adverse events did not differ significantly between groups (BTX-A, 57/534 [10.7%]; placebo, 29/258 [11.2%]; P⫽.808). The adverse events that were reported as severe for at least 3 patients who were treated with BTX-A were depression (n⫽5), arthralgia (n⫽4), arm pain, leg pain, back pain, pain in the body as a whole, and convulsion (n⫽3 each). The adverse events that were reported as severe for at least 3 patients who were treated with placebo were seizure (n⫽5), convulsion, and injection site pain (n⫽3 each). The severity of adverse events was not available for 7 of 534 (1.3%) patients in the BTX-A group and 5 of 258 (1.9%) patients in the placebo group. Respiratory adverse events. No statistically significant difference was noted in the numbers of respiratory adverse events Table 3: Most Frequent Spontaneously Reported Adverse Events (% of patients) Adverse Event
Overall* Seizures Respiratory infection Headache Arm pain Peripheral edema Incoordination Pain Back pain Hypertension Injection site pain Treatment-related (per investigator’s opinion)† Hypertonia Peripheral edema Injection site pain Arm pain Nausea
BTX-A (%) (n⫽534)
Placebo (%) (n⫽258)
6.6 5.2 4.7 4.3 4.3 4.1 3.0 3.0 2.8 2.4
6.6 7.0 3.1 3.5 1.6 7.0 4.7 4.3 4.3 5.4
⬎.999 .334 .347 .702 .058 .118 .304 .404 .292 .037
2.6 2.6 2.2 1.7 1.5
1.6 0.8 4.7 1.2 0.0
.721 .420 .242 .972 .162
*Data includes those occurring in more than 4% of patients in either group. † Data for treatment-related (per the opinion of the individual study investigator) adverse events includes those occurring in more than 1.5% of patients in the BTX-A group. Adverse events ordered according to occurrence in the BTX-A group.
Arch Phys Med Rehabil Vol 87, June 2006
SAFETY OF BOTULINUM TOXIN TYPE A, Turkel
in the BTX-A (23.0%) and placebo (20.9%) groups (P⫽.525). None of the individual respiratory adverse events were reported at a significantly different rate in the BTX-A and placebo groups (all Pⱖ.163). Three of the studies included pulmonary spirometry measures to confirm the safety of BTX-A in these patients, because they might have had compromised respiratory function as a result of their stroke. In all 3 of these studies, FEV1 and FVC were measured. In 1 study, PImax was also measured. In 2 of these studies (1 evaluating upper-limb spasticity, 1 evaluating lower-limb spasticity), a decrease from baseline of at least 15% in FEV1 and/or FVC was specifically evaluated as an adverse event. In these 2 studies, 52 of 134 (38.8%) patients in the BTX-A group and 19 of 53 (35.8%) patients in the placebo group had a decrease from baseline of at least 15% in FEV1 and/or FVC (P⫽.312 and P⫽.523 for the 2 individual studies, respectively). In all cases for which the data were available, the severity was rated as mild by the investigator. In the study in which lung function was assessed using the PImax, no clinically meaningful or statistically significant differences were noted between the 2 BTX-A groups and placebo group in changes from baseline PImax at any of the time points assessed (P⬎.357). In fact, mean PImax improved in all treatment groups. There were no subjective complaints or spontaneous reports of decreased lung function in this study. Of the other respiratory adverse events reported, respiratory infection was the most frequently reported in the BTX-A treated patients (BTX-A, 5.2%; placebo, 7.0%; P⫽.334). The next most frequent respiratory adverse events were bronchitis (BTX-A, 2.4%; placebo, 0.8%; P⫽.163), rhinitis (BTX-A, 2.1%; placebo, 1.9%; P⬎.999), and dyspnea (BTX-A, 1.5%; placebo, 0.8%; P⫽.512). Laboratory Variables Analyses of the laboratory test data based on changes from baseline to follow-up or based on shifts from baseline relative to the normative range did not show any clinically relevant treatment effects. Laboratory tests for which there were statistically significant differences (Pⱕ.05) between the placebo (n⫽113) and BTX-A (n⫽195) groups (change from baseline data compared between groups) were as follows: mean eosinophils (fraction): BTX-A, .0005; and placebo, .0027; and mean alkaline phosphatase (in U/L): BTX-A, ⫺2.50; and placebo, 1.00. No patient was discontinued from any study because of a laboratory adverse event. Between-group comparisons of changes from pretreatment values (ie, pre, post) in vital signs or physical examination findings did not identify any clinically significant differences between the treatment groups. DISCUSSION The present analysis of 9 randomized, double-blind, placebo-controlled trials in more than 500 patients confirms the safety profile of BTX-A in the treatment of poststroke spasticity as reported in other published studies.15,18,24-26 The only adverse event that was reported by significantly more patients treated with BTX-A than placebo was nausea, although the rate of nausea deemed related to treatment by investigators did not differ significantly between groups. Three adverse events were reported by significantly more patients treated with placebo than BTX-A: injection site pain, chest pain, and allergic reaction. The poststroke population is characterized by multiple serious comorbid conditions, such as cardiovascular disease, hypertension, diabetes, and sleep apnea.29,30 These conditions are Arch Phys Med Rehabil Vol 87, June 2006
frequently accompanied by additional complications attributed to stroke, such as depression, deep venous thrombosis, dysphagia and risk of aspiration, seizures, urinary incontinence, osteoporosis, cognitive deficits, and increased risk of falls.30,35-40 Thus, spasticity and other symptoms of the upper motoneuron syndrome constitute only 1 set of difficulties faced by patients following a stroke. Consistent with these observations, more than 40% of patients in the present study reported a medical history of cardiovascular disorders and systemic hypertension, and more than 15% of patients reported a prior history of gastrointestinal disorders and/or musculoskeletal disorders. Following treatment, nearly two thirds of patients in each group reported at least 1 adverse event (BTX-A, 65.9%; placebo, 63.2%), but the rate did not differ significantly between groups, suggesting that BTX-A treatment did not significantly add to the overall rate of untoward events reported by patients with poststroke spasticity. Seizures are an additional complication of stroke.31,40 Approximately 10% of stroke patients experience subsequent seizures, although the rate may be as high as 20% depending on the type of stroke.40,41 In the present study, 6.6% of patients in each group had seizures, which is consistent with the rate reported in the poststroke literature.40 These results suggest that BTX-A did not increase the risk of seizures in this population. In the treatment of poststroke spasticity, as well as other disorders, the adverse events reported with BTX-A are predominantly local and transient.42,43 However, there have been occasional reports of systemic complaints such as flu-like syndrome.44 In this pooled analysis, more generalized complaints such as flu syndrome or respiratory infection are distributed across the entire study population, without a significant difference between BTX-A and placebo. Of the adverse events reported that differed significantly between groups, only nausea was higher in the BTX-A group (did not differ when analyzing only those deemed treatment-related by investigators), whereas chest pain and allergic reaction were significantly higher in the placebo group. These results are consistent with other studies, such as controlled trials of BTX-A (Allergan) for the treatment of primary axillary hyperhidrosis and glabellar lines, where the rates of flu-like reactions and respiratory complaints have not been significantly greater in the BTX-A group than placebo group.45,46 Although BTX-A is administered locally into spastic muscles, it is often compared with oral antispasticity medications. To our knowledge, no published studies have directly compared the rates of adverse events with BTX-A and oral antispasticity medications. However, analysis of the literature suggests that oral agents have broader side effect profiles than BTX-A. For instance, some of the most frequently reported adverse events associated with oral antispasticity medications are sedation, fatigue, cognitive impairment, and dizziness. Periodic liver function tests are recommended with baclofen, tizanidine, and dantrolene due to potential effects on the liver.47,48 These adverse events must also be taken into consideration when comparing medication costs. That is, the acquisition costs of some of these medications may be lower than that of BTX-A (ie, ⬇90 –120d supply of medication vs single treatment session with BTX-A), but the adverse events associated with oral medications may lead to additional economic (eg, physician visits) and QOL costs. Only a few of the oral antispasticity drugs have been examined in controlled trials. In a controlled crossover trial of oral tizanidine, somnolence was reported by 41% of 17 patients following tizanidine but 0 of 17 following placebo, and liver function test results were elevated in 18% of patients following
SAFETY OF BOTULINUM TOXIN TYPE A, Turkel
tizanidine but 0 following placebo.49 Another double-blind crossover trial of baclofen versus placebo in elderly stroke patients was discontinued because the drug produced an unacceptably high level of drowsiness.50 The present results with BTX-A compare favorably with the adverse event profile for oral antispasticity agents, because no adverse event was reported by more than 10% of patients and fewer than 2% of patients in each group discontinued the studies due to adverse events. Side-effect profiles may vary even among different botulinum neurotoxin preparations, which is not unexpected given their different formulations and dosing requirements.51 Patients included in this report only received BTX-A manufactured by Allergan Inc. In the treatment of cervical dystonia, the rate of dry mouth and dysphagia vary among the 2 commercial preparations of BTX-A and the 1 commercially available botulinum toxin type B (BTX-B).51 This is supported by preclinical studies that have demonstrated that the safety margin of BTX-A (Allergan) exceeds that of another formulation of BTX-A (Ipsen) and BTX-B (Solstice Neurosciences).52,53 In this regard, it is notable that dry mouth has been reported as one of the most frequent adverse events with BTX-B in the treatment of upper-limb spasticity, occurring in 9 of 10 patients in an open-label study.54 Dry mouth was reported by only 1 of 534 (0.19%) patients treated with BTX-A in the present analysis (P⬎.999 vs placebo). Taken together, these results suggest that safety information obtained with 1 preparation of botulinum neurotoxin cannot be generalized to other botulinum neurotoxin preparations or serotypes. Although only a third of patients in the present study received more than 1 treatment with BTX-A, most patients with poststroke spasticity require multiple treatments over time. Several studies have reported that BTX-A provides consistent benefits and safety in the treatment of poststroke spasticity following 4 to 6 injection cycles.18,22 These studies also found that the interval between injections18 and functional benefits22 increased with consecutive injections. It has been proposed that BTX-A aids the rehabilitation efforts during poststroke central nervous system plasticity, and further enhances the services of other physical treatment modalities.18,55 In the treatment of focal dystonias and hemifacial spasm, where BTX-A has been studied and used since the late 1970s, published reports have documented consistent safety and benefits of repeated treatments for up to 10 years.56-58 CONCLUSIONS No unexpected safety issues with BTX-A were identified in the present analysis. These results are encouraging given the large number of comorbid conditions and complications observed in poststroke patients. In combination with the documented improvements in muscle tone and functional disability,20 these data support the utility of BTX-A as part of a comprehensive, multimodal treatment program for focal poststroke spasticity. Acknowledgments: All authors had full access to the data. We thank Mary Ann Chapman (contract writer) and Lynn James (Allergan) for their assistance in the writing of the manuscript. References 1. Centers for Disease Control and Prevention. National Center for Health Statistics. Stroke fact sheet. Available at: http:// www.cdc.gov/cvh/library/fs_stroke.htm. Accessed June 21, 2005. 2. Wade D. Stroke (acute cerebrovascular disease). In: Stevens A, Raftery J, editors. Health care needs assessments. Vol 1. Oxford: Radcliffe Medical Pr; 1994. p 111-255. 3. Mayer NH, Esquenazi A, Childers MK. Common patterns of clinical motor dysfunction. Muscle Nerve 1997;20(Suppl 6):S21-35.
4. Viitanen M, Fugl-Meyer KS, Bernspang B, Fugl-Meyer AR. Life satisfaction in long-term survivors after stroke. Scand J Rehabil Med 1988;20:17-24. ˚ ström M, Asplund K, Astrom T. Psychosocial function and life 5. A satisfaction after stroke. Stroke 1992;23:527-31. 6. Jonkman EJ, de Weerd AW, Vrijens NL. Quality of life after a first ischemic stroke. Long-term developments and correlations with changes in neurological deficit, mood and cognitive impairment. Acta Neurol Scand 1998;98:169-75. 7. Duncan PW, Samsa GP, Weinberger M, et al. Health status of individuals with mild stroke. Stroke 1997;28:740-5. 8. Turkel C, Sissins P. Functional activities affected by poststroke spasticity [abstract]. Arch Phys Med Rehabil 2004;85:E52. 9. O’Brien CF, Seeberger LC, Smith DB. Spasticity after stroke. Epidemiology and optimal treatment. Drugs Aging 1996;9:332-40. 10. Brin MF. Dosing, administration, and a treatment algorithm for use of botulinum toxin A for adult-onset spasticity. Muscle Nerve 1997;20(Suppl 6):S208-20. 11. Wissel J, Muller J, Dressnandt J, et al. Management of spasticity associated pain with botulinum toxin A. J Pain Symptom Manage 2000;20:44-9. 12. Farmer SE, James M. Contractures in orthopaedic and neurological conditions: a review of causes and treatment. Disabil Rehabil 2001;23:549-58. 13. Brashear A. Use of botulinum toxin type A in poststroke spasticity. Expert Rev Neurotherapeutics 2003;3:271-7. 14. Das TK, Park DM. Botulinum toxin in treating spasticity. Br J Clin Pract 1989;43:401-3. 15. Hesse S, Lucke D, Malezic M, et al. Botulinum toxin treatment for lower limb extensor spasticity in chronic hemiparetic patients. J Neurol Neurosurg Psychiatry 1994;57:1321-4. 16. Reiter F, Danni M, Lagalla G, Ceravolo G, Provinciali L. Lowdose botulinum toxin with ankle taping for the treatment of spastic equinovarus foot after stroke. Arch Phys Med Rehabil 1998;49: 532-5. 17. Kirazli Y, On AY, Kismali B, Aksit R. Comparison of phenol block and botulinus toxin type A in the treatment of spastic foot after stroke. Am J Phys Med Rehabil 1998;77:510-5. 18. Lagalla G, Danni M, Reiter F, Ceravolo M, Provinciali L. Post-stroke spasticity management with repeated botulinum toxin injections in the upper limb. Am J Phys Med Rehabil 2000;79:377-84. 19. Esquenazi A, Mayer N. Botulinum toxin for the management of muscle overactivity and spasticity after stroke. Curr Atheroscler Rep 2001;3:295-8. 20. Brashear A, Gordon MF, Elovic E, et al. Intramuscular injection of botulinum toxin for the treatment of wrist and finger spasticity after a stroke. N Engl J Med 2002;347:395-400. 21. Childers MK, Brashear A, Jozefczyk P, et al. Dose-dependent response to intramuscular botulinum toxin type A for upper-limb spasticity in patients after a stroke. Arch Phys Med Rehabil 2004;85:1063-9. 22. Gordon MF, Brashear A, Elovic E, et al. Repeated dosing of botulinum toxin type A for upper limb spasticity following stroke. Neurology 2004;63:1971-3. 23. Turner-Stokes L, Ward A. Botulinum toxin in the management of spasticity in adults. Clin Med 2002;2:128-30. 24. Richardson D, Sheean G, Werring D, et al. Evaluating the role of botulinum toxin in the management of focal hypertonia in adults. J Neurol Neurosurg Psychiatry 2000;69:499-506. 25. Bhakta BB. Management of spasticity in stroke. Br Med Bull 2000;46:476-85. 26. Barnes MP. Spasticity: a rehabilitation challenge in the elderly. Gerontology 2001;47:295-9. 27. Simpson DM, Alexander DN, O’Brien CF, et al. Botulinum toxin type A in the treatment of upper extremity spasticity: a randomArch Phys Med Rehabil Vol 87, June 2006
28. 29. 30.
31. 32. 33.
37. 38. 39.
42. 43. 44.
SAFETY OF BOTULINUM TOXIN TYPE A, Turkel
ized, double-blind, placebo-controlled trial. Neurology 1996;46: 1306-10. Beyth RJ, Shorr RI. Epidemiology of adverse drug reactions in the elderly by drug class. Drugs Aging 1999;14:231-9. Walker AE, Robins M, Weinfeld FD. Clinical findings. Stroke 1981;12:I13-31. Black-Schaffer RM, Kirsteins AE, Harvey RL. Stroke rehabilitation. 2. Co-morbidities and complications. Arch Phys Med Rehabil 1999;80(5 Suppl 1):S8-16. Ashworth B. Preliminary trial of carisprodol in multiple sclerosis. Practitioner 1964;192:540-2. Bohannon RW, Smith MB. Interrater reliability of a modified Ashworth scale of muscle spasticity. Phys Ther 1987;67:206-7. Allergan Inc. Evaluation of muscle tone in poststroke patients using two scoring systems. Irvine: Allergan; 1998. Internal study report 191622-007. Allergan Inc. BOTOX prescribing information. Irvine: Allergan Inc; 2005. Evers SM, Driessen GA, Ament AJ. The use of mental health care facilities after stroke. A cost analysis. Int J Technol Assess Health Care 2002;18:33-45. Lindblad U, Rastam L, Ranstam J. Stroke morbidity in patients treated for hypertension—The Skaraborg Hypertension Project. J Intern Med 1993;233:155-63. Marinkovic S, Badlani G. Voiding and sexual dysfunction after cerebrovascular accidents. J Urol 2001;165:359-70. Tuhrim S. Stroke risk factors. CNS Spectrums 2000;5:70-4. Van Heugten CM, Dekker J, Deelman GB, Stehmann-Saris JC, Kinebanian A. Rehabilitation of stroke patients with apraxia: the role of additional cognitive and motor impairments. Disabil Rehabil 2000;22:547-54. Silverman IE, Restrepo L, Mathews GC. Poststroke seizures. Arch Neurol 2002;59:195-201. Bladin CF, Alexandrov AV, Bellavance A, et al. Seizures after stroke: a prospective multicenter study. Arch Neurol 2000;57: 1617-22. Jankovic J, Brin MF. Botulinum toxin: historical perspective and potential new indications. Muscle Nerve 1997;20(Suppl 6):S129-45. Ghosh B, Das SK. Botulinum toxin: a dreaded toxin for use in human being. J Indian Med Assoc 2002;100:607-14. Dutton JJ. Botulinum-A toxin in the treatment of craniocervical muscle spasms: short- and long-term, local and systemic effects. Surv Ophthalmol 1996;41:51-65. Naumann M, Lowe NJ. Botulinum toxin type A in treatment of bilateral primary axillary hyperhidrosis: randomised, parallel group, double blind, placebo controlled trial. BMJ 2001;323: 596-9. Carruthers JA, Lowe NJ, Menter MA, et al. A multicenter, doubleblind, randomized, placebo-controlled study of the efficacy and safety of botulinum toxin type A in the treatment of glabellar lines. J Am Acad Dermatol 2002;46:840-9. Gracies JM, Nance P, Elovic E, McGuire J, Simpson DM. Traditional pharmacological treatments for spasticity. Part II: general and regional treatments. Muscle Nerve 1997;20(Suppl 6):S92120. Kita M, Goodkin DE. Drugs used to treat spasticity. Drugs 2000; 59:487-95. Meythaler JM, Guin-Renfroe S, Johnson A, Brunner RM. Prospective assessment of tizanidine for spasticity due to acquired brain injury. Arch Phys Med Rehabil 2001;82:1155-63.
Arch Phys Med Rehabil Vol 87, June 2006
50. Hulme A, MacLennan WJ, Ritchie RT, John VA, Shotton PA. Baclofen in the elderly stroke patient: its side-effects and pharmacokinetics. Eur J Clin Pharmacol 1985;29:467-9. 51. Brin M, Aoki KR, Dressler D. Pharmacology of botulinum toxin therapy In: Brin MF, Comella C, Jankovic J, editors. Dystonia: etiology, clinical features, and treatment. Philadelphia: Lippincott, Williams & Wilkins; 2004. p 93-112. 52. Aoki RA. Botulinum neurotoxin serotypes A and B preparations have different safety margins in preclinical models of muscle weakening efficacy and systemic safety. Toxicon 2002;40:923-8. 53. Aoki KR. A comparison of the safety margins of botulinum neurotoxin serotypes A, B, and F in mice. Toxicon 2001;39:1815-20. 54. Brashear A, McAfee AL, Kuhn ER, Ambrosius WT. Treatment with botulinum toxin type B for upper-limb spasticity. Arch Phys Med Rehabil 2003;84:103-7. 55. Gormley ME Jr, O’Brien CE, Yablon SA. A clinical overview of treatment decisions in the management of spasticity. Muscle Nerve 1997;20(Suppl 6):S14-20. 56. Defazio G, Abbruzzese G, Girlanda P, et al. Botulinum toxin A treatment for primary hemifacial spasm: a 10-year multicenter study. Arch Neurol 2002;59:418-20. 57. Hsiung GY, Das SK, Ranawaya R, Lafontaine AL, Suchowersky O. Long-term efficacy of botulinum toxin A in treatment of various movement disorders over a 10-year period. Mov Disord 2002;17:1288-93. 58. Naumann M, Jankovic J. Safety of botulinum toxin type A: a systematic review and meta-analysis. Curr Med Res Opin 2004; 20:981-90. 59. Turkel C, Bowen B, Liu J, Brin M. A pooled analysis of the safety of botulinum toxin type A in the treatment of poststroke spasticity [abstract]. Arch Phys Med Rehabil 2004;85:E8. 60. Allergan Inc. A multicenter study evaluating the utility of clinical scales for measuring functional changes in patients with focal, upper-limb spasticity poststroke. Irvine: Allergan; 2003. Internal study report 191622-044. 61. Turkel C, Dru R, Liu J. Double-blind, randomized, dose-ranging study of BOTOX (botulinum toxin type A) purified neurotoxin complex for treating focal spasticity poststroke [abstract]. Naunyn Schmiedebergs Arch Pharmacol 2002;365(Suppl 2):R47 ABS155. 62. de Beyl DZ, Csiba L, Yakovleff A, et al. A multicenter, doubleblind, placebo-controlled trial to evaluate dosing, safety, and efficacy of intramuscular botulinum toxin type A for the management of upper limb spasticity post-stroke [abstract]. Eur J Neurol 2000;7(Suppl 3):23 ABS SC-44. 63. Allergan Inc. A two part multicentre study of BOTOX (botulinum toxin type A) in the treatment of lower-limb spasticity during stroke rehabilitation (part I – double-blind, placebo-controlled, parallel, randomised & part II – open label follow up). Irvine: Allergan; 2002. Internal study report BTOX-702-8051. 64. Allergan Inc. A randomized, double-blind, placebo-controlled, clinical trial to evaluate the safety, efficacy and dosing of BOTOX (botulinum toxin type A) purified neurotoxin complex for the treatment of lower limb spasticity in post-stroke patients. Irvine: Allergan; 2001. Internal study report BTOX-138/139-8051. 65. Allergan Inc. A multicenter, randomized, double-blind, placebocontrolled, clinical trial to evaluate the safety, dosing and efficacy of a single dose of BOTOX (botulinum toxin type A) purified neurotoxin complex for the management of lower limb spasticity after stroke. Irvine: Allergan; 2001. Internal study report 191622501.