Post-stroke distal lower limb spasticity impairs mobility, limiting activities of daily living, requiring additional caregiver time.
Background. OnabotulinumtoxinA injections improve upper-limb spasticity after stroke, but their effect on arm function remains uncertain.
Objective. To determine whether a single treatment with onabotulinumtoxinA injections combined with upper-limb physiotherapy improves grasp release compared with physiotherapy alone after stroke.
Methods. A total of 28 patients, at least 1 month poststroke, were randomized to receive either onabotulinumtoxinA or placebo injections to the affected upper limb followed by standardized upper-limb physiotherapy (10 sessions over 4 weeks). The primary outcome was time to release grasp during a functionally relevant standardized task. Secondary outcomes included measures of wrist and finger spasticity and strength using a customized servomotor, clinical assessments of stiffness (modified Ashworth Scale), arm function (Action Research Arm Test [ARAT], Nine Hole Peg Test), arm use (Arm Measure of Activity), Goal Attainment Scale, and quality of life (EQ5D).
Results. There was no significant difference between treatment groups in grasp release time 5 weeks post injection (placebo median = 3.0 s, treatment median = 2.0 s; t(24) = 1.20; P = .24; treatment effect = −0.44, 95% CI = −1.19 to 0.31). None of the secondary measures passed significance after correcting for multiple comparisons. Both groups achieved their treatment goals (placebo = 65%; treatment = 71%), and made improvements on the ARAT (placebo +3, treatment +5) and in active wrist extension (placebo +9°, treatment +11°).
Conclusions. In this group of stroke patients with mild to moderate spastic hemiparesis, a single treatment with onabotulinumtoxinA did not augment the improvements seen in grasp release time after a standardized upper-limb physiotherapy program.
The US Food and Drug Administration (FDA) has approved onabotulinumtoxinA (Botox, Allergan) to ease lower-limb spasticity in children and adolescents aged 2 years to 17 years, excluding spasticity caused by cerebral palsy (CP), Allergan announces.
“Lower limb spasticity can impact many aspects of a child’s life and have a drastic influence on their overall development and quality of life,” David Nicholson, Allergan’s chief research and development officer, says in a news release.
The FDA approved Botox for lower-limb spasticity on the basis of safety and efficacy data from a phase 3 study involving more than 300 children aged 2 years or older with lower-limb spasticity.
Participants in the trial had CP, but the approved indication excludes lower-limb spasticity caused by CP, owing to marketing exclusivity by another company, according to Allergan.
The approved recommended dose per treatment session is 4 to 8 units/kg divided among affected muscles of the lower limb. The total dose for pediatric patients should not exceed 8 units/kg body weight, or 300 units, whichever is lower.
When treating both lower limbs or upper and lower limbs in combination, the total dose for pediatric patients should not exceed 10 units/kg, or 340 units, whichever is lower, in a 3-month interval, the company states.
“Pediatric lower limb spasticity inhibits normal muscular movement and function and can result in delayed or impaired motor development, as well as difficulty with posture and positioning,” Mark Gormley, Jr, MD, of Gillette Children’s Specialty Healthcare–St. Paul, comments, in the release.
“Botox has a well-established safety and efficacy profile, and supports children and adolescents successfully manage both their upper and lower limb spasticity,” said Gormley.
Botox was approved for pediatric upper-limb spasticity in June.
By Benn Jason Scott Boshell, MSc, BSc (Hons)
When people hear the word “Botox,”a their immediate associations might be with facial injection as an anti-wrinkle treatment or magazine gossip on the latest celebrity to suffer a “botch job” from one-too-many injections. Prior to the modern use of this acetylcholine-blocking neurotoxin, no one other than medical professionals who used it to treat their patients really knew what Botox is. Injections were originally used to treat neurological conditions that result in spastic paralysis, such as cerebral palsy.
In addition to managing neurological conditions and, more recently, for aesthetic enhancement, Botox is now being used to treat musculoskeletal disorders. One of these conditions is plantar fasciitis, the subject of this narrative review of the literature.b
a. Botox, the registered trade name of onabotulinumtoxinA, is used in this article for ease of reading.
b. Treatment of plantar fasciitis is not a US Food and Drug Administration-approved indication for Botox®.
Botox is a neurotoxin that blocks release of the neurotransmitter acetylcholine in overactive muscles. Motor neurons release acetylcholine to activate muscles at the neuromuscular junction; Botox, when injected, causes relaxation of muscles and other local soft tissue.
A body of evidence identifies tightness in calf muscles as a causative factor in plantar fasciitis.1-5 Botox injection into the calf aims to relax contracture in calf muscles, thus reducing tensile strain on the plantar fascia as a result of muscle relaxation. Additionally, Botox can be injected into the muscles of the foot to achieve the same effect.
Several clinical studies have looked at the effectiveness of Botox injection for treating plantar fasciitis.
Botox injection compared with corticosteroid injection (2013). Elizondo-Rodriguez and co-workers’ level-1, double-blind, randomized controlled trial compared Botox injection to corticosteroid injection for the treatment of plantar fasciitis.6The study randomized participants into 2 groups:
Results of treatment were recorded at 2 weeks and at 1, 2, 4, and 6 months. No significant improvement was seen in either group after the initial 2-week review. However, both groups showed significant improvement in pain scores at 1 month. At 2-, 4-, and 6-months follow-up, the Botox group had significantly better pain scores than the corticosteroid group. At the final, 6-month review, the average pain score in the Botox group was 1.1 (on a scale of 1 to 10, with 10 the “worst pain”), a reduction from 7.1 (difference of 6 points); in the corticosteroid group, the average pain score was 3.8, a reduction from 7.7 (difference of 3.9 points).
Elizondo-Rodriguez therefore concluded that Botox injection is superior to corticosteroid injection for the treatment of plantar fasciitis over the short term and mid-term. A limitation of this study is that patients were not followed over a longer period; it is not known, therefore, whether participants would have maintained their improved pain scores 12 months’ posttreatment. Longer follow-up would help ascertain whether Botox is also successful in the long-term management of plantar fasciitis.
A particular point of interest from the Elizondo-Rodriguez study is that Botox was not injected into or around the plantar fascia but into the gastrocnemius and soleus muscles. Following injection, calf muscles went into a state of relaxation, due to the effect of Botox. It is believed that this relaxation reduced additional strain on the plantar fascia that results from increased calf-muscle tension. One could argue that this approach seeks to address the purported cause of plantar fasciitis—unlike corticosteroid injection, which aims to treat symptoms.
Figure 1: Medial (a) and plantar (b) views of the injection entry point for study patients. This is at the distal aspect of the plantar-medial aspect of the calcaneus where the plantar fascia is proximal and the flexor digitorum brevis is adjacent. The X marks the most common spot injected for patients based on their maximum point tenderness. The circle around the X is a 1.5-cm radius where some patients received their injection based on their maximum point of tenderness (used with permission from reference 12).
Botox injection compared with corticosteroid injection (2012). Díaz-Llopis and colleagues also compared Botox injection with corticosteroid injection.7 Their study was likewise a randomized, controlled trial, with 28 patients in each group. As in the Elizondo-Rodriguez study,6 Díaz-Llopis found both that Botox and corticosteroid injections were successful at 1-month review; however, the difference between the 2 treatments grew at 6 months, with the Botox group continuing to improve while the steroid group grew slightly worse.
Long-term follow-up of sustained effects of Botox injection (2013). The lead Díaz-Llopis investigator and a different group of co-workers8 returned to the findings of the original Díaz-Llopis study,7 conducting a 12-month follow-up of the 2012 Botox group to determine whether reported improvements were sustained over the long term, which they were. Their findings provide evidence to support the use of Botox injection as a long-term treatment option.
(Notably, the site of the Botox injection in the 2012 Díaz-Llopis study differed from the site used in the Elizondo-Rodriguez study. Instead of injecting into calf muscles, Díaz-Llopis injected Botox into the plantar fascia attachment to the heel bone and further along the arch of the foot; they decided to use this technique based on a 2005 study by Babcock and co-workers.9 By using the same injection technique that Babcock used, Díaz-Llopis and colleagues were able to determine whether they would achieve similar success.)
Botox injection compared with corticosteroid injection (2018). In a randomized, controlled trial reported this year, Roca and co-workers found Botox superior to corticosteroid injection.10
Botox injection compared with placebo. Babcock and colleagues compared Botox injection and placebo in a double-blind, randomized, placebo-controlled study in 27 patients with plantar fasciitis.9 Results were recorded at 3 weeks and 8 weeks; improvement observed in the Botox group was significantly greater than in the placebo group. The strength of the study was limited by short-term follow-up.
Other studies have also compared Botox injection with placebo and found Botox to be significantly more effective.11,12 Ahmad and colleagues,12 in a double-blind, randomized, controlled trial of 50 patients (25 in each group) found Botox injection to be significantly superior to placebo at 6-month and 12-month reviews (Figure 1). The Botox group also showed significant reduction in plantar fascia thickness, which demonstrated healing of the degenerative plantar fascia—a finding not seen in the control group. A further benefit of Botox injection in this study was that it did not reduce heel fat-pad thickness, a commonly reported complication of corticosteroid injection.
Conversely, a similar study that compared Botox injection and placebo found only a marginal difference in improvement between the 2 groups:13 63.1% of the Botox group perceived improvement compared to 55% of the placebo group.
Botox injection compared with extracorporeal shockwave therapy (ESWT). Roca and co-workers’ study14 is interesting because ESWT has become an established, successful treatment option for plantar fasciitis.15 Because Botox injection is considered a novel treatment with less evidence of effectiveness, comparing it with an established treatment can be considered a good test of its effectiveness.
The Roca study randomized patients to 2 groups, 36 in each group. The researchers found both treatments effective—i.e., both demonstrated improved pain scores after treatment. However, ESWT came out on top, producing a greater reduction in pain than Botox injection.
A limitation of this study is that the researchers reviewed patients only 1 to 2 months after treatment. As noted, previous studies of Botox injection demonstrate continued improvement in pain score with more time. It is possible that the Botox group would have seen greater improvement in pain score if the researchers had reviewed that group at 6 and 12 months (although the same possibility can be considered for the ESWT group).
Botox injection is generally safe; major adverse effects are uncommon when injection is administered by a suitably qualified clinician. There is a possibility (although highly unlikely) that the effect of botulinum toxin will spread to other parts of the body and cause botulism-like signs and symptoms, including:
Overall, it appears that the evidence for Botox injection as a treatment for plantar fasciitis is sufficiently strong to support its use. Nearly all current studies of moderate- to high-quality demonstrate significant success with this treatment option.
Despite that conclusion, Botox injection is not a commonly used treatment option and—in the United Kingdom—is not widely available for treating plantar fasciitis; in the United States, Botox injection is not indicated by the Food and Drug Administration for treating plantar fasciitis. Nevertheless, Botox injection deserves greater study and consideration for its applicability to clinical practice for treating plantar fasciitis. This therapy might replace commonly used corticosteroid injection for plantar fasciitis, which has 1) a lower success rate over the long term and 2) an increased risk of harmful effects, including plantar fascia rupture.
The most effective Botox injection technique remains in question. In most studies, plantar fascia and surrounding tissue were injected directly; in some, calf muscles were injected. To determine which technique is better, it will be necessary to conduct a head-to-head trial of these 2 techniques.
Benn Jason Scott Boshell MSc, BSc (Hons) is clinical lead podiatrist at Hatt Health & Movement Clinic, Devizes, United Kingdom.
Spasticity is a common occurrence following stroke, with an estimated 20% to 40% of patients developing spasticity that hampers activities of daily living (ADL). Lower limb spasticity in particular is associated with impairments of gait and mobility.1
Several types of therapy are available to facilitate post-stroke recovery of movement, including the use of botulinum toxin injections, as well as physical therapy and anti-spasmodic medications as first-line options. Other therapies such as ultrasound, magnetic stimulation, and transcutaneous electrical stimulation may be added to the treatment plan to improve motor performance, but no one treatment stands out as superior to the others. In the most severe and persistent cases, surgery is a final option.
Improvements with these therapies are often less than optimal, according to David M. Simpson, MD, FAAN, director, Clinical Neurophysiology Laboratories and director of the neuromuscular division, Icahn School of Medicine, Mount Sinai Medical Center in New York City. He told Neurology Advisor, “Treatment goals are individualized for each patient. In some more severely affected patients, only passive goals are possible, such as improvement in limb position, caregiver dressing, or applying braces. In others, higher level active functional goals are possible, such as improved arm use and gait.”
In an interview with Neurology Advisor, Randie M. Black-Schaffer, MD, MA, medical director of the stroke program, director of the Stroke Research and Recovery Institute at Spaulding Rehabilitation Hospital in Boston, Massachusetts, and assistant professor of physical medicine and rehabilitation, Harvard Medical School in Cambridge, Massachusetts, explained the common clinical approach to these rehabilitative therapies. “Typically, physical medicine and rehabilitation physicians (physiatrists) recommend physical therapy first to see if a regular stretching program for the spastic muscles will adequately control the muscle tone. If not, the second option is a trial of muscle relaxant medications, [al]though the sedative effects of these medications often limit or preclude their use in neurologically impaired patients. If neither of these approaches provides adequate relief, the next step would be to evaluate the patient for botulinum toxin injections and/or phenol nerve block.”
Botulinum Toxin Type A for Spasticity
“Botulinum toxin is proven as a safe and effective treatment for spasticity and is FDA [US Food and Drug Administration]-approved for that indication,” reported Dr Simpson, who is the co-investigator in several studies on botulinum toxin for upper limb spasticity.2-4 “While there are few head-to-head studies of other treatments, we have published a placebo-controlled trial showing superior tolerability and efficacy of onabotulinumtoxinA compared with oral tizanidine (TZD) for upper extremity spasticity,” he said.2 That study concluded that botulinum toxin was both safer and more effective than TZD in reducing tone and disfigurement in upper extremity spasticity and recommended that it be used as first-line therapy.2
“In the lower extremities, these injections are effective in reducing spastic equinovarus posturing, painful toe flexion, stiff knee, flexed knee posturing, and scissoring leg movements that can interfere with gait, positioning, and/or hygiene,” Dr Black-Schaffer said. “In the upper extremities, injections can reduce painful shoulder adduction, and hand clenching, as well as excessive elbow flexion.”
“The effect of injections usually starts 3 to 8 days after the injections, peaks at 2 to 3 weeks, and lasts for 2-1/2 to 3 months,” Dr Black-Schaffer noted, adding that, “There’s no medical contraindication to repeated botulinum toxin injections in the same muscles over time. Gradually, after years of botulinum toxin injections to the same muscles, they develop some degree of atrophy, which may enable reduction of the dose.”
The main constraint to botulinum toxin use for spasticity is dosage limitation. Concerns over the potential development of resistant antibodies from too frequent injections that might reduce the therapeutic efficacy of the agent led to restrictions of total dosage to a maximum of 400 units every 3 months. As Dr Black-Schaffer pointed out, “Many patients after a stroke have spasticity throughout both their affected arm and affected leg, with many more muscles involved than a physician can inject, given that limitation. So, the physician must evaluate the patient carefully to decide which muscles it will be most helpful to inject and why.”
Dr Black-Schaffer outlined her rationale for determining when to use botulinum toxin following stroke. “The usual reasons for injecting [a patient] are to improve function or ease of ADL performance. For example, it is often possible to increase gait speed and cadence and reduce gait deviations such as inversion and hip hiking by injection of the plantar-flexor and invertor muscles of the effected leg,” she said. “A third reason is to reduce pain that may be caused by the muscle stiffness. An example is painful shoulder due to severe adductor tone in the arm, which can be significantly improved by botulinum toxin injection to the pectoralis major muscle. This may not improve the patient’s ability to move the arm, but can reduce pain with passive abduction, [such] as for bathing and dressing.”
Phenol nerve block injections are also commonly used as a botulinum-toxin-sparing strategy, she reported, explaining that phenol nerve block is an older technique utilized extensively before botulinum toxin became available, that can have muscle-relaxing effects similar to botulinum toxin in large muscles, such as the hip adductors, plantar flexors, and invertors of the affected leg. Injecting phenol into the obturator nerve, for example, reduces contractility of all the hip adductor muscles, saving doses of botulinum toxin for other smaller sites phenol does not have effects on, according to Dr Black-Schaffer.
Dr Simpson pointed to the need to begin therapy when spasticity is first detected. “As soon as spasticity is functionally disabling, one might consider treatment with botulinum toxin,” he said. “Once spasticity has become established in a patient’s muscles, it rarely resolves spontaneously,” Dr Black-Schaffer added.
Some patients, however, have such severe spasticity that 400 units of botulinum toxin provides little relief. “For those patients, there are additional treatment options, including the intrathecal baclofen pump and surgical lengthening of the tendons of specific spastic muscles. The baclofen pump can relieve muscle stiffness with less baclofen and less sedation than when the patient takes baclofen by mouth,” Dr Black-Schaffer said, adding that, “On the other hand, the baclofen pump is more effective for lower than upper extremity spasticity and requires visits to a specialized center several times per year for refills. In addition, there are several possible complications such as catheter dislodgement, breakage, and pump site infection, and the pump itself must be surgically replaced when its battery dies.”
Post-stroke distal lower limb spasticity impairs mobility, limiting activities of daily living, requiring additional caregiver time.
To evaluate the efficacy, safety, and sustained benefit of onabotulinumtoxinA in adults with post-stroke lower limb spasticity (PSLLS).
A multicenter, randomized, double-blind, phase 3, placebo-controlled trial.
60 study centers across North America, Europe, Russia the United Kingdom, and South Korea.
Adult patients (18 to 65 years of age) with PSLLS (Modified Ashworth Scale [MAS] ≥3) of the ankle plantar flexors and the most recent stroke ≥3 months prior to study enrollment. .
During the open-label phase, patients received ≤3 onabotulinumtoxinA treatments (≤400 U) or placebo at approximately 12-week intervals. Treatments were into the ankle plantar flexors (onabotulinumtoxinA 300 U into ankle plantar flexors; ≤100 U, optional lower limb muscles).
The double-blind primary endpoint was MAS change from baseline (average score at weeks 4 and 6). Secondary measures included physician-assessed Clinical Global Impression of Change (CGI), MAS change from baseline in optional muscles, Goal Attainment Scale (GAS), and pain scale.
Of 468 patients enrolled, 450 (96%) completed the double-blind phase and 413 (88%) completed the study. Small improvements in MAS observed with onabotulinumtoxinA during the double-blind phase (onabotulinumtoxinA, –0.8; placebo, –0.6, P=0.01) were further enhanced with additional treatments through week 6 of the third open-label treatment cycle (onabotulinumtoxinA/onabotulinumtoxinA, –1.2; placebo/onabotulinumtoxinA, –1.4). Small improvements in CGI observed during the double-blind phase (onabotulinumtoxinA, 0.9; placebo, 0.7, P=0.01) were also further enhanced through week 6 of the third open-label treatment cycle (onabotulinumtoxinA/onabotulinumtoxinA, 1.6; placebo/onabotulinumtoxinA, 1.6). Physician- and patient-assessed GAS scores improved with each subsequent treatment. No new safety signals emerged.
OnabotulinumtoxinA significantly improved ankle MAS, CGI, and GAS scores compared with placebo; improvements were consistent and increased with repeated treatments of onabotulinumtoxinA over 1 year in patients with PSLLS.
Clinical Trial Registration URL: https://clinicaltrials.gov/ct2/show/NCT01575054?term=NCT01575054&rank=1
Objective: The main aim of this study was to determine
the utilization patterns and effectiveness of onabotulinumtoxinA (Botox®) for treatment of spasticity in clinical practice.
Design: An international, multicentre, prospective, observational study at selected sites in North America, Europe, and Asia.
Patients: Adult patients with newly diagnosed or established focal spasticity, including those who had previously received treatment with onabotulinumtoxinA.
Methods: Patients were treated with onabotulinumtoxinA, approximately every 12 weeks, according to their physician’s usual clinical practice over a period of up to 96 weeks, with a final follow-up interview at 108 weeks. Patient, physician and caregiver data were collected.
Results: Baseline characteristics are reported. Of the 745 patients enrolled by 75 healthcare providers from 54 sites, 474 patients had previously received onabotulinumtoxinA treatment for spasticity. Lower limb spasticity was more common than upper limb spasticity, with stroke the most common underlying aetiology. The Short-Form 12 (SF-12) health survey scores showed that patients’ spasticity had a greater perceived impact on physical rather than mental aspects.
Conclusion: The data collected in this study will guide the development of administration strategies to optimize the effectiveness of onabotulinumtoxinA in the management of spasticity of various underlying
Background: OnabotulinumtoxinA (BoNT-A) can temporarily decrease spasticity following stroke, but whether there is an associated improvement in upper limb function is less clear. This study measured the benefit of adding weekly rehabilitation to a background of BoNT-A treatments for chronic upper limb spasticity following stroke. Methods: This was a multi-center clinical trial. Thirty-one patients with post-stroke upper limb spasticity were treated with BoNT-A. They were then randomly assigned to 24 weeks of weekly upper limb rehabilitation or no rehabilitation. They were injected up to two times, and followed for 24 weeks. The primary outcome was change in the Fugl–Meyer upper extremity score, which measures motor function, sensation, range of motion, coordination, and speed. Results: The ‘rehab’ group significantly improved on the Fugl–Meyer upper extremity score (Visit 1 = 60, Visit 5 = 67) while the ‘no rehab’ group did not improve (Visit 1 = 59, Visit 5 = 59; p = 0.006). This improvement was largely driven by the upper extremity “movement” subscale, which showed that the ‘rehab’ group was improving (Visit 1 = 33, Visit 5 = 37) while the ‘no rehab’ group remained virtually unchanged (Visit 1 = 34, Visit 5 = 33; p = 0.034). Conclusions: Following injection of BoNT-A, adding a program of rehabilitation improved motor recovery compared to an injected group with no rehabilitation.
Continue—> Toxins | Free Full-Text | Rehabilitation plus OnabotulinumtoxinA Improves Motor Function over OnabotulinumtoxinA Alone in Post-Stroke Upper Limb Spasticity: A Single-Blind, Randomized Trial | HTML
To investigate a new botulinum neurotoxin type A, termed letibotulinumtoxinA(Botulax®) and compare its efficacy and safety for post-stroke upper limb spasticity with that of onabotulinumtoxinA(Botox®).
A prospective, double-blinded, multicenter, randomized controlled clinical study.
Six university hospitals in Korea.
A total of 187 stroke participants with upper limb spasticity.
Two kinds of botulinum neurotoxin type A were used. One set of injection was performed and total injected doses were 309.21±62.48U(Botulax) and 312.64±49.99U(Botox)(P>0.05).
Primary outcome was measured using the modified Ashworth scale for wrist flexors at week 4 and secondary outcome was measured using modified Ashworth scale for wrist flexors, elbow flexors, finger flexors, and thumb flexors as well as Global Assessment in spasticity, Disability Assessment Scale, and Caregiver Burden Scale. Safety measures including adverse events, vital signs and physical examination, and laboratory tests were also monitored.
The mean ages for the Botulax group were 56.81±9.49 and which for the Botox group were 56.93±11.93(P>0.05). In primary outcome, the change in modified Ashworth scale for wrist flexors was -1.45±0.61 in the Botulax group and -1.40±0.57 in the Botox group, and the difference between the two groups was -0.06(95% CI:-0.23–0.12,P>0.05). In secondary outcome, both groups demonstrated significant improvements with respect to modified Ashworth scale, Global Assessment in spasticity, Disability Assessment Scale, and Caregiver Burden Scale (P<0.05), and no significant difference was observed between the two groups (P>0.05). In addition, safety measures showed no significant differences between the two groups (P>0.05).
The efficacy and safety of Botulax were comparable with those of Botox in treatment of post-stoke upper limb spasticity.
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Patients with post-stroke spasticity (PSS) commonly experience pain in affected limbs, which may impact quality of life.
To assess onabotulinumtoxinA for pain in patients with PSS from the BOTOX® Economic Spasticity Trial, a multicenter, randomized, double-blind, placebo-controlled trial.
Patients with PSS (N=273) were randomized to 22- to 34-weeks double-blind treatment with onabotulinumtoxinA + standard care (SC) or placebo injection + SC and were eligible to receive open-label onabotulinumtoxinA up to 52 weeks. Assessments included change from baseline on the 11-point pain numeric rating scale, proportion of patients with baseline pain ≥4 achieving ≥30% and ≥50% improvement in pain, and pain interference with work at week 12, end of double-blind treatment, and week 52.
At baseline, most patients (74.3%) experienced pain and 47.4% had pain ≥4 (pain subgroup). Mean pain reduction from baseline at week 12 was significantly greater with onabotulinumtoxinA + SC (–0.77, 95% CI –1.14 to –0.40) than placebo + SC (–0.13, 95% CI –0.51 to 0.24; P < 0.05). Higher proportions of patients in the pain subgroup achieved ≥30% and ≥50% reductions in pain at week 12 with onabotulinumtoxinA + SC (53.7% and 37.0%, respectively) compared with placebo (28.8% and 18.6%, respectively;P<0.05). Reductions in pain were sustained through week 52. Compared with placebo + SC, onabotulinumtoxinA consistently reduced pain interference with work.
This is the first randomized, placebo-controlled trial demonstrating statistically significant and clinically meaningful reductions in pain and pain interference with work with onabotulinumtoxinA in patients with PSS.
Pain prevalence varies widely (10–70%) among post-stroke patients 1, 2, 3 and 4. Several mechanisms may contribute to this range (e.g., peripheral nerve damage, soft tissue trauma, central post-stroke pain, complex regional pain syndrome 5, 6, 7 and 8). Spasticity and pain are factors contributing to “learned non-use” of the affected limb and are often disabling, interfering with daily activities, sleep, walking, physiotherapy, leisure activities, and ultimately affecting patients’ quality of life 9, 10 and 11.
In randomized, double-blind, placebo-controlled trials, onabotulinumtoxinA has been shown to significantly reduce excess muscle tone and decrease disability among patients with upper-limb spasticity 12 and 13, and to further reduce spasms and improve gait in patients with lower-limb spasticity 14 and 15. OnabotulinumtoxinA is effective at reducing pain in patients with cervical dystonia and chronic migraine 16. Prospective open-label studies have shown that onabotulinumtoxinA can reduce pain in patients with post-stroke spasticity (PSS) 8, 17 and 18. However, the efficacy of onabotulinumtoxinA in reducing pain in patients with PSS has not been demonstrated in a large, randomized, placebo-controlled study.
The BOTOX® Economic Spasticity Trial (BEST) was a prospective clinical trial designed to compare the efficacy of onabotulinumtoxinA or placebo (in addition to standard care [SC]) in helping patients with PSS achieve their personal functional goals 19. Here we present results from BEST comparing the effectiveness of onabotulinumtoxinA + SC versus placebo + SC on pain.
Abstract: Poststroke spasticity affects up to one-half of stroke patients and has debilitating effects, contributing to diminished activities of daily living, quality of life, pain, and functional impairments. Botulinum toxin (BoNT) is proven to be safe and effective in the treatment of focal poststroke spasticity. The aim of this review is to highlight BoNT and its potential in the treatment of upper and lower limb poststroke spasticity. We review evidence for the efficacy of BoNT type A and B formulations and address considerations of optimal injection technique, patient and caregiver satisfaction, and potential adverse effects of BoNT.
Spasticity is a velocity-dependent increase in muscle tone as a part of the upper motor neuron syndrome and is seen in a wide variety of neurologic diseases including stroke.1 Poststroke spasticity can develop as early as 1 week after stroke,2 and it is estimated to occur in up to one-half of stroke survivors.3 The most frequent predictors of spasticity include weakness and reduced motor control.2 Long-term spasticity may lead to tendon contractures and limb deformities that can cause significant pain and functional impairment. Depending on the location of the spasticity, this can impact mobility, activities of daily living such as toileting, dressing, and transferring, and quality of life (QoL) and increase the dependence on caregivers.4
The aim of the treatment in poststroke spasticity is focused on muscle limb overactivity reduction. Treatment modalities are used to alleviate spasticity including physical therapy, systemic and intrathecal medications, and surgery. Systemic medications can be helpful if spasticity is generalized. Agents such as baclofen (gamma-aminobutyric acid [GABA]-B receptor agonist) diazepam (GABA-A receptor agonist), dantrolene (decreases calcium release from skeletal muscle sarcoplasmic reticulum), or tizanidine (TZD; alpha-2 adrenergic receptor agonist) often have systemic side effects such as dry mouth, dizziness, sedation, or generalized weakness.5 After several months of treatment, tolerance may develop to systemic medications.
Chemodenervation and neurolytic procedures with alcohol or phenol may be utilized as second-line management. These techniques are more localized and are injected perineurally to destroy the nerve causing spasticity. The effect may be limited by partial nerve regeneration and adverse effects such as bladder, bowel, and sexual dysfunction.6 Intrathecal baclofen acts on GABA receptors in the lumbar spinal cord and may improve walking speed and functional mobility in poststroke spasticity. However, this therapy is invasive and limited by side effects including nausea, vomiting, and urinary retention. Overdosing may lead to death.7,8
The aim of this review is to highlight botulinum toxin (BoNT) and its potential in the treatment of upper and lower limb poststroke spasticity. Optimal treatment may include BoNT injections into focal muscles in conjunction with an integrated multidisciplinary team approach and intensive rehabilitation programs or to help utilize affected muscles.9 Higher-intensity rehabilitation programs (≥3 1-hour weekly session for ~10 weeks) may help patients achieve more upper limb goals following BoNT injections for spasticity when compared with usual care programs (≤2 1-hour weekly sessions).10 A recent consensus panel of 44 neurologists and physiatrists with experience in BoNT therapy recommended starting a rehabilitation program during the first week after BoNT injection therapy.11