PharmacotherapyReview articleContemporary Pharmacologic Treatments for Spasticity of the Upper Limb After Stroke: A Systematic Review
Introduction
Stroke is the third leading cause of death in the United States and the leading cause of long-term disability.1 It has been reported that up to 80% of stroke patients may have motor impairment immediately after the event.2 One manifestation of this motor impairment is muscle spasticity, which can be defined as a velocity-dependent increase in resistance to passive stretch or movement.3 Upper motor neuron lesions—caused by injury to the central nervous system (CNS) secondary to stroke, multiple sclerosis, cerebral palsy, head trauma, or spinal cord trauma—result in abnormal signaling between the CNS and the muscles, leading to muscle excitability.3 Upper motor neuron syndrome may present as positive symptoms (eg, spasticity) or negative symptoms (eg, muscle weakness, decreased dexterity).3 Poststroke spasticity up to 1 year after the event has been reported to occur in 17% to 38% of patients.4, 5, 6
The goals of treatment for patients with poststroke spasticity are to reduce pain, decrease spasm frequency, achieve better limb position, facilitate patient care, reduce muscle tone, and increase passive range of motion.7, 8 A variety of treatment modalities are used to manage this condition.8, 9 In addition to physical and occupational therapy, oral medications (eg, baclofen, dantrolene, tizanidine [TZD], benzodiazepines) may be used, particularly in patients with generalized spasticity or spasticity in multiple locations in whom there is a need for systemic treatment8; patients with refractory or severe spasticity may require surgery. Fewer agents are available for the treatment of focal spasticity (ie, spasticity in smaller, more localized areas), such as upper limb spasticity. Spasticity in the fingers, wrists, elbows, or other areas of the arm may limit the ability to perform activities of daily living, including feeding, washing, and dressing. Thus, treatments that are administered locally to reduce spasticity in the upper limbs would have the potential to improve outcomes in these patients. Chemodenervation with phenol or ethyl alcohol has been used for focal spasticity.10 Botulinum toxin (BTX) agents, given by intramuscular injection, are also available for the treatment of localized spasticity.
BTX agents are increasingly being used by clinicians as treatment options for patients with focal upper limb spasticity. Three BTX agents are commercially available in the United States: 2 BTX type A (BTX-A) formulations (onabotulinumtoxinA⁎11 and abobotulinumtoxinA†12) and 1 BTX type B (BTX-B) formulation (rimabotulinumtoxinB‡13). However, until March 2010, when the FDA approved onabotulinumtoxinA for the treatment of spasms of the elbow, wrist, and fingers, none of these products had been approved for the treatment of arm spasticity. Although not limited to patients with poststroke spasticity, the new indication is clearly relevant to the treatment of upper limb spasticity after stroke.
The most recent American Stroke Association clinical practice guideline for the management of adult stroke rehabilitation care recommended consideration of “use of tizanidine [particularly for chronic stroke patients], dantrolene and oral baclofen for spasticity resulting in pain, poor skin hygiene, or decreased function.”14 The quality of the evidence for this recommendation was rated II-1 (based on at least one well-designed, nonrandomized controlled trial), the overall quality of the evidence was rated fair (high-grade evidence [I or II-1] linked to intermediate outcomes or moderate-grade evidence [II-2, II-3] linked directly to the health outcome), and the recommendation was rated B (intervention may be useful or effective). In addition, the guideline recommended consideration of “use of BTX or phenol/alcohol for selected patients with disabling or painful spasticity or spasticity resulting in poor skin hygiene or decreased function.” The quality of the evidence for this recommendation was rated I (based on at least 1 properly conducted randomized controlled trial [RCT]), the overall quality was rated fair, and the recommendation was labeled B. The guideline included additional recommendations for the use of intrathecal baclofen (ITB), surgical interventions, and other therapies; however, the quality of the evidence for these recommendations was not as strong as those for the oral and focal treatments.
The most recent American Academy of Neurology guidelines also contain recommendations concerning the use of botulinum neurotoxin (BoNT) in adults and children with spasticity (no specific etiology).15 The recommendation for the use of BoNT in adults with upper limb spasticity states that “BoNT should be offered as a treatment option to reduce muscle tone and improve passive function in adults with spasticity and should be considered to improve active function.” This recommendation, which was based on 11 studies considered to be of high quality, was classified level A, indicating that BoNT was effective and had a favorable adverse-effect profile.
In April 2009, concerns about the safety of BTX products prompted the US Food and Drug Administration (FDA) to issue an alert to health care professionals informing them of the addition of a boxed warning to the prescribing information for these products.16 The boxed warning describes potential adverse events associated with the use of these products, as well as clinically important differences in dosing and potency between formulations. The warning highlights the potential for locally injected toxin to spread to distal sites, causing symptoms consistent with botulism, which in severe cases can be fatal. In addition, the alert announced the revised established generic drug names—from botulinum toxin type A for both BOTOX and Dysport, and from botulinum toxin type B for Myobloc—to their present forms to prevent medication errors and emphasize the differences in potency and dosing of the 3 BTX products. Finally, the alert noted the requirement that these products were to be distributed with a medication guide to ensure that patients and caregivers are fully informed of the associated risks and benefits.
The present systematic review was conducted to identify studies of contemporary pharmacologic treatments for upper limb spasticity after stroke, to evaluate the strength of the study designs, to determine the outcome measures used to evaluate the efficacy or effectiveness of treatments, and to determine whether treatments were effective and well tolerated.
Section snippets
Methods
MEDLINE, EMBASE, and the Cochrane Controlled Trials Register were searched for clinical trials that evaluated treatments for upper limb spasticity secondary to stroke in adults. The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) recommendations were followed, as applicable.17 The search terms, used alone or in combination, were spasticity, spasm, stroke, hemiplegia, phenol, baclofen, tizanidine, dantrolene, benzodiazepine, and botulinum toxin. The search was limited
Results
Figure 1 summarizes the results of the literature search. Of 113 studies reviewed to determine their potential relevance, 59 met 1 or more criteria for exclusion. Of the 54 studies that met the inclusion criteria, 23 were RCTs19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 and 31 were open-label, nonrandomized, uncontrolled, or observational studies (Table II).42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65
Discussion
This systematic review of the current literature produced several key findings. BTX formulations were the most frequently studied (51 of 54 studies), possibly because of their efficacy and favorable adverse-effect profiles. However, there was a paucity of comparative data. The results of studies with robust designs (eg, RCTs) supported the efficacy of BTX in the treatment of upper limb spasticity after stroke, consistent with current guideline recommendations. The 2 studies of ITB48, 49 and the
Conclusions
In this systematic review of the literature, most current trials of treatments for upper limb spasticity after stroke involved BTX formulations. Multiple outcomes were measured (eg, spasticity, functional ability/disability, pain, HRQoL) using a variety of instruments. BTX appeared to be an effective and well-tolerated focal treatment for reducing tonicity in patients with upper limb spasticity after stroke. The findings support current guideline recommendations. However, it is important to
Acknowledgments
Partial funding for this research was provided to the Center for Health Outcomes and PharmacoEconomic Research at the University of Arizona College of Pharmacy by Allergan, Inc., manufacturer of one of the BTX-A products. However, Allergan had no role in the content of the manuscript.
The authors contributed equally to the conception of this systematic review, analysis of the data, and preparation of the manuscript. The authors have indicated that they have no conflicts of interest with regard
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2019, Archives of Physical Medicine and RehabilitationCitation Excerpt :Compared to controls, BoNT treatment leads to a mean postintervention reduction on the ordinal AS or MAS of 0.6 points (12%), with sustained beneficial effects of 0.4 points (8%) at follow-up. The sufficiently powered results are in line with the findings of various published reviews and meta-analyses, which have yielded evidence for a favorable effect of BoNT on the MAS in the elbow, wrist, and fingers (MD range 0.87-0.95).7-15 The lack of effect on the shoulder joint may be explained by difficulties of injection and measurement in this complex joint structure, and interference with frequently reported shoulder pain.69
Botuloscope: 1-year follow-up of upper limb post-stroke spasticity treated with botulinum toxin
2019, Annals of Physical and Rehabilitation MedicineCitation Excerpt :The literature is abundant, but few studies reach high-quality standards. Recent systematic reviews on post-stroke upper limb spasticity [1–4] highlight the weakness of publications dedicated to BoNT-A treatment. Among 22 randomized controlled trials identified, 19 analyzed the effects of a single session of BoNT-A injection; 12 trials included fewer than 50 patients.
Ultrasound Elastography to Assess Botulinum Toxin A Treatment for Post-stroke Spasticity: A Feasibility Study
2019, Ultrasound in Medicine and BiologyCitation Excerpt :BoNT-A can reduce flexor tone at the elbow, wrist and fingers by reducing muscle fiber shortening and increasing stretching reflex ability (Foley et al. 2013). The goals of BoNT-A treatment include improving limb function, increasing passive/active range of motion (ROM), facilitating better hand hygiene, reducing pain and improving the ability to control limb position (Olvey et al. 2010). The treatment requires a reliable measure of spasticity to determine the efficacy of the intervention over time.
Nonsurgical Treatment Options for Upper Limb Spasticity
2018, Hand ClinicsCitation Excerpt :There have been case reports of systemic effects of BoNT, including respiratory compromise and dysphagia, in children with CP and preexisting bulbar dysfunction.48 Larger clinical trials have found these adverse events to be rare in both children and adults.48,49 Concomitant oral medications should be considered for painful ULS because BoNT has a delayed onset of action.
Breakthroughs in the spasticity management: Are non-pharmacological treatments the future?
2017, Journal of Clinical Neuroscience