title: botulinum toxin for spasticity: clinical effectiveness and … · botulinum toxin for...
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TITLE: Botulinum Toxin for Spasticity: Clinical Effectiveness and Guidelines
DATE: 07 April 2016 RESEARCH QUESTIONS
1. What is the clinical effectiveness of botulinum toxin for spasticity in adults? 2. What are the clinical guidelines regarding the use of botulinum toxin for spasticity in
adults? KEY FINDINGS
Eight systematic reviews, five systematic reviews with meta-analyses, and 15 randomized controlled trials were identified regarding botulinum toxin for spasticity in adults. In addition, seven evidence-based guidelines were identified regarding the use botulinum toxin for spasticity in adults. METHODS
A limited literature search was conducted on key resources including PubMed, The Cochrane Library, University of York Centre for Reviews and Dissemination (CRD) databases, ECRI, Canadian and major international health technology agencies, as well as a focused Internet search. Methodological filters were applied to limit retrieval to health technology assessments, systematic reviews, meta-analyses, randomized controlled trials, non-randomized studies, and guidelines. Where possible, retrieval was limited to the human population. The search was also limited to English language documents published between January 1, 2011 and March 23, 2016. Internet links were provided, where available. The summary of findings was prepared from the abstracts of the relevant information. Please note that data contained in abstracts may not always be an accurate reflection of the data contained within the full article.
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Botulinum Toxin for Spasticity 2
SELECTION CRITERIA
One reviewer screened citations and selected studies based on the inclusion criteria presented in Table 1.
Table 1: Selection Criteria
Population Adults with spasticity in any setting; adults in long-term care (residential care homes are a subgroup of interest)
Intervention Botulinum toxin
Comparator No comparator
Placebo
Alternate drug
Non-drug interventions (e.g., form of rehabilitation)
Outcomes Q1: Effectiveness, clinical benefit or harm, safety Q2:
Guidelines and recommendations for use and administration,
Guidelines and recommendations for follow-up and management of patients receiving botulinum toxin
Guidelines and recommendations regarding which patients should receive botulinum toxin
Study Designs Health technology assessment, systematic reviews, meta-analyses,
randomized controlled trials, non-randomized studies, and evidence-based guidelines
RESULTS
Rapid Response reports are organized so that the higher quality evidence is presented first. Therefore, health technology assessment reports, systematic reviews, and meta-analyses are presented first. These are followed by randomized controlled trials and evidence-based guidelines. Eight systematic reviews, five systematic reviews with meta-analyses, and 15 randomized controlled trials were identified regarding botulinum toxin for spasticity in adults. In addition, seven evidence-based guidelines were identified regarding the use botulinum toxin for spasticity in adults. No heath technology assessments were identified, and non-randomized studies were not included due to the volume of systematic reviews and randomized controlled trials identified. Additional references of potential interest are provided in the appendix.
OVERALL SUMMARY OF FINDINGS
Eight systematic reviews,1,4-5,8-10,12-13 five systematic reviews with meta-analyses,2-3,6-7,11 and 15 randomized controlled trials (RCTs) 15-29 were identified regarding botulinum toxin for spasticity in adults. Most of the systematic reviews,1,4,10 systematic reviews with meta-analysis,2-3,6-7,11 and the RCTs12,14-22,24,26-28 provided evidence regarding the efficacy and safety associated with botulinum toxin (types A, B, or unspecified) for the treatment of either lower limb and upper limb spasticity or both. Conversely, there were a few studies that did not observe benefits in patients with spasticity treated with botulinum toxin or observed weak benefits;8,13,23,25 however, these
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Botulinum Toxin for Spasticity 3
studies did observe improvements in some other movements upon treatment. One systematic review recommended instrument-guided injections of botulinum toxin for spasticity treatment,5 another systematic review discussed the potential benefits of chemodenervation with botulinum toxin,12 while another systematic review focused on which muscles were used for injection and the effectiveness therein.9 Detailed study characteristics are provided in Table 2.
Table 2: Summary of Included Studies on Botulinum Toxin for Spasticity in Adults
First
Author, Year
Study Characteristics
Botulinum
Toxin-Type, Doses
Outcomes Conclusions
Systematic Reviews and Meta-Analyses Dashtipour, 2016
1 SR
6 RCTs included
LL spasticity in various etiologies
ABO-BTX-A
500-2000 U (range)
Efficacy
Safety
Dosing practices
All studies showed statistically significant reduction in muscle tone
Generally well tolerated with most AEs considered un-related to tmt
Baker, 20152
SR and MA
LL spasticity 12 PL-controlled
RCTs included; various etiologies
MA of 6 UL and 6 LL studies
BTX-A
One dose (NR)
Relating to leg/arm spasticity o Active function
measures o QoL measures
BTX-A may improve active outcomes in UL
Baker, 20153
SR and MA Ease of care in UL
and LL
32 PL-controlled RCTs included
MA of 11 UL and 3 LL studies
BTX-A Dose NR
Efficacy regarding improving ease of care
BTX-A improves ease of care in UL for up to 6 months
No conclusions possible for LL
Dashtipour, 2015
4 SR
Tmt of UL spasticity 12 RCTs included
ABO-BTX-A
500 – 1500 U (range)
Efficacy
Safety Dosing practices
Strong evidence to support use of ABO for UL spasticity in stroke
ABO generally well tolerated with most AEs considered un-related to tmt
Grigoriu, 2015
5 SR Tmt of BTX-A on
focal spasticity and dystonia
10 studies included (7 RCTs)
BTX-A Dose NR
Effectiveness of instrument guided BTX-A in focal spasticity and dystonia
Results strongly recommend instrument guidance (ES or US) of BTX-A for spasticity tmt in adults and for tmt of focal dystonia such as spasmodic torticollis (EMG)
Baker, 20136
SR and MA 37 studies included
MA on 21 for spasticity
BTX-A Dose NR
Efficacy of BTX-A on spasticity
Use of BTX-A for UL and LL spasticity is supported by moderate quality evidence
Foley, 20137
SR and MA
Post-stroke spasticity in UL
16 RCTs (10 RCTs included in pooled
BTX-A
Dose NR
UL activity capacity or performance
BTX-A associated with moderate UL activity capacity or performance
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Botulinum Toxin for Spasticity 4
Table 2: Summary of Included Studies on Botulinum Toxin for Spasticity in Adults
First Author,
Year
Study Characteristics
Botulinum Toxin-Type,
Doses
Outcomes Conclusions
analysis [n=1,000]) Intiso, 2013
8 SR
Post-stroke spasticity
16 RCTs included
BTX-A
Dose NR
Efficacy
Global functionality of activity daily living
After reduced spasticity there was some improvement in oriented-focused UL movements; however, significant benefit still in doubt
No improvement in global functionality of activity daily living
Nalysnyk, 2013
9 SR Adults with
spasticity
70 studies included (28 RCTs, 5 NRS, 37 single-arm)
ABO Dose NR
Injection patterns Most frequent muscles injected with ABO were wrist, elbow, finger flexors, and ankle plantar flexors
McIntyre, 2012
10 SR
BTX-A for reducing spasticity of LL in chronic stroke survivors
9 RCTs included (n=605)
BTX-A
Dose NR
Effectiveness Effective in reducing LL spasticity when initiated 6 months post-stroke
Wu, 201611
SR and MA
LL spasticity in stroke
7 RCTs (n=603) compared against PL or conventional therapy
BTX; unspecified type
Dose NR
Effectiveness BTX showed persistent clinical benefits in LL spasticity and Fugl-Meyer score
BTX could be a useful and safe strategy for LL spasticity post-stroke
Lui, 201512
SR Limb spasticity after
SCI
19 studies included (9 involving BTX; 10 involving phenol/alcohol)
BTX; unspecified type
Dose NR
Efficacy of chemodenervation
Chemodenervation with BTX may improve function and spasticity in patients with SCI
Phadke, 2014
13 SR Spasticity post-
stroke
Number of included studies NR
BTX; unspecified type
Dose NR
Impact of BTX treated spasticity on standing balance
Weak evidence for balance changes in post-stroke patients following BTX tmt
Randomized Controlled Trials
Elovic, 201614
PL-controlled
UL post-stroke spasticity
N=NR
Inco-BTX-A
1:1 400 U or PL
Efficacy
Tolerability
Significant improvement in UL spasticity and associated disability in patients post-stroke
AEs were mainly mild/moderated; inco-BTX-A well-tolerated
Gracies, 2015
15 DB, PL-controlled
Patients 6 months post-stroke or post-brain injury
ABO-BTX-A
1:1:1 500 U, 1000 U, or PL
Efficacy in UL on muscle tone, spasticity, active movement, and function
ABO-BTX-A provided tone reduction and clinical benefit in hemiparesis
AEs were mild or
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Botulinum Toxin for Spasticity 5
Table 2: Summary of Included Studies on Botulinum Toxin for Spasticity in Adults
First Author,
Year
Study Characteristics
Botulinum Toxin-Type,
Doses
Outcomes Conclusions
N=243 o ABO-BTX-A
500 U (n=81) o ABO-BTX-A
1000 U (n=81) o PL (n=81)
Safety moderate; most common was mild muscle weakness
Nam, 201516
DB, active comparator
Post-stroke UL spasticity
N=197 o NABOTA
(n=99) o ONA-BTX-A
(n=98)
NABOTA
ONA-BTX-A
Efficacy
Safety
NABOTA was non-inferior in efficacy and safety for UL spasticity improvement compared to ONA-BTX-A
Seo, 201517
Active comparator
UL spasticity for stroke patients
N=196
Neuronox
ONA-BTX-A
Efficacy
Safety
Neuronox was equivalent to ONA-BTX-A with regard to efficacy and safety for treating UL spasticity in post-stroke patients
Tao, 201518
PL-controlled
Subacute stroke patients
N=23 o BTX-A (n=11) o PL (n=12)
Early, low dose electrical stimulation-guided BTX-A (200 U)
PL
Gait improvement
Spasticity improvement
Improvement in daily living activities
Early low-dose BTX-A may improve gait, spasticity, and daily living activities
Fietzek, 2014
19 DB, PL-controlled
Patients with stroke, traumatic brain injury or hypoxic encephalopathy and spastic pes equinovarus (unilateral or bilateral)
N=52
ONA-BTX-A (230 U or 460 U)
PL
Efficacy (muscular hypertonicity)
Given 3 months after lesions, ONA-BTX-A reduces muscular hypertonicity in spastic pes equines
Picelli, 201420
Double active comparator
Chronic stoke patients with spastic equinus
N=NR
ONA-BTX-A
Therapeutic ultrasound
TENS
Efficacy Results provide evidence that ONA-BTX-A is more effective for treating spasticity in this population that therapeutic ultrasound and TENS
Guarany, 2013
21 DB, active
comparator, crossover
Patients with clinically meaningful spasticity
N=57
BTX-A (Botox[R])
Prosigne[R] (new BTX serotype A)
Efficacy
Safety
Both Botox[R] and Prosigne[R] are comparable in efficacy and safety for 3 month tmt of spasticity
Yazdchi, DB, active BTX-A Efficacy In comparison with TZD,
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Botulinum Toxin for Spasticity 6
Table 2: Summary of Included Studies on Botulinum Toxin for Spasticity in Adults
First Author,
Year
Study Characteristics
Botulinum Toxin-Type,
Doses
Outcomes Conclusions
201322
comparator Post-stroke UL
spasticity
N=68 o BTX-A (n=34) o TZD (n=34)
TZD Safety BTX-A was effective and safe in reducing post-stroke UL spasticity
Dunne, 2012
23 DB, PL-controlled Post-stroke with
plantarflexor overactivity
N=85 o ONA-BTX-A
200 U (n=28) o ONA-BTX-A
300 U (n=28) o PL (n=29)
ONA-BTX-A (at either 200 U or 300 U)
PL
Efficacy Safety
ONA-BTX-A did not alter local spasticity at 12 weeks; however, it did reduce spasms and improve gait quality
No detectable differences between 2 doses
ONA-BTX-A was safe and well-tolerated
Rosales, 2012
24 PL-controlled Asian patients with
post-stroke patients with UL spasticity
N=163 o BTX-A (n=80) o PL (n=93)
Very early use of: o BTX-A
(500 U) o PL
Effectiveness Safety
BTX-A 500 U, within 2-12 weeks of stroke) provided sustained reduction in UL spasticity when combined with rehabilitation in patients with mild-to moderate hypertonicity and voluntary movement
No differences in AS observed
Shaw, 201125
4 week therapy-controlled
Post-stroke patients with spasticity
N=333
BTX-A + 4-week therapy
4-week therapy
Impairment Activity limitation
Pain
BTX-A unlikely to be useful for spasticity post-stroke; however, may improve basic upper limb tasks and pain
Gracies, 2014
26 DB, PL-controlled
Post-stroke or traumatic brain injury hemiparetic patients with spastic UL muscles
N=24
Rima-BTX-B (10,000 U or 15,000 U)
PL
Efficacy
Safety
Rima-BTX-B (up to 15,000 U) improved active elbow extension and subject-perceived stiffness when injected into spastic UL muscles
Rima-BTX-B was well tolerated
Bollens, 2013
27 SB, active
comparator
Chronic stroke patients with spastic equinovarus of the foot
N=16 o Selective tibial
neurotomy (n=8)
o BTX (n=8)
Selective tibial neurotomy
BTX unspecified
Effectiveness Higher reduction in ankle stiffness was observed with selective tibial neurotomy
Both tmts induced improvement of ankle kinematics during gait
Neither induced muscle weakening
Lam, 201228
DB, PL-controlled Long-term care
patients
N=55
BTX-A PL
Primary outcome: decrease of care burden
Secondary
Patients treated with BTX-A had significant decrease in care burden
Improved scores on
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Botulinum Toxin for Spasticity 7
Table 2: Summary of Included Studies on Botulinum Toxin for Spasticity in Adults
First Author,
Year
Study Characteristics
Botulinum Toxin-Type,
Doses
Outcomes Conclusions
outcomes: o Goal attainment
scale o Measure of
spasticity o Difficulty in
basic UL care
Safety
patient-centered outcomes were also improved with BTX-A tmt
No BTX-A AEs were observed
ABO-BTX-A = AboBotulinumtoxinA; AE = adverse event; BTX = botulinum toxin; BTX-A = botulinum toxin type A; DB = double blind; EMG = electromyogram; ES = electrical stimulation; LL = low er limb; MA = meta-analysis; NABOTA = new Botulinum toxin type A (DWP450); NR = not reported; NRS = non-randomized studies; ONA-BTX-A = onaBotulinum toxin A; PL = placebo; QoL = quality of life; RCT = randomized controlled trial; Rima-BTX-B = rimaBotulinumtoxinB; SB = single-blind; SCI = spinal cord injury; SR
= systematic review; TENS = transcutaneous electrical nerve stimulation ; tmt = treatment; TZD = tizanidine; UL = upper limb; US = ultrasonography.
Of the seven identified guidelines containing information on the use of botulinum toxin for spasticity in adults, three provided recommendations regarding its use in patients with acute or post-acute stroke,30,32,35 two provided statements regarding the lack of recommendations in patients with multiple sclerosis (MS),31,34 one guideline provided recommendations for patients with motor neuron disease (MND),33 and the last guideline provided a statement for making no recommendation for the use of botulinum toxin in patients with MND.29
For patients who have suffered a stroke, Health Quality Ontario and the Ministry of Health and Long-Term Care recommends the use of Clostridium botulinum toxin to, a) relieve spasticity when is causes pain or interferes with physical functioning or the maintenance of hand hygiene, b) treat hemiplegic shoulder pain thought to occur due to spasticity (by injecting into the subscapularis and pectoralis muscles), c) relieve pain related to both spasticity and inflammation or injury in a subset of patients experiencing both (and as dual therapy with steroidal injections), and d) treat focal spasticity and/or symptomatically distressing spasticity of the lower extremities in order to decrease pain, to improve gait, and to increase the patient’s range of motion (specifically relates to botulinum toxin A).30 The Heart and Stroke Foundation (HSF) echoes the aforementioned recommendation to chemodenervate using botulinum toxin in order to both decrease pain and increase range of motion in patients with focal and/or symptomatically distressing spasticity in the shoulder, arm, or hand.
32 In addition to being
beneficial in decreasing pain and increasing range of motion, the HSF also recommends the use of botulinum toxin for improving gait in patients with lower limb focal and/or symptomatically distressing spasticity.32 The Royal College of Physicians’ Intercollegiate Stroke Working Party35 recommends the use of intramuscular botulinum toxin in patients with progressing or persistent troublesome focal spasticity affecting one or more joints and who have an identifiable therapeutic goal. Botulinum toxin should be provided in the context of a specialist multidisciplinary team service (including rehabilitation or physical maintenance therapy) over two to 12 weeks post-injection, with a subsequent functional assessment provided three to four months post-injection.35
For patients with MS, the National Institute for Health and Care Excellence (NICE) did not make specific recommendations regarding the use of botulinum toxin for the treatment of spasticity.31 Instead, they provided a statement affirming that it may have a place for use in patients with severe spasticity or complications from their spasticity under the care of specialized services.31 The Spanish Society of Neurology 34 also have stated that botulinum toxin A may be required in
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Botulinum Toxin for Spasticity 8
selected cases of patients with MS; however, they did not provide any specific recommendations regarding its use for the treatment of spasticity. For patients with MND, Esquenazi et al.33 recommends the use of botulinum neurotoxin type A, Abo-A, and Ona-A (Level A evidence), and Inco-A (Level B evidence) for the treatment of upper limb spasticity. For lower limb spasticity, Esquenazi et al.33 recommends the use of botulinum neurotoxin Ona-A and Type A in aggregate (Level A), and Abo-A (Level C); however, there was insufficient identified evidence to recommend either Inco-A or Rima-B (a form of botulinum neurotoxin type B). While NICE29 made no specific recommendations regarding the use of botulinum toxin in patients with MND, they did state that patients may benefit from receiving botulinum toxin from a specialist for focal spasticity when they are not responding to other treatments.
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Botulinum Toxin for Spasticity 9
REFERENCES SUMMARIZED
Health Technology Assessments
No literature identified. Systematic Reviews and Meta-analyses
Botulinum Toxin A 1. Dashtipour K, Chen JJ, Walker HW, Lee MY. Systematic literature review of
AboBotulinumtoxinA in clinical trials for lower limb spasticity. Medicine (Baltimore) [Internet]. 2016 Jan [cited 2016 Apr 5];95(2):e2468. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4718273 PubMed: PM26765447
2. Baker JA, Pereira G. The efficacy of Botulinum Toxin A for limb spasticity on improving
activity restriction and quality of life: A systematic review and meta-analysis using the GRADE approach. Clin Rehabil. 2015 Jul 6. PubMed: PM26150020
3. Baker JA, Pereira G. The efficacy of Botulinum Toxin A on improving ease of care in the
upper and lower limbs: a systematic review and meta-analysis using the Grades of Recommendation, Assessment, Development and Evaluation approach. Clin Rehabil. 2015 Aug;29(8):731-40. PubMed: PM25352614
4. Dashtipour K, Chen JJ, Walker HW, Lee MY. Systematic literature review of
abobotulinumtoxinA in clinical trials for adult upper limb spasticity. Am J Phys Med Rehabil [Internet]. 2015 Mar [cited 2016 Apr 5];94(3):229-38. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4340600 PubMed: PM25299523
5. Grigoriu AI, Dinomais M, Remy-Neris O, Brochard S. Impact of injection-guiding techniques on the effectiveness of botulinum toxin for the treatment of focal spasticity and dystonia: a systematic review. Arch Phys Med Rehabil. 2015 Nov;96(11):2067-78. PubMed: PM25982240
6. Baker JA, Pereira G. The efficacy of Botulinum Toxin A for spasticity and pain in adults: a systematic review and meta-analysis using the Grades of Recommendation, Assessment, Development and Evaluation approach. Clin Rehabil. 2013 Dec;27(12):1084-96. PubMed: PM23864518
7. Foley N, Pereira S, Salter K, Fernandez MM, Speechley M, Sequeira K, et al. Treatment with Botulinum toxin improves upper-extremity function post stroke: a systematic review and meta-analysis. Arch Phys Med Rehabil. 2013 May;94(5):977-89. PubMed: PM23262381
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Botulinum Toxin for Spasticity 10
8. Intiso D, Simone V, Di Rienzo F, Santamato A, Russo M, Tolfa M, et al. Does spasticity reduction by botulinum toxin type A improve upper limb functionality in adult post-stroke patients? A systematic review of relevant studies. J Neurol Neurophysiol [Internet]. 2013 Oct 15 [cited 2016 Apr 5];4(4):167. Available from: http://www.omicsonline.org/does-spasticity-reduction-by-botulinum-toxin-type-a-improve-upper-limb-functionality-in-adult-poststroke-patients-a-systematic-review-of-relevant-studies-2155-9562.1000167.php?aid=19618
9. Nalysnyk L, Papapetropoulos S, Rotella P, Simeone JC, Alter KE, Esquenazi A.
OnabotulinumtoxinA muscle injection patterns in adult spasticity: a systematic literature review. BMC Neurol [Internet]. 2013 Sep 8 [cited 2016 Apr 5];13:118. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3848723 PubMed: PM24011236
10. McIntyre A, Lee T, Janzen S, Mays R, Mehta S, Teasell R. Systematic review of the effectiveness of pharmacological interventions in the treatment of spasticity of the hemiparetic lower extremity more than six months post stroke. Top Stroke Rehabil. 2012 Nov-Dec;19(6):479-90. PubMed: PM23192713
Unspecified Botulinum Toxin Type 11. Wu T, Li JH, Song HX, Dong Y. Effectiveness of botulinum toxin for lower limbs spasticity
after stroke: a systematic review and meta-analysis. Topics in Stroke Rehabilitation [Internet]. 2016 Feb 8 [cited 2016 Apr 5]. Available from: http://www.tandfonline.com/doi/abs/10.1080/10749357.2016.1139294?journalCode=ytsr20
12. Lui J, Sarai M, Mills PB. Chemodenervation for treatment of limb spasticity following spinal
cord injury: a systematic review. Spinal Cord. 2015 Apr;53(4):252-64. PubMed: PM25582713
13. Phadke CP, Ismail F, Boulias C, Gage W, Mochizuki G. The impact of post-stroke
spasticity and botulinum toxin on standing balance: a systematic review. Expert Rev Neurother. 2014 Mar;14(3):319-27. PubMed: PM24506569
Randomized Controlled Trials
Botulinum Toxin A 14. Elovic EP, Munin MC, Kanovsky P, Hanschmann A, Hiersemenzel R, Marciniak C.
Randomized, placebo-controlled trial of incobotulinumtoxina for upper-limb post-stroke spasticity. Muscle Nerve. 2016 Mar;53(3):415-21. PubMed: PM26201835
http://www.omicsonline.org/does-spasticity-reduction-by-botulinum-toxin-type-a-improve-upper-limb-functionality-in-adult-poststroke-patients-a-systematic-review-of-relevant-studies-2155-9562.1000167.php?aid=19618http://www.omicsonline.org/does-spasticity-reduction-by-botulinum-toxin-type-a-improve-upper-limb-functionality-in-adult-poststroke-patients-a-systematic-review-of-relevant-studies-2155-9562.1000167.php?aid=19618http://www.omicsonline.org/does-spasticity-reduction-by-botulinum-toxin-type-a-improve-upper-limb-functionality-in-adult-poststroke-patients-a-systematic-review-of-relevant-studies-2155-9562.1000167.php?aid=19618http://www.omicsonline.org/does-spasticity-reduction-by-botulinum-toxin-type-a-improve-upper-limb-functionality-in-adult-poststroke-patients-a-systematic-review-of-relevant-studies-2155-9562.1000167.php?aid=19618http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3848723http://www.ncbi.nlm.nih.gov/pubmed/24011236http://www.ncbi.nlm.nih.gov/pubmed/23192713http://www.tandfonline.com/doi/abs/10.1080/10749357.2016.1139294?journalCode=ytsr20http://www.tandfonline.com/doi/abs/10.1080/10749357.2016.1139294?journalCode=ytsr20http://www.ncbi.nlm.nih.gov/pubmed/25582713http://www.ncbi.nlm.nih.gov/pubmed/24506569http://www.ncbi.nlm.nih.gov/pubmed/26201835
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Botulinum Toxin for Spasticity 11
15. Gracies JM, Brashear A, Jech R, McAllister P, Banach M, Valkovic P, et al. Safety and efficacy of abobotulinumtoxinA for hemiparesis in adults with upper limb spasticity after stroke or traumatic brain injury: a double-blind randomised controlled trial. Lancet Neurol. 2015 Oct;14(10):992-1001. PubMed: PM26318836
16. Nam HS, Park YG, Paik NJ, Oh BM, Chun MH, Yang HE, et al. Efficacy and safety of
NABOTA in post-stroke upper limb spasticity: a phase 3 multicenter, double-blinded, randomized controlled trial. J Neurol Sci. 2015 Oct 15;357(1-2):192-7. PubMed: PM26233808
17. Seo HG, Paik NJ, Lee SU, Oh BM, Chun MH, Kwon BS, et al. Neuronox versus BOTOX in
the treatment of post-stroke upper limb spasticity: a multicenter randomized controlled trial. PLoS ONE [Internet]. 2015 Jun 1 [cited 2016 Apr 5];10(6):e0128633. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4452301 PubMed: PM26030192
18. Tao W, Yan D, Li JH, Shi ZH. Gait improvement by low-dose botulinum toxin A injection treatment of the lower limbs in subacute stroke patients. J Phys Ther Sci [Internet]. 2015 Mar [cited 2016 Apr 5];27(3):759-62. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4395709 PubMed: PM25931725
19. Fietzek UM, Kossmehl P, Schelosky L, Ebersbach G, Wissel J. Early botulinum toxin treatment for spastic pes equinovarus--a randomized double-blind placebo-controlled study. Eur J Neurol. 2014 Aug;21(8):1089-95. PubMed: PM24754350
20. Picelli A, Dambruoso F, Bronzato M, Barausse M, Gandolfi M, Smania N. Efficacy of therapeutic ultrasound and transcutaneous electrical nerve stimulation compared with botulinum toxin type A in the treatment of spastic equinus in adults with chronic stroke: a pilot randomized controlled trial. Top Stroke Rehabil. 2014;21 Suppl 1:S8-S16. PubMed: PM24722047
21. Guarany FC, Picon PD, Guarany NR, dos Santos AC, Chiella BP, Barone CR, et al. A double-blind, randomised, crossover trial of two botulinum toxin type a in patients with spasticity. PLoS ONE [Internet]. 2013 [cited 2016 Apr 5];8(2):e56479. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3585303 PubMed: PM23468866
22. Yazdchi M, Ghasemi Z, Moshayedi H, Rikhtegar R, Mostafayi S, Mikailee H, et al. Comparing the efficacy of botulinum toxin with tizanidine in upper limb post stroke spasticity. Iran J Neurol [Internet]. 2013 [cited 2016 Apr 5];12(2):47-50. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3829280 PubMed: PM24250901
http://www.ncbi.nlm.nih.gov/pubmed/26318836http://www.ncbi.nlm.nih.gov/pubmed/26233808http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4452301http://www.ncbi.nlm.nih.gov/pubmed/26030192http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4395709http://www.ncbi.nlm.nih.gov/pubmed/25931725http://www.ncbi.nlm.nih.gov/pubmed/24754350http://www.ncbi.nlm.nih.gov/pubmed/24722047http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3585303http://www.ncbi.nlm.nih.gov/pubmed/23468866http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3829280http://www.ncbi.nlm.nih.gov/pubmed/24250901
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23. Dunne JW, Gracies JM, Hayes M, Zeman B, Singer BJ; Multicentre Study Group. A prospective, multicentre, randomized, double-blind, placebo-controlled trial of onabotulinumtoxinA to treat plantarflexor/invertor overactivity after stroke. Clin Rehabil. 2012 Sep;26(9):787-97. PubMed: PM22308557
24. Rosales RL, Kong KH, Goh KJ, Kumthornthip W, Mok VC, Delgado-De Los Santos MM, et
al. Botulinum toxin injection for hypertonicity of the upper extremity within 12 weeks after stroke: a randomized controlled trial. Neurorehabil Neural Repair. 2012 Sep;26(7):812-21. PubMed: PM22371239
25. Shaw LC, Price CI, van Wijck FM, Shackley P, Steen N, Barnes MP, et al. Botulinum
Toxin for the Upper Limb after Stroke (BoTULS) Trial: effect on impairment, activity limitation, and pain. Stroke. 2011 May;42(5):1371-9. PubMed: PM21415398
Botulinum Toxin B 26. Gracies JM, Bayle N, Goldberg S, Simpson DM. Botulinum toxin type B in the spastic arm:
a randomized, double-blind, placebo-controlled, preliminary study. Arch Phys Med Rehabil. 2014 Jul;95(7):1303-11. PubMed: PM24709034
Unspecified Botulinum Toxin 27. Bollens B, Gustin T, Stoquart G, Detrembleur C, Lejeune T, Deltombe T. A randomized
controlled trial of selective neurotomy versus botulinum toxin for spastic equinovarus foot after stroke. Neurorehabil Neural Repair. 2013 Oct;27(8):695-703. PubMed: PM23757297
Long-Term Care Specified 28. Lam K, Lau KK, So KK, Tam CK, Wu YM, Cheung G, et al. Can botulinum toxin decrease
carer burden in long term care residents with upper limb spasticity? A randomized controlled study. J Am Med Dir Assoc. 2012 Jun;13(5):477-84. PubMed: PM22521630
Guidelines and Recommendations
29. National Clinical Guideline Centre. Motor neurone disease: assessment and management
[Internet]. London, United Kingdom: National Institute for Health and Care Excellence; 2016 Feb [cited 2016 Apr 5]. (NICE guideline NG42). Available from: https://www.nice.org.uk/guidance/ng42/evidence/full-guideline-2361774637 See: Section on Muscle stiffness, page 194
http://www.ncbi.nlm.nih.gov/pubmed/22308557http://www.ncbi.nlm.nih.gov/pubmed/22371239http://www.ncbi.nlm.nih.gov/pubmed/21415398http://www.ncbi.nlm.nih.gov/pubmed/24709034http://www.ncbi.nlm.nih.gov/pubmed/23757297http://www.ncbi.nlm.nih.gov/pubmed/22521630https://www.nice.org.uk/guidance/ng42/evidence/full-guideline-2361774637
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30. Quality-based procedures: clinical handbook for stroke (acute and postacute) [Internet]. Toronto: Health Quality Ontario; 2015 December [cited 2016 Apr 5]. Available from: http://www.hqontario.ca/Portals/0/Documents/evidence/clinical-handbooks/community-stroke-20151802-en.pdf See: Section 9.40.1, pages 76 and 125 Section 9.47.4, pages 78 and 127 Section 9.47.6, pages 78 and 127 Section 9.54.1, pages 80 and 129
31. National Clinical Guideline Centre. Multiple sclerosis: management of multiple sclerosis in
primary and secondary care [Internet]. London, United Kingdom: National Institute for Health and Care Excellence; 2014 Oct [cited 2016 Apr 5]. (NICE clinical guideline 186). Available from: https://www.nice.org.uk/guidance/cg186/evidence/full-guideline-193254301
See: Section 9 Pharmacological management of MS symptoms, page 124 Table 48: Clinical evidence profile: Botulinum versus placebo, pages 149-151 Botulinum versus placebo, page 166 Botulinum Toxin not recommended, page 169
32. Dawson AS, Knox J, McClure A, Foley N, Teasell R. Chapter 5: stroke rehabilitation. In: Lindsay MP, Gubitz G, Bayley M, Phillips S, editors. Canadian best practice recommendations for stroke care [Internet]. 4th ed. Ottawa: Heart & Stroke Foundation; 2013 Jul 10 [cited 2016 Apr 6]. Available from: http://www.strokebestpractices.ca/wp-content/uploads/2010/10/Ch5_SBP2013_Stroke-Rehabilitation-_July-2013_FINAL-EN.pdf See 5.5.2 page 43, 5.6.2 page 53
33. Esquenazi A, Albanese A, Chancellor MB, Elovic E, Segal KR, Simpson DM, et al.
Evidence-based review and assessment of botulinum neurotoxin for the treatment of adult spasticity in the upper motor neuron syndrome. Toxicon. 2013 Jun 1;67:115-28. PubMed: PM23220492
34. Gold R, Oreja-Guevara C. Advances in the management of multiple sclerosis spasticity:
multiple sclerosis spasticity guidelines. Expert Rev Neurother. 2013 Dec;13(12 Suppl):55-9. PubMed: PM24289845
35. Intercollegiate Stroke Working Party. National clinical guideline for stroke [Internet]. 4th ed. London, United Kingdom: Royal College of Physicians; 2012 Sep [cited 2016 Apr 5]. Available from: https://www.rcplondon.ac.uk/guidelines-policy/stroke-guidelines See: Section on 6.10 Impaired tone – spasticity and spasms and Recommendations 6.10.1, page 87
PREPARED BY:
Canadian Agency for Drugs and Technologies in Health Tel: 1-866-898-8439 www.cadth.ca
http://www.hqontario.ca/Portals/0/Documents/evidence/clinical-handbooks/community-stroke-20151802-en.pdfhttp://www.hqontario.ca/Portals/0/Documents/evidence/clinical-handbooks/community-stroke-20151802-en.pdfhttps://www.nice.org.uk/guidance/cg186/evidence/full-guideline-193254301http://www.strokebestpractices.ca/wp-content/uploads/2010/10/Ch5_SBP2013_Stroke-Rehabilitation-_July-2013_FINAL-EN.pdfhttp://www.strokebestpractices.ca/wp-content/uploads/2010/10/Ch5_SBP2013_Stroke-Rehabilitation-_July-2013_FINAL-EN.pdfhttp://www.ncbi.nlm.nih.gov/pubmed/23220492http://www.ncbi.nlm.nih.gov/pubmed/24289845https://www.rcplondon.ac.uk/guidelines-policy/stroke-guidelineshttp://www.cadth.ca/
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Botulinum Toxin for Spasticity 14
APPENDIX – FURTHER INFORMATION:
Previous CADTH Reports
36. Botulinum toxin for spasticity in long-term care residents: clinical effectiveness and
guidelines [Internet]. Ottawa: CADTH; 2011 Dec 9 [cited 2016 Apr 5]. (Rapid response report: reference list). Available from: https://www.cadth.ca/media/pdf/htis/dec-2011/RA0560-000%20Botox%20for%20Pain%20Final.pdf
Randomized Controlled Trials – Injection Site or Technique Comparisons
37. Im S, Park JH, Son SK, Shin JE, Cho SH, Park GY. Does botulinum toxin injection site
determine outcome in post-stroke plantarflexion spasticity? Comparison study of two injection sites in the gastrocnemius muscle: a randomized double-blind controlled trial. Clin Rehabil. 2014 Jan 22;28(6):604-13. PubMed: PM24452704
38. Ploumis A, Varvarousis D, Konitsiotis S, Beris A. Effectiveness of botulinum toxin injection with and without needle electromyographic guidance for the treatment of spasticity in hemiplegic patients: a randomized controlled trial. Disabil Rehabil. 2014;36(4):313-8. PubMed: PM23672209
39. Santamato A, Micello MF, Panza F, Fortunato F, Baricich A, Cisari C, et al. Can botulinum
toxin type A injection technique influence the clinical outcome of patients with post-stroke upper limb spasticity? A randomized controlled trial comparing manual needle placement and ultrasound-guided injection techniques. J Neurol Sci. 2014 Dec 15;347(1-2):39-43. PubMed: PM25263601
40. Picelli A, Tamburin S, Bonetti P, Fontana C, Barausse M, Dambruoso F, et al. Botulinum
toxin type A injection into the gastrocnemius muscle for spastic equinus in adults with stroke: a randomized controlled trial comparing manual needle placement, electrical stimulation and ultrasonography-guided injection techniques. Am J Phys Med Rehabil. 2012 Nov;91(11):957-64. PubMed: PM23085706
Clinical Practice Guidelines – Unspecified Methodology 41. Semenko B, Thalman L, Ewert E, Delorme R, Hui S, Flett H, et al. An evidence based
occupational therapy toolkit for assessment and treatment of the upper extremity post stroke [Internet]. Winnipeg: Winnipeg Health Region Occupational Therapy Upper Extremity Working Group; 2015 Apr [cited 2016 Apr 5]. Available from: http://www.wrha.mb.ca/professionals/occupational-therapy/files/Stroke-UEToolkit.pdf See 8.1.7 page 39
https://www.cadth.ca/media/pdf/htis/dec-2011/RA0560-000%20Botox%20for%20Pain%20Final.pdfhttps://www.cadth.ca/media/pdf/htis/dec-2011/RA0560-000%20Botox%20for%20Pain%20Final.pdfhttp://www.ncbi.nlm.nih.gov/pubmed/24452704http://www.ncbi.nlm.nih.gov/pubmed/23672209http://www.ncbi.nlm.nih.gov/pubmed/25263601http://www.ncbi.nlm.nih.gov/pubmed/23085706http://www.wrha.mb.ca/professionals/occupational-therapy/files/Stroke-UEToolkit.pdf
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42. Guidelines for the rehabilitation of patients with metastatic spinal cord compression (MSCC): assessment and care provision by occupational therapists and physiotherapists in the acute sector [Internet]. Belfast: Guidelines and Audit Implementation Network; 2014 Jan [cited 2016 Apr 5]. Available from: http://www.gain-ni.org/images/GAIN-Guidelines-for-Rehabilitation-of-Assessment-and-Care-Provision-by-Occupational-Therapists-and-Physiotherapists-in-the-Acute-Sector.PDF See pages 32, 57
43. Hertfordshire Medicines Management Committee. Botulinum toxin type A for focal
spasticity in adults. Recommended for restricted use [Internet]. Welwyn Garden City, United Kingdom: NHS Hertfordshire; 2012 Sep [cited 2016 Apr 5]. Available from: http://hertsvalleysccg.nhs.uk/uploads/file/Pharmacy/Local%20Decisions/Botulinum%20toxin%20for%20focal%20spasticity%20of%20upper%20limb%20201209(HMMC).pdf
44. Traumatic brain injury medical treatment guidelines [Internet]. Denver: State of Colorado,
Division of Workers' Compensation; 2012 Nov 26 [cited 2016 Apr 5]. Available from: https://www.colorado.gov/pacific/sites/default/files/MTG_Ex10_TBI.pdf See pages 86-87 e.
45. Ells G. Botulinum toxin to manage spasticity in stroke rehabilitation and multiple sclerosis
[Internet]. Lewes, United Kingdom: East Sussex Downs and Weald Primary Care Trust; 2011 Feb 1 [cited 2016 Apr 5]. Available from: http://www.eastbournehailshamandseafordccg.nhs.uk/EasysiteWeb/getresource.axd?AssetID=366869&type=Full&servicetype=Attachment
46. Jabeen A, Kandadai RM, Kannikannan MA, Borgohain R. Guidelines for the use of
Botulinum toxin in movement disorders and spasticity. Ann Indian Acad Neurol [Internet]. 2011 Jul [cited 2016 Apr 5];14(Suppl 1):S31-S34. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3152173 PubMed: PM21847327
Management Pathway 47. Spasticity management pathway [Internet]. Adelaide: Government of South Australia, SA
Health; 2013 Jan [cited 2016 Apr 5]. Available from: http://www.sahealth.sa.gov.au/wps/wcm/connect/c2e6a7804e5de262963df6fefb3fa04f/Spasticity+management+pathway-HealthReform-RCH-20130130.pdf?MOD=AJPERES&CACHEID=c2e6a7804e5de262963df6fefb3fa04f
http://www.gain-ni.org/images/GAIN-Guidelines-for-Rehabilitation-of-Assessment-and-Care-Provision-by-Occupational-Therapists-and-Physiotherapists-in-the-Acute-Sector.PDFhttp://www.gain-ni.org/images/GAIN-Guidelines-for-Rehabilitation-of-Assessment-and-Care-Provision-by-Occupational-Therapists-and-Physiotherapists-in-the-Acute-Sector.PDFhttp://www.gain-ni.org/images/GAIN-Guidelines-for-Rehabilitation-of-Assessment-and-Care-Provision-by-Occupational-Therapists-and-Physiotherapists-in-the-Acute-Sector.PDFhttp://hertsvalleysccg.nhs.uk/uploads/file/Pharmacy/Local%20Decisions/Botulinum%20toxin%20for%20focal%20spasticity%20of%20upper%20limb%20201209(HMMC).pdfhttp://hertsvalleysccg.nhs.uk/uploads/file/Pharmacy/Local%20Decisions/Botulinum%20toxin%20for%20focal%20spasticity%20of%20upper%20limb%20201209(HMMC).pdfhttps://www.colorado.gov/pacific/sites/default/files/MTG_Ex10_TBI.pdfhttp://www.eastbournehailshamandseafordccg.nhs.uk/EasysiteWeb/getresource.axd?AssetID=366869&type=Full&servicetype=Attachmenthttp://www.eastbournehailshamandseafordccg.nhs.uk/EasysiteWeb/getresource.axd?AssetID=366869&type=Full&servicetype=Attachmenthttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3152173http://www.ncbi.nlm.nih.gov/pubmed/21847327http://www.sahealth.sa.gov.au/wps/wcm/connect/c2e6a7804e5de262963df6fefb3fa04f/Spasticity+management+pathway-HealthReform-RCH-20130130.pdf?MOD=AJPERES&CACHEID=c2e6a7804e5de262963df6fefb3fa04fhttp://www.sahealth.sa.gov.au/wps/wcm/connect/c2e6a7804e5de262963df6fefb3fa04f/Spasticity+management+pathway-HealthReform-RCH-20130130.pdf?MOD=AJPERES&CACHEID=c2e6a7804e5de262963df6fefb3fa04fhttp://www.sahealth.sa.gov.au/wps/wcm/connect/c2e6a7804e5de262963df6fefb3fa04f/Spasticity+management+pathway-HealthReform-RCH-20130130.pdf?MOD=AJPERES&CACHEID=c2e6a7804e5de262963df6fefb3fa04f
Research questionSkey FINDINGSMethodsResultsOverall summary of findingsReferences summarizedAppendix – Further information: