Consensus Statement on the Use of Botulinum Neurotoxin: REVIEW PROCESS

REVIEW PROCESS

The authors of this article—academic-affiliated neurologists and physiatrists with experience in the use of neurotoxins for spasticity, pain, headache, and other conditions—were recruited by a health care consultant under a grant from Allergan. Most of us met twice in person to review the evidence and to arrive at a consensus. Several telephone conferences and electronic communications aided the development of our Consensus Statement (see page 674).

We conducted a literature search using Ovid Medline and PubMed to identify clinical trials involving adults with spasticity that were published between 1965 and May 2005 (Table 1). Our findings revealed 570 articles on spasticity and BoNT; 17 of these satisfied the a priori selection criteria for rigorous study design (Table 2). buy tadacip

TABLE 1 Strategy for Selecting Review Papers for Analysis and Arriving at the Consensus Statement

Parameter (Database Searched) Information (Ovid Medline and PubMed, 1965-May 2005)
Search parameter: key words and boolean* terms (and, or, not) •  MAJ=MUS* SPAST* ORTIW=SPASTIC* (wild card for spasticity)•  and BOTULINUM or BOTOX or MYOBLOC

•  and STUDY=CLINICAL*

•  not CEREB* PALS* (not cerebral palsy)

•  not STUDY=REVIEW* orTYPE=NEW*

(filtering limited search to clinical studies with exclusion of reviews)

Exclusion criteria for a citation/study •  Study not in English•  Study focus not exclusively spasticity

•  Reference with missing data (e.g., dose, number of patients, toxin type, invalid scales, statistical analyses)

•  Study design: open-label or retrospective

•  Study containing only case reports or case series

•  Abstracts and/or posters

•  Expert opinion

Most of the trials used BoNT-As (Botox and Dysport); only one study involved BoNT-B (Myobloc). Our Consensus Group decided to review nine studies using BoNT available for clinical use in the U.S. (Botox and Myobloc). These studies involved 400 adults with spasticity from a number of causes, such as stroke, head injury, and multiple sclerosis (MS). Based on the Oxford Centre for Evidence-Based Medicine (OCEBM) criteria (Tables 3 and 4), six of the reviewed studies were rated “Level 1b” and three were rated “Level lb-minus” (Table 5).
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TABLE 2 Results of Search Strategy

Parameter No.
Spasticity citations (studies), all toxin types 570
Citations meeting all criteria 17
Spasticity citations for BoNT-A (Botox) 8
Spasticity citations for BoNT-A (Dysport) 8
Spasticity citations for BoNT-B (Myobloc) 1
Citations reviewed 9*
* Only citations involving FDA-approved botulinum neurotoxins for clinical use.Botoxand Myobloc were reviewed.BoNT-A = botulinum neurotoxin type A; BoNT-B = botulinum neurotoxin type B.

Disclosures

Dr. Davis has been an advisor to Allergan for this project and has received a Speaker’s Bureau honorarium from the company. He is also an investigator in a Myobloc clinical trial and has received salary support from Solstice Neuroscience (formerly from Elan).

The Division of Movement Disorders has received unrestricted research grants from Allergan to support clinical research.

Dr. Brodsky has been an advisor to Allergan for this project and has been on Allergan’s Speaker’s Bureau;he has also received research grant support from Allergan and has been an advisor to Solstice Neuroscience.

TABLE 3 Criteria for Levels of Evidence

Level* Therapy/Prevention Economic and Decision Analysis
1a Systematic review (with homogeneity!) of randomized, controlled trials Systematic review (with homogeneity!) of Level 1 economic studies
1b Individual double-blinded randomized, controlled trial Analysis based on:•    Clinically sensible costs or alternatives

•    Systematic review(s) of the evidence, including multi-way sensitivity analyses

1c All or none Absolute better-value or worse-value analyses!
2a Systematic review (with homogeneity!) of cohort studies Systematic review (with homogeneity!) of Level >2 economic studies
2b Individual cohort study (including low-quality randomized, controlled trial§ and prospective open-label trial) Analysis based on:•    Clinically sensible costs or alternatives

•    Limited review(s) of the evidence or single studies, including multi-way sensitivity analyses

2c Outcomes research Audit or outcomes research
3a Systematic review (with homogeneity!) of case-control studies Systematic review (with homogeneity!) of Level 3b and better studies
3b Individual case-control/retrospective studies Analysis based on:•    Limited alternatives or costs

•    Poor-quality estimates of data but including sensitivity analyses incorporating clinically sensible variations

4 Case studies/series Analysis with no sensitivity analysis
5 Expert opinion without explicit critical appraisal, or based on physiology, bench research, or “first principles” Expert opinion without explicit critical appraisal or based on economic theory or “first principles”

Dr.Carter has been an advisor to Allergan for this project and has received honoraria from Allergan for lectures and teaching.

Dr. DiFazio has been an advisor to Allergan for this project and has received honoraria from the company for lectures and teaching;his wife is an Allergan employee.

Dr. Frishberg has been an advisor to Allergan for this project; he has also been on the Speaker’s Bureau, has been a Principal Investigator,and is an Advisory Board member for  Allergan.

TABLE 4 Grades of Recommendation

Grade of Recommendation Parameter
A Consistent Level 1 studies
B Consistent Level 2/Level 3 studies or extrapolations from Level 1 studies
C Level 4 studies or extrapolations from Level 2 and Level 3 studies
D Level 5 studies: disturbingly inconsistent or inconclusive studies of any level

Dr.Lai has been an advisor to Allergan for this project and has received research grant support from Allergan.

Dr. McGuire has been an advisor to Allergan for this project and has received an unrestricted research grant and honoraria from Allergan for lectures and teaching.

Mr.Meyer has been an advisor to Allergan for this project and a consultant for Allergan.

TABLE 5 Level of Evidence Rating of Spasticity and Botulinum Neurotoxin Studies

Reference Level of Evidence Study Spasticity Diagnosis/ Etiology Dose Injection Site Outcome Measures/Results Primary             Secondary
Snowet al.(l990)7 lb •   Randomized, double-blind, placebo-controlled, crossover•n = l0

•  Duration: 6 weeks

•  Lower limb•   Multiple sclerosis

•   Subject retention: 90% (9/l0)

400 units ofBoNT-A •  Hip adductors•   Single treatment (+) Spasticity score = ASH x spasm frequency: week 6 (+) Hygiene score (measure of caregiver difficulty): week 6
Grazko et al. (1995)8 lb •   Randomized, double-blind, placebo-controlled, crossover• n = l2

•  Duration: 8-l6 weeks

•   Lower limb, upper limb•   Stroke, multiple sclerosis, trau­matic brain injury, perinatal hypoxia

•  Subject retention:

l00% (l2/l2)

25-290 units of BoNT-A(mean, l38 units) •   Muscles of the upper and lower limbs•   Single treatment (+) ASH:2-grade improvement in all patients with spasticity •  (+) Spasm frequency•  (-) ADEs

• (+) 2-grade improve­ment in UPDRS for rigidity

Simpson et al.(l996)9 lb •   Randomized, double-blind, placebo-controlled, dose- ranging•n = 39

•  Duration: l6 weeks

•  Upper limb•  Stroke

•  Subject retention:

95% (37/39)

75,l50,and300 units of

BoNT-A

•   Elbow and wrist flexors•   Single treatment (+) ASH:300-unit group at weeks 2, 4, and 6 (wrist) and at week 2 (elbow) •   (+) Global assess­ment: 75-unit and 300-unit groups•   (-) FIM,Rand-36, Fugl-Meyer Scale, other, ADEs
Kirazliet al.(l998)10 lb-minus • Randomized,double-blind, parallel-group (BoNT-A vs. phenol)•n = 20

•  Duration: l2 weeks

•  Lower limb•  Stroke

•  Subject retention:

l00% (20/20)

400 units of BoNT-A or 3 ml of 5% phenol •   Ankle plantar flexor and foot inverter•   Single treatment (+) ASH superi­ority for BoNT-A vs. phenol at weeks 2 and 4 •   (-) Passive and active ROM similar for both groups•   (+) Global assess­ment, ambulation, clonus duration

•   (+) ADEs: no signifi­cant ADEs in BoNT-A group, 30% devel­oped dysesthesia in phenol group

Richardson et al.(2000)11 lb •   Randomized, double-blind, placebo-controlled•  n = 52

•  Duration: l2 weeks

•   Upper limb, lower limb•   Stroke, traumatic brain injury, spinal cord injury, cere­bral palsy, neo­plasm, hypoxia

•   Subject retention: not reported

30-500 units of BoNT-A •   Muscles of the upper and lower limbs•   Single treatment (+) MAS:aggregate scores summed from weeks 3, 6, 9,

and l2

•  (+) passive ROM:aggregate

•  (+) SRPS:aggregate

•  (+) RMAS: aggregate

•  (-) Ambulation

•  (-) 9HPT

•  (-) MGAS

• (-) ADEs:none reported other than injection-site pain

Brashear et al. (2002)12 lb •   Randomized, double-blind, placebo- controlled•  n = l26

•  Duration: l2 weeks

•  Upper limb•  Stroke

•   Subject reten­tion:

97% (l22/l26)

200-240units of

BoNT-A

•   Wrist, finger, and thumb flexors•   Single treatment (+) DAS atweek 6 •   (+) ASH at all time points•  (+) Global

assessment

•   (-) ADEs:no between-group differences in inci­dence of ADEs

Level of Spasticity Diagnosis/ Etiology Outcome Measures/Results
Reference Evidence Study Dose Injection Site Primary Secondary
Brashear lb • Randomized, • Upper limb l0,000 units • Elbow, wrist, (-) ASH at all • (-) Global
et al. double-blind, • Stroke of BoNT-B and finger time points assessments
(2004)l:! placebo-controlled • Subject reten- flexors except week 2 • (-) Pain
•n = l5 tion: • Single (wrist only) • (-) 9HPT
• Duration: l6 weeks 93% (l4/l5) treatment • (-) ADEs:dry mouthin 89% (8/9) BoNT-B

subjects in the dou­ble-blind phase

Childers lb-minus • Randomized, • Upper limb 90, l80, and • Elbow, wrist, (+) MAS,with • (+) Global assess-
et al.(2004)l’t double-blind, • Stroke 360 units of and finger dose-dependent ments: l80-unit and
placebo-controlled, • Subject retention: BoNT-A flexors response gener- 360-unit groups
dose-ranging 74% (67/9l) • Two treatments ally observed • (-) Pain
• n = 9l • (-) AFD
• Duration: 24 weeks •  (-) FIM•  (-) SF-36

•   (-) ADEs: treatment-related ADEs more frequent among BoNT-A subjects

Verplancke lb-minus • Randomized, • Lower limb Casting + 400 • Gastocnemius (-) ROM: casting • (+) MAS:both casting
et aL(2005)li; double-blind, • Traumatic brain units of and soleus plus BoNT-A vs. groups vs. baseline;
placebo-controlled, injury BoNT-A or muscles control (+l3.59 (-) no difference be-
parallel-group • Subject retention: saline or • Two treatments degrees vs. +4.59 tween casting groups
• n = 35 80% (28/35) control degrees) • (+) GOS: casting +
• Duration: l2 weeks (P = .07) BoNT-A vs. casting + saline at week l2 • ADEs: About 30% of casting + saline and control groups required rescue treatment compared with 0% of casting + BoNT-A group

Dr.Ostrem and Dr.Sarwar have been advisors to Allergan for this project. tadalis sx

Mr.White has been an advisor to Allergan for this project and others.

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Tags: Botulinum Neurotoxin, Consensus Statement

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