[Skip to Content]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 34.236.170.48. Please contact the publisher to request reinstatement.
[Skip to Content Landing]
Figure 1.
CONSORT Flow Diagram of Patients Randomized to OnabotulinumtoxinA, AbobotulinumtoxinA, and IncobotulinumtoxinA Treatment Groups
CONSORT Flow Diagram of Patients Randomized to OnabotulinumtoxinA, AbobotulinumtoxinA, and IncobotulinumtoxinA Treatment Groups

A total of 28 patients with 6 patients enrolled multiple times account for 10 of the 38 treatments studied. SAQ indicates Synkinesis Assessment Questionnaire.

Figure 2.
Pretreatment Synkinesis Assessment Questionnaire (SAQ) Scores for the Repeat-Treatment vs Single-Treatment Groups
Pretreatment Synkinesis Assessment Questionnaire (SAQ) Scores for the Repeat-Treatment vs Single-Treatment Groups

For all botulinum toxin neuromodulators, pretreatment SAQ scores were not significantly different for patients receiving repeat treatments compared with patients receiving a single treatment. This comparison demonstrates a lack of significant effect on the pretreatment SAQ scores by history of treatment and supports the appropriateness of treating patients receiving repeat injections as individual observations. Error bars indicate SD.

Figure 3.
Synkinesis Assessment Questionnaire (SAQ) Scores by Treatment and Time
Synkinesis Assessment Questionnaire (SAQ) Scores by Treatment and Time

Error bars indicate SD.

Table 1.  
Demographic and Pretreatment SAQ Score Dataa
Demographic and Pretreatment SAQ Score Dataa
Table 2.  
SAQ Scores by Botulinum Toxin Type and Time
SAQ Scores by Botulinum Toxin Type and Time
1.
Crumley  RL.  Mechanisms of synkinesis.  Laryngoscope. 1979;89(11):1847-1854.PubMedGoogle ScholarCrossref
2.
Dall’Angelo  A, Mandrini  S, Sala  V,  et al.  Platysma synkinesis in facial palsy and botulinum toxin type A.  Laryngoscope. 2014;124(11):2513-2517.PubMedGoogle ScholarCrossref
3.
Husseman  J, Mehta  RP.  Management of synkinesis.  Facial Plast Surg. 2008;24(2):242-249.PubMedGoogle ScholarCrossref
4.
Finn  JC.  Botulinum toxin type A: fine-tuning treatment of facial nerve injury.  J Drugs Dermatol. 2004;3(2):133-137.PubMedGoogle Scholar
5.
Hadlock  TA, Greenfield  LJ, Wernick-Robinson  M, Cheney  ML.  Multimodality approach to management of the paralyzed face.  Laryngoscope. 2006;116(8):1385-1389.PubMedGoogle ScholarCrossref
6.
Choi  KH, Rho  SH, Lee  JM, Jeon  JH, Park  SY, Kim  J.  Botulinum toxin injection of both sides of the face to treat post-paralytic facial synkinesis.  J Plast Reconstr Aesthet Surg. 2013;66(8):1058-1063.PubMedGoogle ScholarCrossref
7.
Nettar  KD, Yu  KC, Bapna  S, Boscardin  J, Maas  CS.  An internally controlled, double-blind comparison of the efficacy of onabotulinumtoxinA and abobotulinumtoxinA.  Arch Facial Plast Surg. 2011;13(6):380-386.PubMedGoogle ScholarCrossref
8.
Laskawi  R.  The use of botulinum toxin in head and face medicine: an interdisciplinary field.  Head Face Med. 2008;4:5.PubMedGoogle ScholarCrossref
9.
Saad  J, Gourdeau  A.  A direct comparison of onabotulinumtoxina (Botox) and incobotulinumtoxinA (Xeomin) in the treatment of benign essential blepharospasm: a split-face technique.  J Neuroophthalmol. 2014;34(3):233-236.PubMedGoogle ScholarCrossref
10.
Mehta  RP, WernickRobinson  M, Hadlock  TA.  Validation of the Synkinesis Assessment Questionnaire.  Laryngoscope. 2007;117(5):923-926.PubMedGoogle ScholarCrossref
11.
Moers-Carpi  M, Dirschka  T, Feller-Heppt  G,  et al.  A randomised, double-blind comparison of 20 units of onabotulinumtoxinA with 30 units of incobotulinumtoxinA for glabellar lines.  J Cosmet Laser Ther. 2012;14(6):296-303.PubMedGoogle ScholarCrossref
12.
Prager  W, Rappl  T.  Phase IV study comparing incobotulinumtoxinA and onabotulinumtoxinA using a 1:1.5 dose-conversion ratio for the treatment of glabellar frown lines.  J Cosmet Dermatol. 2012;11(4):267-271.PubMedGoogle ScholarCrossref
13.
Dunnett  C.  A multiple comparison procedure for comparing several treatments with a control.  J Am Stat Assoc. 1955;50(272):1096-1121.Google ScholarCrossref
14.
Tukey  JW.  Comparing individual means in the analysis of variance.  Biometrics. 1949;5(2):99-114.PubMedGoogle ScholarCrossref
15.
Seaman  Ma, Levin  JR, Serlin  RC.  New developments in pairwise multiple comparisons: some powerful and practicable procedures.  Psychol Bull. 1991;110(3):577-586.Google ScholarCrossref
16.
Muller  K, Cohen  J.  Statistical power analysis for the behavioral sciences.  Technometrics. 1989;31(4):499.Google ScholarCrossref
17.
Mehta  RP, Hadlock  TA.  Botulinum toxin and quality of life in patients with facial paralysis.  Arch Facial Plast Surg. 2008;10(2):84-87.PubMedGoogle ScholarCrossref
18.
Toffola  ED, Furini  F, Redaelli  C, Prestifilippo  E, Bejor  M.  Evaluation and treatment of synkinesis with botulinum toxin following facial nerve palsy.  Disabil Rehabil. 2010;32(17):1414-1418.PubMedGoogle ScholarCrossref
19.
Filipo  R, Spahiu  I, Covelli  E, Nicastri  M, Bertoli  GA.  Botulinum toxin in the treatment of facial synkinesis and hyperkinesis.  Laryngoscope. 2012;122(2):266-270.PubMedGoogle ScholarCrossref
20.
Terzis  JK, Karypidis  D.  Therapeutic strategies in post-facial paralysis synkinesis in adult patients.  Plast Reconstr Surg. 2012;129(6):925e-939e.PubMedGoogle ScholarCrossref
21.
Armstrong  MW, Mountain  RE, Murray  JA.  Treatment of facial synkinesis and facial asymmetry with botulinum toxin type A following facial nerve palsy.  Clin Otolaryngol Allied Sci. 1996;21(1):15-20.PubMedGoogle ScholarCrossref
22.
Couch  SM, Chundury  RV, Holds  JB.  Subjective and objective outcome measures in the treatment of facial nerve synkinesis with onabotulinumtoxinA (Botox).  Ophthal Plast Reconstr Surg. 2014;30(3):246-250.PubMedGoogle ScholarCrossref
23.
Frevert  J.  Xeomin: an innovative new botulinum toxin type A.  Eur J Neurol. 2009;16(suppl 2):11-13.PubMedGoogle ScholarCrossref
24.
Copay  AG, Subach  BR, Glassman  SD, Polly  DW  Jr, Schuler  TC.  Understanding the minimum clinically important difference: a review of concepts and methods.  Spine J. 2007;7(5):541-546.PubMedGoogle ScholarCrossref
25.
Norman  GR, Sloan  JA, Wyrwich  KW.  Interpretation of changes in health-related quality of life.  Med Care. 2003;41(5):582-592.PubMedGoogle Scholar
26.
Norman  GR, Sloan  JA, Wyrwich  KW.  The truly remarkable universality of half a standard deviation: confirmation through another look.  Expert Rev Pharmacoecon Outcomes Res. 2004;4(5):581-585.PubMedGoogle ScholarCrossref
27.
Pickett  A, Caird  D.  Discussion regarding botulinum toxin, immunologic considerations with long-term repeated use, with emphasis on cosmetic applications: minimal risk of antibody formation after aesthetic treatment with type a botulinum toxin.  Facial Plast Surg Clin North Am. 2009;17(4):633-634.PubMedGoogle ScholarCrossref
28.
Borodic  G, Johnson  E, Goodnough  M, Schantz  E.  Botulinum toxin therapy, immunologic resistance, and problems with available materials.  Neurology. 1996;46(1):26-29.PubMedGoogle ScholarCrossref
29.
Elston  JS.  Botulinum toxin A in clinical medicine.  J Physiol (Paris). 1990;84(4):285-289.PubMedGoogle Scholar
30.
Naumann  M, Albanese  A, Heinen  F, Molenaers  G, Relja  M.  Safety and efficacy of botulinum toxin type A following long-term use.  Eur J Neurol. 2006;13(s4)(suppl 4):35-40.PubMedGoogle ScholarCrossref
31.
Ravenni  R, De Grandis  D, Mazza  A.  Conversion ratio between Dysport and Botox in clinical practice: an overview of available evidence.  Neurol Sci. 2013;34(7):1043-1048.PubMedGoogle ScholarCrossref
32.
Scaglione  F.  Conversion Ratio between Botox®, Dysport®, and Xeomin® in Clinical Practice.  Toxins (Basel). 2016;8(3):65.PubMedGoogle ScholarCrossref
Original Investigation
Mar/Apr 2018

Effect of 3 Commercially Available Botulinum Toxin Neuromodulators on Facial Synkinesis: A Randomized Clinical Trial

Author Affiliations
  • 1Division of Otolaryngology–Head and Neck Surgery, University of Utah School of Medicine, Salt Lake City
JAMA Facial Plast Surg. 2018;20(2):141-147. doi:10.1001/jamafacial.2017.1393
Key Points

Question  Is there a difference in efficacy of the botulinum toxin neuromodulators onabotulinumtoxinA, abobotulinumtoxinA, and incobotulinumtoxinA for treatment of facial synkinesis?

Findings  In this randomized clinical trial, all botulinum toxins demonstrated similar efficacy at 1 and 2 weeks after treatment based on Synkinesis Assessment Questionnaire scores. However, at 4 weeks, incobotulinumtoxinA had significantly less effect on Synkinesis Assessment Questionnaire score improvement than did onabotulinumtoxinA.

Meaning  IncobotulinumtoxinA may be less efficacious for treatment of facial synkinesis compared with onabotulinumtoxinA.

Abstract

Importance  Botulinum toxin neuromodulators are an important treatment for facial synkinesis. Whether a difference in efficacy exists among the 3 different botulinum neuromodulators used in treating this condition remains unknown.

Objective  To evaluate the effectiveness of 3 commercially available botulinum toxin neuromodulators in the treatment of facial synkinesis.

Design, Setting, and Participants  In this single-blind, 3-arm comparison randomized clinical trial, 28 patients at the Facial Nerve Center, University of Utah, Salt Lake City, were randomized to onabotulinumtoxinA, abobotulinumtoxinA, or incobotulinumtoxinA treatment. Each patient was given the Synkinesis Assessment Questionnaire (SAQ) to assess severity of synkinesis before treatment and 1, 2, and 4 weeks after treatment, and improvements were compared among the groups. Data were collected from July 3, 2012, to March 31, 2015.

Interventions  Botulinum toxin type A neuromodulator (onabotulinumtoxinA, abobotulinumtoxinA, or incobotulinumtoxinA) injected into synkinetic areas of the face.

Main Outcomes and Measures  Synkinesis assessed using the SAQ (score range, 20-100; lower scores indicate less severe synkinesis) before treatment and 1, 2, and 4 weeks after treatment.

Results  A total of 28 patients (mean [SD] age, 49.1 [18.5] years; 8 [28.6%] male and 20 [71.4%] female), with 6 patients enrolled multiple times, received 38 treatments (15 onabotulinumtoxinA, 13 abobotulinumtoxinA, and 10 incobotulinumtoxinA). No significant difference existed in baseline pretreatment SAQ scores among the 3 groups. Mean (SD) SAQ score improvement at 4 weeks was 41% (31%) for the onabotulinumtoxinA, 42% (20%) for the abobotulinumtoxinA, and 17% (18%) for the incobotulinumtoxinA groups. No significant differences were noted in SAQ score improvements among the 3 groups at weeks 1 and 2 after treatment (week 1 mean improvements of 42% in the onabotulinumtoxinA, 45% in the abobotulinumtoxinA, and 26% in the incobotulinumtoxinA groups; P = .19; week 2 mean improvements of 43% in the onabotulinumtoxinA, 46% in the abobotulinumtoxinA, and 28% in the incobotulinumtoxinA groups; P = .20). The difference in mean SAQ score improvement for abobotulinumtoxinA vs incobotulinumtoxinA from pretreatment to 4 weeks after treatment was not significant (30 vs 12 points; P = .11) despite a significant difference in mean total SAQ score for abobotulinumtoxinA vs incobotulinumtoxinA (40.34 vs 58.00; P = .02).

Conclusions and Relevance  AbobotulinumtoxinA had similar efficacy to onabotulinumtoxinA and incobotulinumtoxinA for the management of facial synkinesis up to 4 weeks after treatment. IncobotulinumtoxinA had significantly less effect on SAQ score improvement than onabotulinumtoxinA at 4 weeks, perhaps because of the shorter duration of action. Shorter intervals between treatments or larger doses may be required when using incobotulinumtoxinA treatment for facial synkinesis.

Trial Registration  clinicaltrials.gov Identifier: NCT03048383

Level of Evidence  1.

Introduction

Facial synkinesis is a distressing complication after facial paralysis or paresis and is difficult to treat.1-3 Synkinesis commonly occurs after facial nerve injury and is defined as the unintentional motion of one area of the face during intentional movement of another area of the face. There are several theories regarding the pathophysiology of synkinesis.1 Abnormal nerve action leads to synkinetic movements, such as the closing of an eye with voluntary oral movement or midfacial movement on voluntary closure of the eye. Synkinesis can also be present in the platysma, leading to uncomfortable neck contractions.2 Synkinesis may lead to functional limitations with activities such as eating, drinking, and smiling and can lead to social isolation and decreased quality of life.3,4 The management of facial synkinesis consists of a combination of facial biofeedback routines, facial physical therapy, the chemodenervation of affected muscle groups using botulinum toxin type A injections, and surgical modification of the offending muscle group if possible.3-6

Botulinum toxin is a potent neuromodulator produced by the bacteria Clostridium botulinum, which acts at the neuromuscular junction by blocking the exocytosis of synaptic vesicles that contain acetylcholine.7,8 This process is accomplished through metalloproteinase action of the toxin that cleaves key fusion proteins required for vesicle docking and exocytosis. Prevention of acetylcholine release from presynaptic motor neurons by the toxin leads to muscle paralysis.

There are 3 brands of botulinum toxin type A products that are commonly used and commercially available in the United States: onabotulinumtoxinA (Botox, Allergan), abotulinumtoxinA (Dysport, Medicis), and incobotulinumtoxinA (Xeomin, Merz). Recently, the efficacy of onabotulinumtoxinA and abobotulinumtoxinA was compared for the cosmetic treatment of lateral periorbital lines.7 Another study9 that compared the efficacy of onabotulinumtoxinA and incobotulinumtoxinA in the treatment of benign essential blepharospasm was also recently completed, with the results revealing incobotulinumtoxinA to be more effective. To date, to our knowledge, no study has compared the efficacy of all 3 neuromodulators. Furthermore, no study has compared the efficacy of these botulinum products specifically in the treatment of facial synkinesis. The goal of the present study was to determine, using patient-reported outcome measures, whether a difference in efficacy exists among the 3 commercially available botulinum toxin type A neuromodulators used in the management of facial synkinesis.

Methods

Patients were prospectively enrolled in a single-blind randomized clinical trial from July 3, 2012 to March 31, 2015. All patients 18 years and older with facial synkinesis who presented to the Facial Nerve Center, University of Utah, Salt Lake City, for treatment and were appropriate candidates for botulinum toxin chemodenervation therapy were offered voluntary participation by one of us (P.D.W.). Exclusion criteria included previous complication from botulinum toxin neuromodulator injection, inability to understand or complete the Synkinesis Assessment Questionnaire (SAQ) survey, inability to participate in follow-up, and pregnancy. Written informed consent was obtained from each patient before enrollment in the study. Institutional review board approval was received from the University of Utah institutional review board.

A total of 28 patients were randomly assigned to treatment with onabotulinumtoxinA, abobotulinumtoxinA, or incobotulinumtoxinA by drawing of a random folder by one of us (P.D.W.), which was prepared by the research nurse at the Facial Nerve Center and contained the assigned treatment (Figure 1). Patients were masked to the treatment received, and all treatments were administered in the same fashion. After randomization, a previously validated instrument, the SAQ, was administered to evaluate patient-perceived severity of the synkinesis.10 No clinician-graded facial nerve outcomes were recorded in this trial. After completion of the SAQ, patients were administered the assigned treatment. OnabotulinumtoxinA, abobotulinumtoxinA, or incobotulinumtoxinA was injected at a 3:1:1 ratio as recommended by previous studies7,11,12 and the clinical experience of one of us (P.D.W.). One of us (P.D.W.), a facial plastic surgeon with 4 years of experience in these procedures at the start of the trial, was solely responsible for advising patients on facial regions to treat and for performing the injections. The trial protocol can be found in the Supplement.

At 1, 2, and 4 weeks after treatment, patients were again administered the SAQ. The SAQ scores were calculated for each follow-up time point. The mean SAQ score in each treatment group (onabotulinumtoxinA, abobotulinumtoxinA, and incobotulinumtoxinA) for each week was calculated, as was the mean improvement in SAQ scores. Lower SAQ scores represented less severe patient-reported disease. The percentage of improvement in SAQ score was calculated for each time point as the mean posttreatment score divided by the mean pretreatment score for the treatment group subtracted from 1. The SAQ scores for each time point and treatment group were found to be normally distributed (passing both the D’Agostino-Pearson omnibus normality test and the Shapiro-Wilk normality test), allowing for an assumption of gaussian distribution in the following tests of statistical significance. Comparisons among treatments and time points within treatment groups were made using a 1-way analysis of variance (ANOVA) followed by appropriate follow-up tests for multiple comparisons. Comparisons within treatment groups among each follow-up time point and the control pretreatment time point were made using the Dunnett test (compares every mean to a control mean),13 whereas comparisons of different treatments at a given time point were made with the Tukey test (compares every mean to every other mean).14 A threshold of P ≤ .05 (2-tailed) was used for statistical significance.

Patients who had returned to their baseline SAQ score after a minimum of 12 weeks since their previous treatment were permitted to reenroll in the study for subsequent treatments. Twenty-eight patients were studied, and 6 of these patients were enrolled multiple times, accounting for 10 of the 38 treatments studied. To ensure that the baseline SAQ scores of these patients receiving repeated treatments did not differ from patients receiving a single treatment, we compared the mean pretreatment SAQ score for repeat-treatment patients with the mean pretreatment SAQ score of single-treatment patients for each type of botulinum toxin neuromodulator. These groups were evaluated for normality of distribution by the same method as described above, with single-treatment patients passing tests of normality; normality for the patients undergoing repeated treatments could not be determined because of the small number of treatments for each of these patients. Statistical comparisons were then made between the pretreatment SAQ scores for repeat-treatment patients and the respective (same type of botulinum toxin) single-treatment patients. To preference type I error and identify any possible difference among these groups, we made an assumption of normality and used a 1-way ANOVA followed by a Holm-Sidak multiple comparison test. The Holm-Sidak method was chosen because it has more power to identify significant differences than other possible methods, such as that of Bonferroni.15 All analyses were performed for the groups originally assigned, with no crossover of patients among the treatment groups during the study period.

To put the changes in posttreatment scores in greater clinical context, we calculated effect sizes of the posttreatment changes. An estimation of effect size was calculated as the difference in pretreatment to posttreatment SAQ score divided by the pretreatment score SD, and by convention, we considered scores of 0.2 to be small, 0.5 to be moderate, and 0.8 to be large.16 Cost comparisons among the products were made using the actual costs of these products at the clinic where the study was conducted. The trial ended after the designated study period expired.

Results

A total of 28 patients (8 [28.6%] male and 20 [71.4%] female; mean [SD] age, 49.1 [18.5] years), with 6 patients enrolled multiple times to account for 10 of the 38 treatments studied (15 [39%] male and 23 [61%] female among the 38 treatments; mean [SD] age at the time of treatment, 49.1 [17.3] years), met the inclusion criteria. Of the 38 treatments, 15 were onabotulinumtoxinA, 13 abobotulinumtoxinA, and 10 incobotulinumtoxinA. The pretreatment SAQ scores were not statistically different among the treatment groups (mean [SD] pretreatment SAQ scores, 79.56 [15.05], 70.09 [15.28], and 69.56 [9.72]; the differences among groups were not significant by 1-way ANOVA; P = .13) (Table 1). For patients reenrolled and receiving repeat treatments with botulinum toxin type A, the return of their pretreatment SAQ score to a baseline consistent with patients undergoing a single treatment was confirmed, with no significant difference in pretreatment scores between single-treatment and repeat-treatment patients. A comparison of repeat-treatment patients and single-treatment patients is shown in Figure 2. Having confirmed no significant differences in the pretreatment SAQ scores and baseline characteristics of the botulinum toxin type A treatment groups, we evaluated the change in SAQ score from pretreatment at 1, 2, and 4 weeks after treatment. The mean SAQ scores and percentage of improvement during the study for each treatment group are reported in Table 2. A significant decrease in SAQ score from the respective pretreatment score was seen for all botulinum toxins at all time points except for incobotulinumtoxinA, which demonstrated no significant change in SAQ score from pretreatment at 4 weeks. A comparison of mean total SAQ scores by treatment group at each time point is shown in Figure 3. The locations of treatments were wide ranging within each treatment group because they were uniquely administered for each patient, although these locations were overall grossly similar among the treatment groups.

When compared statistically using a 1-way ANOVA followed by the Dunnett posttest, there was a significant decrease in SAQ score at each time point for onabotulinumtoxinA (scores of 45.93 at week 1, 45.19 at week 2, and 46.37 at week 4; P < .001) and abobotulinumtoxinA (scores of 38.80 at week 1, 37.61 at week 2, and 40.34 at week 4; P < .001) compared with the pretreatment score. However, for incobotulinumtoxinA, there was a significant decrease in SAQ scores at week 1 (score of 51.33; P = .003) and week 2 (score of 49.78; P = .001) but no significant difference from pretreatment scores at 4 weeks (score of 58.00; P = .08) (Table 2).

No significant difference was noted in SAQ score improvements among the onabotulinumtoxinA, abobotulinumtoxinA, and incobotulinumtoxinA groups at weeks 1 and 2 after treatment (week 1 mean improvements of 42% in the onabotulinumtoxinA group, 45% in the abobotulinumtoxinA group, and 26% in the incobotulinumtoxinA group; 1-way ANOVA overall 1-week P = .19; week 2 mean improvements of 43% in the onabotulinumtoxinA group, 46% in the abobotulinumtoxinA group, and 28% in the incobotulinumtoxinA group; 1-way ANOVA overall 2-week P = .20. A significant difference among the groups was observed at week 4 (week 4 mean improvements of 41% in the onabotulinumtoxinA group, 42% in the abobotulinumtoxinA group, and 17% in the incobotulinumtoxinA group; 1-way ANOVA overall P = .045). Post-hoc Tukey test for multiple comparisons at week 4 after treatment showed significantly better SAQ score improvement for onabotulinumtoxinA vs incobotulinumtoxinA (41% vs 17%; P = .046). The abobotulinumtoxinA group had greater mean SAQ score improvement vs the incobotulinumtoxinA group, although this finding did not reach statistical significance at any time point (44% vs 24%, P = .21). The difference in SAQ score improvement for abobotulinumtoxinA vs incobotulinumtoxinA at 4 weeks was not statistically significant (42% vs 17%; P = .11) despite a statistically significant difference in total SAQ score at this time point for abobotulinumtoxinA vs incobotulinumtoxinA (40.34 vs 58.00; P = .02). We focused on the more clinically relevant SAQ score improvement because this takes into account differences in the pretreatment groups, unlike comparing the total SAQ score at each time point.

Minor adverse effects reported during the study included redness, bruising, swelling, and fullness at the injection sites; these adverse effects were not believed to be meaningful or noted to be qualitatively different among the products. No major adverse treatment effects were reported during the study.

Discussion

Synkinesis can be a distressing consequence of facial paralysis and can lead to impaired facial functionality, social isolation, and decreased quality of life.3,10,12 Facial neuromuscular training with biofeedback and botulinum neuromodulator injections have proven to be effective therapies in the management of facial synkinesis and have emerged as the standard of care in its treatment.3-6,17-21 Although botulinum toxin type A is known to be effective for treating synkinesis,5-8,22,23 we are not aware of any studies that compare the efficacy of the 3 commercially available botulinum products. The purpose of this study was to determine whether there was a difference in the efficacy of the 3 commercially available botulinum neuromodulators (onabotulinumtoxinA, abobotulinumtoxinA, and incobotulinumtoxinA) in the treatment of facial synkinesis.

We found no significant difference in the efficacy of onabotulinumtoxinA, abobotulinumtoxinA, and incobotulinumtoxinA based on the SAQ score improvements at 1 and 2 weeks after treatment. However, at 4 weeks after treatment, the SAQ score improvement associated with onabotulinumtoxinA administration was significantly greater than that associated with incobotulinumtoxinA (Table 2). Although the overall means of all posttreatment SAQ scores at 1, 2, and 4 weeks were not statistically different among the treatment groups, the mean SAQ scores for the incobotulinumtoxinA group at all posttreatment time points were greater than those for the other treatment groups despite a slightly lower mean pretreatment score. Consistent with this, the mean improvements in the SAQ scores for abobotulinumtoxinA (42% improvement) and onabotulinumtoxinA (44% improvement) were larger than those for incobotulinumtoxinA (24% improvement) during the entire study period (Table 2). This finding was surprising because we had noted no qualitative concerns from patients about incobotulinumtoxinA compared with the other botulinum toxins.

This finding of a statistically significant difference in SAQ score improvement associated with onabotulinumtoxinA and incobotulinumtoxinA treatments raises an important consideration in clinical research. A statistically significant difference is not necessarily clinically significant. The SAQ used as the primary source of measurement in this study has been previously validated as an effective tool for the assessment of facial synkinesis.10 Although it demonstrates statistical validity in measuring synkinesis and identifying changes with botulinum therapy, the minimum clinically important difference (MCID) of this score is unclear. The MCID is the smallest improvement in score that is considered to be important to the patient.24 There are multiple methods that have been suggested for estimating the MCID, and although none is perfect, they may help put numbers into clinical context. An MCID of 0.5 SD is applicable to many different clinical contexts, and its general applicability has been attributed to the human ability of mentally discriminating differences of approximately 1 in 7, or 0.5 SD.25,26 Applying this concept to our study, we found a mean 0.5 SD for the pretreatment conditions to be approximately 7.2 and that all pretreatment to posttreatment SAQ changes at each time point and for each botulinum toxin type A exceed the 0.5 SD–defined MCID. Furthermore, the statistically significant difference in SAQ score improvement of onabotulinumtoxinA compared with incobotulinumtoxinA at week 4 (21.33) was above this threshold for MCID, suggesting not only a statistical difference but also a clinical difference in effect. Similarly, the difference in SAQ score improvement between abobotulinumtoxinA and incobotulinumtoxinA at week 4 (18.18) was above the MCID despite failing to reach statistical significance. Effect size was also estimated to further place the statistical findings in a clinical context, and the changes in SAQ score from before to after treatment at all time points and for all botulinum toxins were above what is considered to be a large effect (≥0.8 by convention).

Limitations

A potential weakness of our study is the reenrollment of patients already treated with botulinum toxin type A for synkinesis. The primary concern with recurrent botulinum toxin type A injections is the possibility of immunogenicity and the development of tolerance. The formation of neutralizing and nonneutralizing antibodies against botulinum toxin type A has been observed in human studies27-29 in the past, leading to unresponsiveness to the treatment. This unresponsiveness was specifically associated with large doses of botulinum toxin type A, and 20% of patients taking repetitive large doses of toxins were unresponsive to treatment at 5 years.27 Tachyphylaxis may also lead to decreased responsiveness with repeat treatments, and 15% of patients have been reported to become resistant to treatment with botulinum toxin type A after 5 years of treatment because of tachyphylaxis.27

Despite the aforementioned concerns associated with the repetitive use of botulinum toxin type A injections, we do not believe repeat botulinum injections have confounded the results of this study. Before reenrolling patients and considering them as unique patients, we ensured that they had returned to their baseline synkinetic state. Pretreatment SAQ scores in each group were not statistically different, and the mean pretreatment scores for the patients undergoing repeat treatments were not significantly different from the mean pretreatment scores of those patients receiving a single treatment (Figure 2). In addition to no significant difference in baseline characteristics, there is biologic plausibility for a lack of effect from repeat injections because our study used small doses of botulinum toxin type A, which carries less risk of immunogenicity and tolerance.27 Our study was also conducted during a short period and not the multiple-year duration of treatment often reported for the development of antibody-related resistance. Furthermore, the application of botulinum toxin type A has not been found to lead to persistent histologic changes in the nerve terminal or the target muscle, allowing for repetitive injection without concern that these changes that would affect our study.30 Finally, each patient who reenrolled in the study was required to be at least 12 weeks past their last botulinum toxin type A treatment; this strategy was believed to safely ensure that the effects of the prior treatment had ended before patients entered the study again.

Another weakness of the study was the small number of patients enrolled and treatments assessed; however, we achieved adequate power to identify the statistically significant associations described. Our sample size was most constrained by performing the trial at a less busy practice location, where it was approved and where all 3 botulinum neuromodulators were available. However, the limited sample size does not reflect limited experience of the performing physician because approximately 200 to 300 of these procedures were performed annually when all other practice locations were considered.

The facial locations treated were individualized to each patient’s specific pattern of synkinesis so that each patient could achieve the full benefit of chemodenervation. Thus, the anatomical treatment areas varied widely from patient to patient. However, the overall ranges of anatomical treatment locations were similar for each of the types of botulinum toxin type A administered, suggesting that the differences in efficacy among the toxins were not related to gross differences in facial areas treated; for example, onabotulinumtoxinA was not used exclusively for treatment of the neck, and incobotulinumtoxinA was not used exclusively for treatment of the brow.

The dosage ratio of abobotulinumtoxinA to onabotulinumtoxinA and incobotulinumtoxinA used in this study was 3:1:1. This ratio was selected based on previous studies31,32 and for ease in calculation. The recommended dosage ratio for abobotulinumtoxinA, onabotulinumtoxinA, and incobotulinumtoxinA is 2.5:1:1. This difference may cause a slight inflation in scores and improvements for the abobotulinumtoxinA group and is most likely the cause of the abobotulinumtoxinA scores being slightly better than the onabotulinumtoxinA scores in our study. Although the scores were elevated, they did not reach statistical significance and therefore did not appear to change the outcomes of this study.

The value (outcome and cost) of these treatments is important to consider as we work to improve outcomes and decrease costs of care. We therefore evaluated relative costs of these products in addition to the synkinesis outcomes that we reported. The costs used here for our comparison may not be generalizable to other practice environments where purchase quantity of product, units per vial, and individual price negotiations may alter cost. Our costs were $5.79 per unit of onabotulinumtoxinA (100-U vial), $1.71 per unit of abobotulinumtoxinA (300-U vial), and $4.66 per unit (50- or 100-U vial) of incobotulinumtoxinA. At the 3:1:1 ratio of abobotulinumtoxinA to units of the other botulinum toxins used in this study, the cost of an equivalent dose of abobotulinumtoxinA (3 U) was $5.13. On the basis of our costs, incobotulinumtoxinA is the cheapest per equivalent units. However, the cost of incobotulinumtoxinA is 80% of the cost of onabotulinumtoxinA and 91% of the cost of onabotulinumtoxinA (3-U cost), with our findings demonstrating relative mean SAQ reductions with incobotulinumtoxinA of only 57% and 55%, respectively, compared with these other 2 products. This finding suggests that the somewhat lower cost of incobotulinumtoxinA is not sufficient to achieve equivalent value with the other products in regard to SAQ outcomes.

Conclusions

In a prospective, single-blind randomized clinical trial of the efficacy of 3 commercially available botulinum neuromodulators in the treatment of facial synkinesis, all 3 had similar efficacy at 1 and 2 weeks after treatment. Four weeks after treatment, abobotulinumtoxinA and onabotulinumtoxinA had similar efficacy, whereas incobotulinumtoxinA had decreased efficacy at this particular time point after treatment and reached a statistically significant difference compared with abobotulinumtoxinA. Further research into the differences between these products should be undertaken to help determine whether particular products may be better suited to certain applications or whether the dosage should be adjusted to establish clinical equivalence of these products. IncobotulinumtoxinA was associated with a lower cost per unit at our institution, although this was not proportionate to the reduced magnitude of SAQ improvement; therefore, the value of this product for treatment of facial synkinesis may be relatively less than abobotulinumtoxinA and onabotulinumtoxinA.

Back to top
Article Information

Corresponding Author: P. Daniel Ward, MD, MS, Division of Otolaryngology–Head and Neck Surgery, University of Utah School of Medicine, 50 N Medical Dr, Room 3C-120, Salt Lake City, UT 84132 (pdanielward@hsc.utah.edu).

Accepted for Publication: July 1, 2017.

Published Online: September 28, 2017. doi:10.1001/jamafacial.2017.1393

Author Contributions: Mr Larson and Dr Thomas contributed equally to this work as co–first authors. Dr Ward had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Braden, Cannon, Ward.

Acquisition, analysis, or interpretation of data: Thomas, Larson, Braden, Cannon.

Drafting of the manuscript: Thomas, Larson, Cannon.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Thomas, Larson, Braden, Cannon.

Administrative, technical, or material support: Braden, Cannon, Ward.

Study supervision: Thomas, Cannon, Ward.

Conflict of Interest Disclosures: None reported.

Meeting Presentation: This work was presented as a poster at the Annual Meeting of the American Academy of Facial Plastic and Reconstructive Surgery; October 6-8, 2016; Nashville, Tennessee.

References
1.
Crumley  RL.  Mechanisms of synkinesis.  Laryngoscope. 1979;89(11):1847-1854.PubMedGoogle ScholarCrossref
2.
Dall’Angelo  A, Mandrini  S, Sala  V,  et al.  Platysma synkinesis in facial palsy and botulinum toxin type A.  Laryngoscope. 2014;124(11):2513-2517.PubMedGoogle ScholarCrossref
3.
Husseman  J, Mehta  RP.  Management of synkinesis.  Facial Plast Surg. 2008;24(2):242-249.PubMedGoogle ScholarCrossref
4.
Finn  JC.  Botulinum toxin type A: fine-tuning treatment of facial nerve injury.  J Drugs Dermatol. 2004;3(2):133-137.PubMedGoogle Scholar
5.
Hadlock  TA, Greenfield  LJ, Wernick-Robinson  M, Cheney  ML.  Multimodality approach to management of the paralyzed face.  Laryngoscope. 2006;116(8):1385-1389.PubMedGoogle ScholarCrossref
6.
Choi  KH, Rho  SH, Lee  JM, Jeon  JH, Park  SY, Kim  J.  Botulinum toxin injection of both sides of the face to treat post-paralytic facial synkinesis.  J Plast Reconstr Aesthet Surg. 2013;66(8):1058-1063.PubMedGoogle ScholarCrossref
7.
Nettar  KD, Yu  KC, Bapna  S, Boscardin  J, Maas  CS.  An internally controlled, double-blind comparison of the efficacy of onabotulinumtoxinA and abobotulinumtoxinA.  Arch Facial Plast Surg. 2011;13(6):380-386.PubMedGoogle ScholarCrossref
8.
Laskawi  R.  The use of botulinum toxin in head and face medicine: an interdisciplinary field.  Head Face Med. 2008;4:5.PubMedGoogle ScholarCrossref
9.
Saad  J, Gourdeau  A.  A direct comparison of onabotulinumtoxina (Botox) and incobotulinumtoxinA (Xeomin) in the treatment of benign essential blepharospasm: a split-face technique.  J Neuroophthalmol. 2014;34(3):233-236.PubMedGoogle ScholarCrossref
10.
Mehta  RP, WernickRobinson  M, Hadlock  TA.  Validation of the Synkinesis Assessment Questionnaire.  Laryngoscope. 2007;117(5):923-926.PubMedGoogle ScholarCrossref
11.
Moers-Carpi  M, Dirschka  T, Feller-Heppt  G,  et al.  A randomised, double-blind comparison of 20 units of onabotulinumtoxinA with 30 units of incobotulinumtoxinA for glabellar lines.  J Cosmet Laser Ther. 2012;14(6):296-303.PubMedGoogle ScholarCrossref
12.
Prager  W, Rappl  T.  Phase IV study comparing incobotulinumtoxinA and onabotulinumtoxinA using a 1:1.5 dose-conversion ratio for the treatment of glabellar frown lines.  J Cosmet Dermatol. 2012;11(4):267-271.PubMedGoogle ScholarCrossref
13.
Dunnett  C.  A multiple comparison procedure for comparing several treatments with a control.  J Am Stat Assoc. 1955;50(272):1096-1121.Google ScholarCrossref
14.
Tukey  JW.  Comparing individual means in the analysis of variance.  Biometrics. 1949;5(2):99-114.PubMedGoogle ScholarCrossref
15.
Seaman  Ma, Levin  JR, Serlin  RC.  New developments in pairwise multiple comparisons: some powerful and practicable procedures.  Psychol Bull. 1991;110(3):577-586.Google ScholarCrossref
16.
Muller  K, Cohen  J.  Statistical power analysis for the behavioral sciences.  Technometrics. 1989;31(4):499.Google ScholarCrossref
17.
Mehta  RP, Hadlock  TA.  Botulinum toxin and quality of life in patients with facial paralysis.  Arch Facial Plast Surg. 2008;10(2):84-87.PubMedGoogle ScholarCrossref
18.
Toffola  ED, Furini  F, Redaelli  C, Prestifilippo  E, Bejor  M.  Evaluation and treatment of synkinesis with botulinum toxin following facial nerve palsy.  Disabil Rehabil. 2010;32(17):1414-1418.PubMedGoogle ScholarCrossref
19.
Filipo  R, Spahiu  I, Covelli  E, Nicastri  M, Bertoli  GA.  Botulinum toxin in the treatment of facial synkinesis and hyperkinesis.  Laryngoscope. 2012;122(2):266-270.PubMedGoogle ScholarCrossref
20.
Terzis  JK, Karypidis  D.  Therapeutic strategies in post-facial paralysis synkinesis in adult patients.  Plast Reconstr Surg. 2012;129(6):925e-939e.PubMedGoogle ScholarCrossref
21.
Armstrong  MW, Mountain  RE, Murray  JA.  Treatment of facial synkinesis and facial asymmetry with botulinum toxin type A following facial nerve palsy.  Clin Otolaryngol Allied Sci. 1996;21(1):15-20.PubMedGoogle ScholarCrossref
22.
Couch  SM, Chundury  RV, Holds  JB.  Subjective and objective outcome measures in the treatment of facial nerve synkinesis with onabotulinumtoxinA (Botox).  Ophthal Plast Reconstr Surg. 2014;30(3):246-250.PubMedGoogle ScholarCrossref
23.
Frevert  J.  Xeomin: an innovative new botulinum toxin type A.  Eur J Neurol. 2009;16(suppl 2):11-13.PubMedGoogle ScholarCrossref
24.
Copay  AG, Subach  BR, Glassman  SD, Polly  DW  Jr, Schuler  TC.  Understanding the minimum clinically important difference: a review of concepts and methods.  Spine J. 2007;7(5):541-546.PubMedGoogle ScholarCrossref
25.
Norman  GR, Sloan  JA, Wyrwich  KW.  Interpretation of changes in health-related quality of life.  Med Care. 2003;41(5):582-592.PubMedGoogle Scholar
26.
Norman  GR, Sloan  JA, Wyrwich  KW.  The truly remarkable universality of half a standard deviation: confirmation through another look.  Expert Rev Pharmacoecon Outcomes Res. 2004;4(5):581-585.PubMedGoogle ScholarCrossref
27.
Pickett  A, Caird  D.  Discussion regarding botulinum toxin, immunologic considerations with long-term repeated use, with emphasis on cosmetic applications: minimal risk of antibody formation after aesthetic treatment with type a botulinum toxin.  Facial Plast Surg Clin North Am. 2009;17(4):633-634.PubMedGoogle ScholarCrossref
28.
Borodic  G, Johnson  E, Goodnough  M, Schantz  E.  Botulinum toxin therapy, immunologic resistance, and problems with available materials.  Neurology. 1996;46(1):26-29.PubMedGoogle ScholarCrossref
29.
Elston  JS.  Botulinum toxin A in clinical medicine.  J Physiol (Paris). 1990;84(4):285-289.PubMedGoogle Scholar
30.
Naumann  M, Albanese  A, Heinen  F, Molenaers  G, Relja  M.  Safety and efficacy of botulinum toxin type A following long-term use.  Eur J Neurol. 2006;13(s4)(suppl 4):35-40.PubMedGoogle ScholarCrossref
31.
Ravenni  R, De Grandis  D, Mazza  A.  Conversion ratio between Dysport and Botox in clinical practice: an overview of available evidence.  Neurol Sci. 2013;34(7):1043-1048.PubMedGoogle ScholarCrossref
32.
Scaglione  F.  Conversion Ratio between Botox®, Dysport®, and Xeomin® in Clinical Practice.  Toxins (Basel). 2016;8(3):65.PubMedGoogle ScholarCrossref
×