Conditions: Spasmodic Dysphonia
Keywords: Pain
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 32
Healthy volunteers: no

Brief summary:
This study aims to identify adjuvant methods to improve patient comfort during in-office laryngology procedures.

Detailed description:
Hypothesis:

The use of local anesthetic or vibrating instrument will decrease overall pain experienced by a patient with spasmodic dysphonia undergoing Botox injections.

Aims, purpose, or objectives:

To identify adjuvant methods to improve patient comfort during in-office laryngology procedures. Results demonstrated here should be transferrable to other transcutaneous in-office procedures in laryngology.

Background:

Spasmodic dysphonia is a vocal disorder characterized by uncontrollable voice breaks. Injection of botulinum neurotoxin into the laryngeal muscles is the mainstay of treatment. Patients require repeated treatments due to the temporary effect of botulinum neurotoxin. Laryngeal injections are commonly performed through the skin of the neck and can be associated with pain and discomfort. Local anesthetic administration prior to laryngeal injection is commonly performed in clinical practice, however its efficacy hasn't been evaluated and a third of surveyed otolaryngologists do not administer local anesthesia prior to the laryngeal injection of botulinum neurotoxin. Vibratory anesthesia involves the application of a local vibratory stimulus and has been found to reduce pain during various needle-related procedures. Vibratory anesthesia has not previous been evaluated for laryngeal injections.

This study will utilize the need for spasmodic dysphonia patients to receive repeated injections to incorporate a crossover design where patients receive three consecutive laryngeal injections of botulinum toxin experiencing injection without additional anesthesia, with local anesthesia, and with vibration anesthesia in a randomized order.

Arms:
arm 1: Patients will receive standard of care laryngeal injection of Botox via a transcricothyroid approach without additional anesthesia arm 2: Patients will receive standard of care laryngeal injection of Botox via a transcricothyroid approach following subcutaneous injection of lidocaine (approximately 2 minutes before Botox injection). arm 3: Patients will receive standard of care laryngeal injection of Botox via a transcricothyroid approach while using the vibrating wand.

Interventions: intervention 1: Lidocaine intervention 2: Vibrating wand
Intervention descriptions: intervention 1: Subcutaneous injection 0.5cc 2% in 1:100,000 epinephrine intervention 2: a vibrating instrument held adjacent to the cricothyroid space

Protocol document:
Prot_SAP_000.pdf: 
 
 
Spasmodic Dysphonia Pain Study 
 
NCT04648891 
 
7/5/2020 


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General Study Information 
 
Principal Investigator:       Dr. William Karle 
 
 
 
 
 
 
 
 
Study Title:    Spasmodic Dysphonia Pain Study 
 
Protocol version number and date:     Version 1. 07/05/20 
 
Research Question and Aims 
 
Hypothesis: The use of local anesthetic or vibrating instrument will decrease overall pain experienced by a 
patient with spasmodic dysphonia undergoing Botox injections. 
 
Aims, purpose, or objectives: To identify adjuvant methods to improve patient comfort during in-office 
laryngology procedures.  Results demonstrated here should be transferrable to other transcutaneous in office 
procedures in laryngology. 
 
Background (Include relevant experience, gaps in current knowledge, preliminary data, etc.): 
 


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  BACKGROUND AND SIGNIFICANCE 
Spasmodic Dysphonia (SD)  
Spasmodic dysphonia (SD) is a task-specific focal laryngeal dystonia characterized by irregular and 
uncontrolled voice breaks that interrupt normal speech flow.1 The condition was first described by Critchley in 
1939 and was for some time considered a psychiatric disorder.2 The estimated prevalence in western society is 
between 1 in 50,000 and 1 in 100,000.3,4 There are likely multiple neurological processes involved in the 
pathophysiology of SD: reduced cortical inhibition, sensory-processing and reflex disturbances, and 
neuroanatomical findings at several different levels. Thus, SD should be considered an integrative system 
disorder, rather than a disorder with a single pathological focus.1 Its etiology is multifactorial, including 
neurological, genetic, and environmental factors. Epidemiological risk factors have been suggested from several 
large cohort studies. The most commonly identified characteristics are females in their middle decades of life, a 
family history of neurological diseases including dystonia, recent life stressors, upper respiratory tract 
infections, and a history of childhood measles or mumps.1 The eventual development of SD may be viewed as a 
multiple-hit mechanism, with endogenous predispositions and environmental triggers resulting in the 
development of its phenotype. Adductor spasmodic dysphonia (AdSD), characterized by a harsh, strain-
strangled voice with breaks on vowels in speech, is the most common variant of the condition.5 Vocal tremor 
co-occurs in 30% to 60% of AdSD patients.1,5 
A three-tiered approach, involving clinical history, followed by speech assessment and in-office laryngoscopy is 
the most widely accepted method for making the diagnosis of SD.5 Diagnosis is often made years after 
symptom onset and following assessment by numerous physicians.6 In clinical practice, a history of speech 
therapy failing to ameliorate symptoms and positive treatment response to botulinum neurotoxin is a reliable 
adjunct to diagnosis. Botox (onabotulinumtoxinA) is the most frequently used and studied formulation of 
botulinum neurotoxin. 
Based on the significant symptom response of blepharospasm to intermittent injections of Botox, Blitzer et al. 
performed the first laryngeal injection of Botox for SD in 1984.7,8 Botulinum neurotoxin is internalized at the 
nerve terminal and works by cleaving proteins in the SNARE (soluble n-ethylmaleimide-sensitive factor [NSF] 
attachment protein receptor) complex, which facilitate the binding of vesicles containing acetylcholine to the 
nerve terminal.9,10 Botulinum neurotoxin cleaves SNAP-25 inhibiting presynaptic acetylcholine release and 
muscle activity.9 The precise mechanism by which botulinum neurotoxin improves SD symptomatology is 
unknown. Its effect is not fully explained by chemodenervation of the thyroarytenoid muscle since other 
adductor muscles are relatively unaffected and some patients experience improvement in concurrent 
extralaryngeal dystonias.9 It may therefore result in disease modulation at a central level.11  
Despite its use in the larynx being considered “off-label” by the U.S. Food and Drug Administration (FDA), 
botulinum neurotoxin has remained the first-line treatment for spasmodic dysphonia.12 botulinum neurotoxin is 
the recommended primary management strategy in the American Academy of Otolaryngology-Head and Neck 
Surgery’s Clinical Practice Guideline for dysphonia.13 Alternative treatment options for SD include surgical 
treatments, which include thyroarytenoid myotomy/myectomy, thyroplasty, selective laryngeal adductor 
denervation-reinnervation, laryngeal nerve crush, and recurrent laryngeal nerve resection.14 There are no 
published randomized controlled trials comparing the effect of Botox injections and surgical treatment.14 A 
systematic review published in 2017 reported that preference for one treatment could not be demonstrated.14 
The effect of bilateral Botox injections was evaluated and the authors found an improvement in the objective 
outcome, subjective outcome, and quality of life. The mean duration of effect ranged between 14 and 18 weeks. 
There is currently no cure for the condition. Thalamic deep brain stimulation may become a future treatment 
option to interfere with the central pathophysiology of SD.15 


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Laryngeal Injections 
In-office procedures are increasingly common in laryngology.16 Their success is dependent on adequate 
analgesia, and while these procedures are generally considered to be well-tolerated, few studies address pain or 
patient experience. A systematic review published in 2019 analyzed the literature for studies reporting 
qualitative or quantitative data for periprocedural pain assessment in adult patients undergoing in-office 
otolaryngology procedures.16 A total of 86 studies met inclusion criterial, of which 31 related to laryngology. Of 
the 86 studies, only 13 were prospective studies comparing interventions and none of these studies addressed 
analgesia in laryngeal injections.16 This study will be the first to compare the impact of anesthetic techniques in 
laryngeal injections. 
Vocal fold injections (VFI) are commonly performed in-office procedures in laryngology that can be used as a 
treatment modality in vocal fold paralysis and in a number of other laryngeal pathologies, in addition to 
enabling the injection of botulinum neurotoxin in the treatment of SD. These can be performed transcutaneously 
(with multiple techniques), transnasally, or transorally. The transcricothyroid approach (a needle is passed 
through the skin, soft tissue, and cricothyroid membrane) is the most studied technique overall. Specific to the 
treatment of SD, a transcricothyroid approach is favored by 90% of laryngologists treating SD with botulinum 
neurotoxin.12 
The patient experience and pain associated with laryngeal injections have been previously studied.17,18,19 Young 
et al. reported the patient tolerance of 154 in-office laryngeal procedures including 108 VFIs, of which 8 were 
Botox injections.17 Transcutaneous VFI was performed following injection of subcutaneous local anesthetic. 
The rate of completion of the first-choice VFI approach was 93%. Average patient-reported pain on the VAS 
was approximately 40. There was no statistically significant difference in pain between percutaneous and per-
oral VFI approaches (VAS 43.1 versus 38.4). Discomfort score differed significantly between those patients 
who had a VFI successfully completed with the first-choice VFI technique versus those who required more than 
one VFI approach (36.03 versus 61.29).17 Birkent et al. enrolled 26 patients receiving VFI with a 
transcricothyroid approach under local anesthesia with a mean reported VAS of 44.18 Crawley et al. enrolled 45 
patients to study the perception and duration of pain after VFI.19 Injection was performed with a 
transcricothyroid approach following local and topical anesthesia. Almost 80% of patients reported increased 
pain from baseline to during the procedure and from baseline to after the procedure. The majority of patients 
reported that their pain persisted or worsened during the first post-procedure day. Almost half of patients took 
additional pain medication. A third of patients were still experiencing some discomfort on the third post-
procedure day. They found that the magnitude of the increase in pain during the procedure was significantly 
associated with the presence of pain on the third post-procedure day. This data supports the hypothesis that 
nociceptive sensitization is responsible for lingering pain. In this study, patients reported a significant increase 
in sickening and punishing sensations as well as exhaustion and fear during the procedure.19  
None of these studies controlled or compared anesthetic techniques. In each of the aforementioned studies, 
subcutaneous local anesthetic was delivered prior to transcutaneous injections. However, one-third of 
laryngologists report not using local anesthesia when treating SD with Botox.12 Nor were alternative anesthetic 
techniques utilized. 
 
 
 


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Vibration Anesthesia 
Vibratory stimulation is defined as the performance of continuous, quick, slight shaking movements on the skin 
using devices or fingers.20 The application of a vibratory stimulus has been shown to improve patient 
discomfort associated with various needle-related procedures including botulinum neurotoxin injections for 
cosmetic indications.21 The application of intense stimuli to the skin as a means of pain relief is not a novel 
concept.22 Countless generations of bruised knees have been taken to mother so that she could "rub it to make it 
better". Ancient Greeks used vigorous massage to deal with sporting injuries, and by the early renaissance, de 
Mandeville was able to include percussion as a recognized treatment for pain. Percussion analgesia for 
amputation stump pain was recognized in the aftermath of the American Civil War, but this approach was not 
reported until the mid-1940s.22  
 
In the 1960s a mechanism for the anesthetic capability of vibration was proposed. Melzack and Wall’s “gate 
control” theory of pain postulates that the intensity of pain can be reduced by concurrent non-noxious 
stimulation, such as vibration.23 Their hypothesis states that the transmission of the sense of vibration from 
mechanoreceptors located in the skin via A-β nerve fibers results in the shutting down of a “gate” through 
which pain signals are transmitted to the brain through A-δ and C fibers.23 Despite this physiologic concept 
being well-recognized, in addition to much empirical evidence existing to support its validity, prospective 
controlled trials assessing its utility during awake procedures have only recently been produced.  
 
A number of studies exist in the facial plastic surgery literature analyzing the analgesic properties of vibratory 
stimulation while performing cosmetic injections.21,24-26 Sharma et al. applied a vibratory stimulus during the 
cosmetic facial injection of Botox.21 There was a statistically significant reduction in patient’s pain scores (1.3 
vs 2.4 on a five-point Likert-type scale). Of the 50 patients, 82% noted that the vibration side of the face had 
lower pain than the side of their face injected without vibration. Further, 86% these patients preferred to utilize 
vibratory analgesia for subsequent injections.21 Mally et al. applied a vibratory stimulus during injection of the 
nasolabial folds with dermal filler.24 They found improved patient tolerance with vibratory stimulation. While 
88% of patients found the injections moderate to severely painful without vibration, only 14% with vibration 
experienced moderate to severe pain.24 This finding was replicated by Guney et al. in a randomized split-lip 
study assessing vibration anesthesia during lip augmentation with cosmetic filler.25 The overall pain score on 
the vibration-assisted side was significantly reduced (3.8 vs 5.6 on a ten-point Likert-type scale). Of the 25 
patients enrolled in this study, 23 stated that they would want to have vibration anesthesia for future injections. 
The 2 patients who declined vibration stimuli for the future stated that they felt an increase of pain and anxiety 
with the addition of vibration. Both of these patients underwent lip augmentation for the first time. All patients 
that had undergone previous lip augmentation treatments expressed a desire for vibration anesthesia in the 
future.25 Chorney et al. published a prospective, randomized, self-control trial of cosmetic botulinum toxin 
injections comparing vibration anesthesia to topical ice analgesia to no additional analgesia.26 There were 30 
injections given with vibration analgesia, with a mean VAS of 26.5. There were 28 injections given with ice 
that resulted in a mean VAS of 24.4. Among the 30 injections given without any analgesia, patients had mean 
VAS of 29.4. There was no statistically significant difference between these groups. Of note this study design 
resulted in a lack of power given only a maximum of 30 injections were present in each arm. 
 
There is additional support for the analgesic properties of vibratory stimulation outside of the facial plastic 
surgery literature. A systematic review evaluated evidence of the effectiveness of vibratory stimulation to 
reduce needle-related procedural pain in children.20 The meta-analysis of this systematic review showed 


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that vibratory stimulation was significantly effective according to both self-rated and observer-rated pain 
measurements regardless of age group, type of procedure, or type of vibration device.20 Within the dermatology 
literature further support can be found. Park et al. studied VAS scores when vibration anesthesia 
was used during keloid triamcinolone injections. Intralesional injection therapy without vibration 
yielded mean VAS scores of 59 compared to 33 when vibration was used (P < .05).27 Fix et al. studied vibration 
anesthesia during the injection of lidocaine in an open label, randomized, controlled, split-body 
trial. The median VAS pain score was 26 for injections without vibration versus 7.5 with vibration (P<0.01).28 
 
However, no study to date has analyzed the use of vibration analgesia during VFI. 
 
 
 
Study Design and Methods 
 
Methods:  Describe in lay terms, completely detailing the research activities that will be conducted by Mayo 
Clinic staff under this protocol. 
 
 
Each patient will undergo each of the three treatment modalities.  The order in which they receive these will be 
randomized.   
Treatment Group A (control): No anesthesia 
Treatment Group B: 0.5cc subcutaneous 2% lidocaine in 1:100,000 epinephrine (done approximately 2 minutes 
before Botox injection) 
Treatment Group C: Vibrating instrument held adjacent to cricothyroid space as Botox injection is performed 
 
The nurse assisting the procedure will also time the Botox portion of the procedure to enable analysis of 
whether pain is associated with longer procedure time.   
          
Patient participation is expected to last approximately 6-12 months. The study specific questionnaire #1 will be 
given at only their first visit.  Study specific questionnaire #2 will be given immediately after each Botox 
injection.   
 
 
 
Subject Information 
 
Target accrual is the proposed total number of subjects to be included in this study at Mayo Clinic. A “Subject” 
may include medical records, images, or specimens generated at Mayo Clinic and/or received from external 
sources.    
 
Target accrual: 50 
 
Subject population (children, adults, groups):  Adults with spasmodic dysphonia 
 


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Inclusion Criteria:  
                -spasmodic dysphonia with or without tremor 
                -receiving botox as treatment via a transcricothyroid approach 
                 
Exclusion Criteria:   
 
    -allergy to lidocaine  
 
 
 
 
Biospecimens 
 
Collection of blood samples. When multiple groups are involved copy and paste the appropriate section below 
for example repeat section b when drawing blood from children and adults with cancer.  
 
a. From healthy, non-pregnant, adult subjects who weigh at least 110 pounds. For a minimal risk 
application, the amount of blood drawn from these subjects may not exceed 550ml in an 8 week period 
and collection may not occur more frequently than 2 times per week. 
Volume per blood draw: _____ml   
Frequency of blood draw (e.g. single draw, time(s) per week, per year, etc.) ___________ 
 
b. From other adults and children considering age, weight, and health of subject. For a minimal risk 
application, the amount of blood drawn from these subjects may not exceed the lesser of 50 ml or 3 ml 
per kg in an 8 week period, and collection may not occur more frequently than 2 times per week.   
Volume per blood draw: _____ml 
Frequency of blood draw (e.g. single draw, time(s) per week, per year, etc.) ___________  
 
Prospective collection of biological specimens other than blood: ______________________________ 
 
 
Review of medical records, images, specimens  
 
 
Check all that apply (data includes medical records, images, specimens).  
 
  Only data that exists before the IRB submission date will be collected.   
 
Date Range for Specimens and/or Review of Medical Records:   
Examples: 01/01/1999 through 12/31/2015, or all records through mm/dd/yyyy.  
 
Note: The Date Range must include the period for collection of baseline data, as well as follow-up data, 
if applicable. 


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X
  The study involves data that exist at the time of IRB submission and data that will be generated after IRB 
submission. Include this activity in the Methods section.  
Examples 
• The study plans to conduct a retrospective chart review and ask subjects to complete a questionnaire.  
• The study plans to include subjects previously diagnosed with a specific disease and add newly 
diagnosed subjects in the future.  
 
  The study will use data that have been collected under another IRB protocol. Include in the Methods section 
and enter the IRB number from which the research material will be obtained. When appropriate, note when 
subjects have provided consent for future use of their data and/or specimens as described in this protocol.  
 
Enter one IRB number per line, add more lines as needed 
 
 Data    
 Specimens  
 Data & Specimens  ______________________________________ 
 
 Data    
 Specimens  
 Data & Specimens  ______________________________________ 
 
 Data    
 Specimens  
 Data & Specimens  ______________________________________ 
 
 
Data Analysis 
 
 
Power analyses may not be appropriate if this is a feasibility or pilot study, but end-point analysis plans are 
always appropriate even if only exploratory. Provide all information requested below, or provide justification if 
not including all of the information.  
 
Power Statement:   
Sample size estimation is estimated based on the repeated methodology; that is, the VAS score will be measured 
at three time points (initial visit, 3 months and 6 months) for each patient. The comparisons between treatment 
arms (treatment B and C) and control arm (A) are of interest. To preserve the family wise type I error rate, 0.05, 
Bonferroni approach is used to adjust the pairwise type I error (0.05/2 = 0.025). We further assume the standard 
deviation across subjects at the same time point is 3.00, and there is a weak correlation between the VAS (<= 
0.3) within each patient. To achieve 80% to detect statistically significant differences in the mean VAS between 
A and B, and between A and C, the required sample size based on different value of correlation are listed 
below: 
 
 
 
VAS 
Required sample size 
A 
B 
C 
Correlation = 0.3 
Correlation = 0.1 
Correlation = 
0.05 
4 
1 
1 
18 
21 
22 


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2 
2 
32 
40 
42 
3 
3 
114 
145 
153 
5 
2 
2 
18 
31 
22 
3 
3 
33 
40 
42 
4 
4 
114 
145 
153 
6 
2 
2 
13 
14 
14 
3 
3 
18 
21 
22 
4 
4 
32 
40 
42 
5 
5 
114 
145 
153 
 
Note: The weaker the correlation and the smaller the mean difference in VAS the larger the sample size. 
Randomization schedule will be generated by the study statistician. Randomization will determine the order 
they get these treatments and can follow any permutation. 
 
Data Analysis Plan:  
Data Handling 
 
The study data will be entered and saved in REDCap. The REDCap database will be created by the 
study personnel. Only the PI and study personnel will have access to the database. 
Data analysis  
Data will be summarized by mean (standard deviation) or median (interquartile range) for 
continuous variables, and frequency count (percentage) for categorical variable. The number of 
patients without the VAS score at 3- and 6-months after the initial visit will be reported. Generalized 
estimating equation will be used to compare the mean VAS score between groups, and the point 
estimate of the mean difference and 95% confidence interval will be reported. 
 
Endpoints 
Primary: Response to the Visual Analogue Scale 
Secondary: Patient preference regarding injection analgesia 
 
 


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REFERENCES 
 
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Hintze JM, Ludlow CL, Bansberg SF, Adler CH, Lott DG. Spasmodic dysphonia: a review. part 1: pathogenic 
factors. Otolaryngology–Head and Neck Surgery. 2017 Oct;157(4):551-7 
2. 
Critchley M. Spastic dysphonia (“inspiratory speech”). Brain. 1939 Mar 1;62(1):96-103. 
3. 
White LJ, Hapner ER, Klein AM, Delgaudio JM, Hanfelt JJ, Jinnah HA, Johns III MM. Coprevalence of anxiety 
and depression with spasmodic dysphonia: a case-control study. Journal of Voice. 2012 Sep 1;26(5):667-e1. 
4. 
Konkiewitz EC, Trender-Gerhard I, Kamm C, Warner T, Ben-Shlomo Y, Gasser T, Conrad B, Ceballos-Baumann 
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5. 
Patel AB, Bansberg SF, Adler CH, Lott DG, Crujido L. The Mayo Clinic Arizona spasmodic dysphonia 
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6. 
Creighton FX, Hapner E, Klein A, Rosen A, Jinnah HA, Johns MM. Diagnostic delays in spasmodic dysphonia: a 
call for clinician education. Journal of Voice. 2015 Sep 1;29(5):592-4. 
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Blitzer A, Brin MF, Fahn S, Lovelace RE. Localized injections of botulinum toxin for the treatment of focal 
laryngeal dystonia (spastic dysphonia). The Laryngoscope. 1988 Feb;98(2):193-7. 
8. 
Blitzer A. Spasmodic dysphonia and botulinum toxin: experience from the largest treatment series. European 
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9. 
Novakovic D, Waters HH, D'Elia JB, Blitzer A. Botulinum toxin treatment of adductor spasmodic dysphonia: 
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10. 
Humeau Y, Doussau F, Grant NJ, Poulain B. How botulinum and tetanus neurotoxins block neurotransmitter 
release. Biochimie. 2000 May 1;82(5):427-46. 
11. 
Giladi N. The mechanism of action of botulinum toxin type A in focal dystonia is most probably through its dual 
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12. 
Shoffel‐Havakuk H, Rosow DE, Lava CX, Hapner ER, Johns III MM. Common practices in botulinum toxin 
injection for spasmodic dysphonia treatment: A national survey. The Laryngoscope. 2019 Jul;129(7):1650-6.  
13. 
Stachler RJ, Francis DO, Schwartz SR, Damask CC, Digoy GP, Krouse HJ, McCoy SJ, Ouellette DR, Patel RR, 
Reavis CC, Smith LJ. Clinical practice guideline: hoarseness (dysphonia)(update). Otolaryngology–Head and 
Neck Surgery. 2018 Mar;158(1_suppl):S1-42. 
14. 
Van Esch BF, Wegner I, Stegeman I, Grolman W. Effect of Botulinum Toxin and Surgery among Spasmodic 
Dysphonia Patients: A Systematic Review. Otolaryngology–Head and Neck Surgery. 2017 Feb;156(2):238-54. 
15. 
Poologaindran A, Ivanishvili Z, Morrison MD, Rammage LA, Sandhu MK, Polyhronopoulos NE, Honey CR. The 
effect of unilateral thalamic deep brain stimulation on the vocal dysfunction in a patient with spasmodic 
dysphonia: interrogating cerebellar and pallidal neural circuits. Journal of neurosurgery. 2018 Feb 1;128(2):575-
82. 
16. 
Frank E, Carlson B, Hu A, Randall DR, Tamares S, Inman JC, Crawley BK. Assessment and treatment of pain 
during in-office otolaryngology procedures: a systematic review. Otolaryngology–Head and Neck Surgery. 2019 
Aug;161(2):218-26. 
17. 
Young VN, Smith LJ, Sulica L, Krishna P, Rosen CA. Patient tolerance of awake, in‐office laryngeal procedures: 
a multi‐institutional perspective. The Laryngoscope. 2012 Feb;122(2):315-21. 
18. 
Birkent H, Sardesai M, Hu A, Merati AL. Prospective study of voice outcomes and patient tolerance of in‐office 
percutaneous injection laryngoplasty. The Laryngoscope. 2013 Jul;123(7):1759-62. 
19. 
Crawley BK, Dehom S, Kutzner E, Murry T, Krishna P, Hata J. Perception and duration of pain after office‐based 
vocal fold injection augmentation. The Laryngoscope. 2018 Apr;128(4):929-34. 
20. 
Ueki S, Yamagami Y, Makimoto K. Effectiveness of vibratory stimulation on needle-related procedural pain in 
children: a systematic review protocol. JBI Evidence Synthesis. 2018 Apr 1;16(4):825-30. 
21. 
Sharma P, Czyz CN, Wulc AE. Investigating the efficacy of vibration anesthesia to reduce pain from cosmetic 


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botulinum toxin injections. Aesthetic surgery journal. 2011 Nov 1;31(8):966-71. 
22. 
Vibration therapy for pain. Lancet. 1992;339(8808):1513-1514. 
23. 
Melzack R, Wall PD. Pain mechanisms: a new theory. Science. 1965 Nov 19;150(3699):971-9. 
24. 
Mally P, Czyz CN, Chan NJ, Wulc AE. Vibration anesthesia for the reduction of pain with facial dermal filler 
injections. Aesthetic plastic surgery. 2014 Apr 1;38(2):413-8. 
25. 
Guney K, Sezgin B, Yavuzer R. The efficacy of vibration anesthesia on reducing pain levels during lip 
augmentation: worth the buzz?. Aesthetic Surgery Journal. 2017 Oct 1;37(9):1044-8. 
26. 
Chorney SR, Villwock JA, Suryadevara AC. Vibration Versus Ice to Reduce Cosmetic Botulinum Toxin Injection 
Pain—A Randomized Controlled Trial. Ear, Nose & Throat Journal. 2019 Jul;98(6):351-5. 
27. 
Park KY, Lee Y, Hong JY, Chung WS, Kim MN, Kim BJ. Vibration anesthesia for pain reduction during 
intralesional steroid injection for keloid treatment. Dermatologic Surgery. 2017 May 1;43(5):724-7. 
28. 
Fix WC, Chiesa-Fuxench ZC, Shin T, Etzkorn J, Howe N, Miller CJ, Sobanko JF. Use of a vibrating kinetic 
anesthesia device reduces the pain of lidocaine injections: a randomized split-body trial. Journal of the American 
Academy of Dermatology. 2019 Jan 1;80(1):58-9.