Clinical trial NCT02351544
Conditions: Migraine Headaches
Sponsor: Ohio State University
Start date: 2015-09-01; Completion date: 2022-06-01
Enrollment: 44 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
According to the peripheral trigger theory of migraine headaches, nociceptive inputs from irritated or compressed cranial nerve branches can lead to neurovascular changes in the brain that cause migraine headaches. Advanced treatments aimed at deactivating the peripheral trigger points can be administered to patients who have failed medical management of migraines. Those accepted advanced treatments include botulinum toxin A injection in order to temporarily paralyze muscles causing nerve compression, and surgery to release those compression points permanently. An advantage of surgery is the ability to release non-muscular causes of nerve compression, such as fascial bands or intersecting arteries.

Botulinum toxin A injection into trigger sites has been shown in multiple studies to be effective at reducing the frequency and severity of migraine headaches, and is a very commonly administered treatment for refractory migraines. It is approved by the FDA for the treatment of chronic migraines.

Similarly, surgical decompression of trigger sites has previously been shown to have superior clinical outcomes to medical management, through a randomized, blinded controlled-trial performed at Case Western Reserve in 2009. Patients either received actual decompression of the trigger sites, or sham surgery (exposure and visualization of the trigger sites, without decompression). At one-year follow-up, the group who underwent actual surgery demonstrated a statistically higher proportion with significant improvement in their migraines (83.7% vs. 57.7%, p=0.014), and with complete elimination of their migraines (57.1% vs. 3.8%, p\<0.001). Several other reports have confirmed the good clinical outcomes of surgery demonstrated in this trial, and surgical decompression is now commonly performed by several surgeons around the United States.

Prognostic factors predicting the success of surgical decompression in migraine headache treatment include older age of migraine onset, visual symptoms/aura, and 4-site decompression. Factors predicting failure of surgery include excessive operative blood loss, and surgery on only one or two trigger sites.

One criticism of the studies on peripheral trigger decompression surgery for migraines has been that most of the results have originated from the same institution (Case Western Reserve), and from the same author (Guyuron). While several studies at other institutions have demonstrated positive outcomes of peripheral trigger decompression, these have only included a small number of patients.

In addition, the sham surgery randomized-controlled trial has been criticized for not clarifying any prior treatments that patients had undergone before peripheral trigger deactivation, and for not showing how medication use patterns changed after surgery. Another criticism of that study was the fact that patients were examined by neurologists before the study but not after the study, and that surgery was performed on some patients with episodic migraines, who are known to not benefit from botulinum toxin. It is unclear what migraine types are most likely to benefit from surgical decompression.

The investigators' goal is to perform a multi-center, prospective trial to demonstrate the effectiveness of peripheral trigger decompression in the treatment of migraine headaches, which would address the criticisms mentioned above. The main aim is to demonstrate that the positive results demonstrated by Guyuron et al are reproducible at other institutions and by other surgeons using similar techniques on different patient populations.

Detailed description:

Arms: arm 1: Patients in this arm will receive botulinum toxin for migraine headaches arm 2: Patients in this arm will receive surgery for migraine headaches
Interventions: intervention 1: Botulinum Toxin Type A intervention 2: Surgery intervention 3: Daily headache diary intervention 4: Migraine Disability Assessment Test (MIDAS) intervention 5: Migraine Work and Productivity Loss Questionnaire (MWPLQ) intervention 6: Migraine-Specific Quality of Life Questionnaire (MSQ)
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None intervention 5: None intervention 6: None

Protocol documents:
Prot_000.pdf: 
Prospective, Multi-Center Evaluation of the Efficacy 
of Migraine Surgery 
Research Protocol 
IRB Approval #:2015H0024
NCT02351544
Document Date Version: February 16, 2014
Principal Investigator: Jeffrey Janis, MD, FACS (The 
Ohio State University)


Prospective, Multi-Center Evaluation of the Efficacy of 
Migraine Surgery 
Research Protocol ID:2015H0024
NCT02351544
Document Date Version: February 16, 2014
Principal investigator: 
-Jeffrey E. Janis, MD, FACS (Professor of Plastic Surgery, The Ohio State University,
Columbus, OH)
Co-investigators: 
-Bahman Guyuron, MD (Professor of Plastic Surgery, Case Western Reserve University,
Cleveland, OH)
-Robert Hagan, MD (Plastic Surgeon, St. Louis, MO)
-Ahmed Afifi, MD (Assistant Professor of Plastic Surgery, The University of Wisconsin,
Madison, WI)
-Ziv Peled, MD (Plastic Surgeon, San Francisco, CA)
-John B. Moore, MD (Plastic Surgeon, Olathe, KS)
-Ivica Ducic, MD (Professor of Plastic Surgery, Georgetown University, Washington,
DC)
-William Jay Austen, Jr, MD (Professor of Plastic Surgery, Harvard Medical School,
Boston, MA)
-Ibrahim Khansa, MD (Resident in Plastic Surgery, The Ohio State University,
Columbus, OH)
I. Background and rationale
According to the peripheral trigger theory of migraine headaches, nociceptive 
inputs from irritated or compressed cranial nerve branches can lead to neurovascular 
changes in the brain that cause migraine headaches.1-3 Advanced treatments aimed at 
deactivating the peripheral trigger points can be administered to patients who have failed 
medical management of migraines. Those accepted advanced treatments include 
botulinum toxin A injection in order to temporarily paralyze muscles causing nerve 
compression, and surgery to release those compression points permanently. An advantage 
of surgery is the ability to release non-muscular causes of nerve compression, such as 
fascial bands or intersecting arteries. 
Botulinum toxin A injection into trigger sites has been shown in multiple studies to 
be effective at reducing the frequency and severity of migraine headaches,4-6 and is a very 
commonly administered treatment for refractory migraines. It is approved by the FDA for 
the treatment of chronic migraines. 
1 


2 
Similarly, surgical decompression of trigger sites has previously been shown to 
have superior clinical outcomes to medical management, through a randomized, blinded 
controlled-trial performed at Case Western Reserve in 2009.7 Patients either received 
actual decompression of the trigger sites, or sham surgery (exposure and visualization of 
the trigger sites, without decompression). At one-year follow-up, the group who 
underwent actual surgery demonstrated a statistically higher proportion with significant 
improvement in their migraines (83.7% vs. 57.7%, p=0.014), and with complete 
elimination of their migraines (57.1% vs. 3.8%, p<0.001). Several other reports have 
confirmed the good clinical outcomes of surgery demonstrated in this trial,6,8 and surgical 
decompression is now commonly performed by several surgeons around the United 
States. 
Prognostic factors predicting the success of surgical decompression in migraine 
headache treatment include older age of migraine onset, visual symptoms/aura, and 4-site 
decompression. Factors predicting failure of surgery include excessive operative blood 
loss, and surgery on only one or two trigger sites.9 
One criticism of the studies on migraine surgery has been that most of the results 
have originated from the same institution (Case Western Reserve), and from the same 
author (Guyuron). While several studies at other institutions have demonstrated positive 
outcomes of migraine surgery,6 these have only included a small number of patients.  
In addition, the sham surgery randomized-controlled trial has been criticized for not 
clarifying any prior treatments that patients had undergone before migraine surgery, and 
for not showing how medication use patterns changed after surgery. Another criticism of 
that study was the fact that patients were examined by neurologists before the study but 
not after the study, and that surgery was performed on some patients with episodic 
migraines, who are known to not benefit from botulinum toxin. It is unclear what 
migraine types are most likely to benefit from surgical decompression. 
Our goal is to perform a multi-center, prospective trial to demonstrate the 
effectiveness of migraine surgery, which would address the criticisms mentioned above. 
The main aim is to demonstrate that the positive results demonstrated by Guyuron et al 
are reproducible at other institutions and by other surgeons using similar techniques on 
different patient populations. 
II. Objectives
Our goals in this study are:
1. To evaluate the effectiveness of surgical decompression in migraine
headaches prospectively, using validated instruments, and to compare it to
the effectiveness of a botulinum toxin injection protocol
a.
Our hypothesis is that migraine surgery decreases the frequency and
severity of migraine headaches significantly, as measured by


 
3 
validated questionnaires, and that the reduction is greater and more 
sustainable than that seen with a botulinum toxin injection protocol 
2. To determine which types of migraine headaches benefit most from surgical 
decompression and/or botulinum toxin injection 
3.  To identify prognostic factors for the success or failure of surgical 
decompression in migraine headache 
a. These have been demonstrated in a previous study,9 but have not 
evaluated in a multi-center fashion. 
4. To compare the long-term direct and indirect costs in patients with migraine 
headaches undergoing botulinum toxin A injections versus surgical 
decompression 
a. We hypothesize that, over the long-term, surgical decompression is 
more cost-efficient than a botulinum toxin injection protocol 
 
 
 
III. Procedures 
a. Research design 
This is a prospective, multi-center evaluation of the short, medium and long-term 
efficacy of surgical decompression in migraine headaches, comparing it to the efficacy of 
a botulinum toxin injection protocol. 
 
 
b. Sample 
Inclusion criteria: 
-Patients with migraines related to a trigger site at the location of a branch of a cranial 
nerve (frontal, temporal, occipital) 
-Patients with chronic migraine (≥15 days per month) as dictated by the FDA indication 
for botulinum, and as diagnosed by a board-certified neurologist 
 
Exclusion criteria:  
-Patients deemed by the senior author or the neurologist to not have migraine headaches, 
but an alternative diagnosis 
-Patients with systemic conditions that make them poor candidates for surgery (coronary 
artery disease, uncontrolled diabetes mellitus, etc…) 
-Patients with migraines related to inferior turbinate hypertrophy or septal deviation 
-Patients with a frontal, temporal or occipital trigger point who do not respond to a 
diagnostic botulinum toxin injection 
-Hypersensitivity to any botulinum toxin preparation or to any of the components in the 
formulation 
-Infection at the proposed injection site for botulinum 
 
 
Sample size (power analysis) 


 
4 
Since there are several endpoints in this study, the required sample size can be calculated 
in several ways: 
 
-Using efficacy as an endpoint: 
In Janis et al,6 patients undergoing botulinum toxin injections had an average 
improvement in their Migraine Headache Index of 87.5%. In comparison, patients 
undergoing surgery had an average improvement of 96.6%. 
Assuming a standard deviation of 20%, an alpha error of 5%, and a power of 80%, 
the required sample size using this method is 30 patients in each group. 
 
 
-Using total cost of treatment as an endpoint: 
Assuming an average injection volume of 75 Units of botulinum toxin every 3 
months, and assuming a cost of $12-15 per Unit, the estimated cost of a botulinum toxin 
A injection protocol over one year is $3,600-$4,500.  
In comparison, the estimated cost of surgery (including facility fee, surgeon fee, 
preoperative testing and follow-up) is $8,378.10 
Therefore, in order to demonstrate a financial superiority of surgery versus 
botulinum toxin, the patients would need to be follow-up for 1.9 to 2.3 years. 
Assuming a study follow-up of 2.5 years, and average costs of botulinum and surgery of 
$10,125 ± $2,000  and $8,378 ± $2,000, respectively, and assuming an alpha error of 5%, 
a power of 80%, the required sample size using this method is 16 patients in each 
group. 
 
-Using treatment success by trigger site as an endpoint: 
 According to Larson et al,9 the success rates for surgery by trigger site were as 
follows: Frontal 83.3%, temporal 75.8%, and occipital 45.5%. In order to discern a 
difference between the outcomes for the two sites with the closest outcomes (frontal and 
temporal), and assuming a standard deviation of 10%, an alpha error of 5%, and a power 
of 80%, the required sample size using this method is 14 patients in each group. 
 
Looking at the three methods above, keeping the method yielding the highest required 
number of participants, and accounting for any participant drop-out, we will seek to 
enroll 50 patients in each group. 
 
 
c. Detailed study procedures 
A neurologist will evaluate patients presenting for evaluation for treatment of 
migraine headaches, for confirmation of the diagnosis of migraine. The type of migraine 
that they suffer from will be recorded. If the diagnosis of migraine is confirmed, they will 
sign an informed consent form, and they will be asked to complete a daily headache 
diary, and keep track of their 1) daily use of medications for migraines, 2) physician 
visits for migraines, 3) ER visits for migraines, 4) days of work lost due to migraines, 5) 
other costs directly related to migraines for 2 months. They will also be asked to 


 
5 
complete three questionnaires: the Migraine Work and Productivity Loss 
Questionnaire (MWPLQ),11 the Migraine Disability Assessment questionnaire 
(MIDAS)12 and the Migraine-Specific Quality of Life questionnaire (MSQ) at the time 
of enrollment. 
All patients will undergo a history and physical examination, including an 
intranasal examination. This will include determination of the possible trigger site: frontal, 
temporal, occipital, and inferior turbinate/septum. The trigger site can be determined 
using a combination of three methods: 1) Physical examination, 2) Diagnostic botulinum 
toxin injection into a specific trigger point, and 3) Nerve block using a local anesthetic 
injected into a specific trigger point in patients having active symptoms. 
The patients will be asked whether they prefer to undergo surgical decompression 
or a botulinum toxin protocol, and their preference will be recorded. 
 
50 patients who prefer surgery, and who satisfy the inclusion and exclusion criteria, 
will be included in the study as Group A. The location of the trigger site(s) will be 
determined based on history, physical examination, a diagnostic botulinum toxin 
injection and/or a nerve block. If those patients are found to have a trigger site that 
responds to botulinum injection, they will undergo surgical decompression of their trigger 
site, as described in Janis et al6 and Guyuron et al.7 Those patients will be followed 
postoperatively. They will be asked to continue tracking their 1) daily use of medications 
for migraines, 2) physician visits for migraines, 3) ER visits for migraines, 4) days of 
work lost due to migraines, and 5) other costs directly related to migraines for 2 months. 
At 1 year, 2 years and 2.5 years postoperatively, they will be asked to fill the Migraine 
Work and Productivity Loss Questionnaire (MWPLQ), the Migraine Disability 
Assessment questionnaire (MIDAS) and the Migraine-Specific Quality of Life 
questionnaire (MSQ) again. They will also be examined by a board-certified neurologist 
at 1 year postoperatively. 
 
A separate sample of 50 patients from the pool of patients undergoing the 
botulinum toxin injection protocol will be selected (Group B). Those patients will be 
matched to the individual patients in group A based on gender, age (in 5 year intervals), 
migraine severity (based on the Migraine Disability Assessment questionnaire, 5 –point 
intervals) and trigger site (pair-matching). For example, for a patient in Group A who is a 
47 year-old woman with temporal migraines and a MIDAS severity score of 14, a patient 
on the botulinum injection protocol will be included in Group B is she is a 45 to 50 year 
old female with temporal migraines and a MIDAS severity score of 10 to 15. 
 
The patients in group B will receive the botulinum injection protocol, and will 
continue to track their 1) daily use of medications for migraines, 2) physician visits for 
migraines, 3) ER visits for migraines, 4) days of work lost due to migraines, and 5) other 
costs directly related to migraines for 2 months. At 1 year, 2 years and 2.5 years after the 
start of the protocol, they will be asked to fill the Migraine Work and Productivity Loss 
Questionnaire (MWPLQ), the Migraine Disability Assessment questionnaire (MIDAS) 


 
6 
and the Migraine-Specific Quality of Life questionnaire (MSQ). They will also be 
examined by a board-certified neurologist at 1 year postoperatively. 
 
The Botox injections and the surgeries are being done as part of the routine 
clinical care for the patients enrolled in the study. The only procedures being done 
solely for research purposes are having the patients fill out the surveys and diaries. 
 
 
 
d. Measurements 
The measurements will include 
1) Number of migraine headaches per 30 days 
2) Cost of migraine-related medications, physician visits, ER visits 
3) Cost of days of work lost due to migraine as calculated from the Migraine 
Work and Productivity Loss Questionnaire (MWPLQ)  
4) Score on the Migraine Disability Assessment Questionnaire (MIDAS) (0-
21) 
5) Scores on the emotional, restrictive and preventive portions of the Migraine-
Specific Quality of Life questionnaire (MSQ) 
 
The following comparisons will be made for the above measurements: 
-Within Group A, compare all measurements before surgery to 1 year, 2 years and 2.5 
years after surgery, using a t-test 
-Within Group B, compare all measurements before start of injection protocol to 1 year, 2 
years and 2.5 years after injection protocol, using a t-test 
-Compare all measurements between Group A and Group B using a paired t-test analysis 


 
7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pool of patients receiving 
the botulinum toxin A 
injection protocol 
Patients presenting for 
migraine evaluation 
Patients included in the 
study 
•
Evaluation by a neurologist 
•
History and physical examination 
•
Localize trigger point using physical examination, botulinum 
injection and/or nerve block 
•
Exclude patients with migraines triggered by inferior 
turbinate hypertrophy or septal deviation 
•
Exclude patients with no response to diagnostic botulinum 
toxin injection 
•
Determine type of migraine 
•
Daily headache diary 
•
Track migraine-related medications, physician visits, 
ER visits, days of work lost, other costs directly 
related to migraines for 2 months 
•
Complete MIDAS questionnaire 
•
Complete MWPLQ 
•
Complete MSQ 
Patients receiving surgery 
(Group A) 
•
Follow each patient for 2.5 years from 
the day of surgery 
•
Daily headache diary 
•
Track migraine-related medications, 
physician visits, ER visits, days of work 
lost, other costs directly related to 
migraines for 2 months 
•
Complete MIDAS, MWPLQ and MSQ 
at 1 year, 2 years and 2.5 years postop 
•
Evaluation by a neurologist at 1 year 
Group B 
50 patients 
50 patients 
Match pair-wise based on gender, 
sex, migraine severity and 
migraine location 
•
Follow each patient for 2.5 years from 
the inclusion into the study 
•
Daily headache diary 
•
Track migraine-related medications, 
physician visits, ER visits, days of work 
lost, other costs directly related to 
migraines for 2 months 
•
Complete MIDAS, MWPLQ and MSQ 
at 1 year, 2 years and 2.5 years after start 
of injection protocol 
•
Evaluation by a neurologist at 1 year 


 
8 
 
e. Internal validity 
The study avoids confounding by virtue of the matched-pair analysis. The study 
avoids recall bias by having the patients fill-out the questionnaires preoperatively and 
postoperatively, rather than having them retrospectively assess their improvement after 
surgery. 
Blinding is very difficult in such a study. In order to avoid experimenter bias, all 
assessment will be made by the patients themselves, without influence by the 
experimenters. 
The main threat to internal validity is the possible placebo effect inherent to 
migraine headache treatments. This may threaten the validity of the data on differences in 
clinical outcomes between the two groups. It will not threaten the validity of the data on 
financial cost 
 
f. External validity 
Because this is a multi-center trial that includes different patient populations treated 
by different clinicians, this study is generalizable to the general population of patients 
with migraines in the United States. 
 
 
g. Data analysis 
Group B will be selected by matching individual participants to members of Group 
A based on gender, age, migraine severity and migraine location. 
Within Group A, compare the measurements before surgery to 1 year, 2 years and 
2.5 years after surgery, using a t-test 
Within Group B, compare the measurements before the start of the injection 
protocol to 1 year, 2 years and 2.5 years after the start of the injection protocol, using a t-
test 
Compare the measurements between Group A and Group B using a paired t-test 
analysis 
 
h. Bibliography 
1. Calandre EP, Hidalgo J, Garcia-Leiva JM, Rico-Villademoros F. Trigger point 
evaluation in migraine patients: An indication of peripheral sensitization linked to 
migraine predisposition? Eur J Neurol 2006;13:244–249. 
 
2. Olesen J. Clinical and pathophysiological observations in migraine and tension-
type headache explained by integration of vascular, supraspinal and myofascial 
inputs. Pain 1991; 46: 125–132. 
 
3. Kidd RF, Nelson R. Musculoskeletal dysfunction of the neck in migraine and 
tension headache. Headache 1993; 33: 563–569. 
 
4. Binder WJ, Brin MF, Blitzer A, Schoenrock LD, Pogoda JM. Botulinum toxin 


 
9 
type A (BOTOX) for treatment of migraine headaches: An open-label study. 
Otolaryngol Head Neck Surg. 2000;123:669-676. 
 
5. Jackson JL, Kuriyama A, Hayashino Y. Botulinum toxin A 
for prophylactic treatment of migraine and tension headaches in adults: a meta-
analysis. JAMA. 2012 Apr 25;307(16):1736-45. 
 
6. Janis JE, Dhanik A, Howard JH. Validation of the peripheral trigger point theory 
of migraine headaches: single-surgeon experience using botulinum toxin and 
surgical decompression. Plast Reconstr Surg 2011;128:123-131. 
 
7. Guyuron B, Reed D, Kriegler JS, Davis J, Pashmini N, Amini S. A placebo-
controlled surgical trial of the treatment of migraine headaches. Plast Reconstr 
Surg 2009;124:461-468. 
 
8. Guyuron B, Kriegler JS, Davis J, Amini S. Five-year outcome of surgical 
treatment of migraine headaches. Plast Reconstr Surg 2011;127:603-608. 
 
9. Larson K, Lee M, Davis J, Guyuron B. Factors contributing to migraine headache 
surgery failure and success. Plast Reconstr Surg 2011;128:1069-1075. 
 
10. Faber C, Garcia RM, Davis J, Guyuron B. A socioeconomic analysis of surgical 
treatment of migraine headaches. Plast Reconstr Surg 2012;129:871-877. 
 
11. Lerner DJ, Amick BC, Malspeis S, Rogers WH, Santanello NC, Gerth WC, 
Lipton RB. The migraine work and productivity loss questionnaire: concepts and 
design. Quality of Life Research 1999;8:699-710. 
 
12. Stewart WF, Lipton RB, Kolodner K. Migraine Disability Assessment (MIDAS) 
score: Relation to headache frequency, pain intensity, and headache symptoms. 
Headache 2003;43:258–265 
 
 

SAP_001.pdf: 
Prospective, Multi-Center Evaluation of the Efficacy
of Migraine Surgery
Statistical Analysis Plan
IRB Approval #:2015H0024
NCT02351544
Document Date Version: February 16, 2014
Principal Investigator: Jeffrey Janis, MD, FACS (The
Ohio State University)


Outcomes 
**Outcomes modeled were: MHI, MIDAS A, MIDAS B, MIDAS Total, MSQ Sum and MWPLQ7 Total 
Data Analysis 
Descriptive statistics, such as frequency and percents, were displayed for sex (male or female), 
treatment (Botox or Surgery) and site (OSU or MGH). Descriptive statistics, such as mean, standard 
deviation, median, lower quartile and upper quartile, were reported for age and the patient reported 
outcomes with the respect to their migraine for each time point (baseline, 1 year, 2 years and 2.5 years). 
Each of six outcomes were highly skewed and therefore natural logarithm was applied to each one 
before it was modeled. A constant of 1 was added to outcome values before applying natural log 
function so as to include raw values of zeros.  
Linear mixed models with a random effect for patient were used to evaluate the changes in each of six 
outcomes between two different treatments over time with inclusion of interaction between treatment 
and time. These models were used given to account for correlation between repeated measurements on 
the same patient and to account for missing data across time points. P-values for both the main and 
interaction effects of time and treatment were reported for each model and Tukey’s post hoc method 
was used to adjust for pairwise comparisons. For the ease of interpretation, raw means and SDs are 
presented for each time point within specific treatment.  
Analyses were performed using SAS v9.4 (SAS Institute; Cary, NC; www.sas.com). Statistical significance 
was defined as two-sided alpha<0.05.