The Effect of Music Therapy on Episodic Migraine Patients Under the Care of Chronic Pain Department - A Pilot Trial
Phase: NA
Conditions: Migraine Headache
Sponsor: Association de Musicothérapie Applications et Recherches Cliniques

 
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Prophylactic effect of music therapy on episodic 
migraine patients under the care of chronic pain 
department  
MusicMig 
 
 
PROTOCOL OF STANDARD CARE EVALUATION  
 
Version n°1.0 dated of 21/09/2018 
 
 
Administrator: 
University Hospital Center (CHU) 
Site of GHSR  
97 448 Saint Pierre cedex  
Site du CHFG  
97 405 Saint Denis cedex 
 
Research responsible: 
Dr Emmanuelle De Diego 
Chronic Pain Department CHU-GHSR Site Saint Louis 
BP350 97448 saint Pierre Cedex 
Tel.: 02 62 91 20 37 - Fax: 02 62 91 20 31 
Email: emmanuelle.dediego@chu-reunion.fr 
 
Methodology and Data Management Centre: 
Methodological support unit 
CHU The Reunion 
Site de Bellepierre 
Allée Topaze 
97400 Saint-Denis 
Tel.: 02 62 90 62 83 - Fax: 02 62 90 69 21 
Email: usm@chu-reunion.fr 
 
 
 
 
 
 
 

 
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DOCUMENT HISTORY 
 
VERSION 
DATE 
REASON OF CHANGE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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SIGNATURE PAGE OF THE PROTOCOL 
 
« Prophylactic effect of music therapy on episodic migraine patients under 
the care of chronic pain department » 
MusicMig  
 
Version n°1.0 dated of 21/09/2018 
 
 
 
 
 
Research responsible 
Dr Emmanuelle De Diego 
Chronic Pain Department CHU-GHSR Site Saint Louis 
BP350 97448 saint Pierre Cedex 
Tel.: 02 62 91 20 37 - Fax: 02 62 91 20 31 
Email: emmanuelle.dediego@chu-reunion.fr 
 
 
From Saint Louis 
Date: 21/09/2018 
 
 
 
 
 
 
 
        Dr Emmanuelle De Diego 
 
 
Signature 
 
 
 
 
 
 
 

 
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PRINCIPAL CORRESPONDING 
 
 
Research responsible 
Dr Emmanuelle De Diego 
Chronic Pain Department CHU-GHSR Site Saint 
Louis 
BP350 97448 saint Pierre Cedex 
Tel.: 02 62 91 20 37 - Fax: 02 62 91 20 31 
Email: emmanuelle.dediego@chu-reunion.fr 
 
 
Methodology and Data Management Centre 
Methodological support unit 
CHU La Réunion 
Site of Bellepierre 
Allée Topaze 
97400 Saint-Denis 
Tel.: 02 62 90 62 83 - Fax: 02 62 90 69 21 
Email: usm@chu-reunion.fr 
 
 
 
 
 
Administrator Centre 
University Hospital Center 
Site of GHSR  
97 448 Saint Pierre Cedex  
Site du CHFG  
97 405 Saint Denis Cedex 
 
Administrator Responsible 
Gaelle DUFOUR  
Associate Director for Research 
Tel: 02 62 71 98 52 – Fax: 02 62 71 98 34 
Email: gaelle.dufour@chu-reunion.fr 
 
 
Monitor Manager 
Vanessa BASQUE 
CHU of The Reunion – Site of GHSR 
Bd François Mitterrand – BP 350 
97448 Saint Pierre Cedex 
Tel.: 02 62 35 90 00 (Poste 54813) - Fax: 02 62 
35 97 21 
Email: vanessa.basque@chu-reunion.fr 
 
 
 
 
 
 
 
 
 

 
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TABLE OF CONTENTS 
 
DOCUMENT HISTORY 
2 
SIGNATURE PAGE OF THE PROTOCOL 
3 
1. 
PROTOCOL SYNOPSIS 
7 
2. 
SCIENTIFIC JUSTIFICATION 
9 
2.1. 
CURRENT STATE OF KNOWLEDGE 
9 
2.1.1. 
On the pathology 
9 
2.1.2. 
On the strategies/reference procedures 
9 
2.2. 
RESEARCH HYPOTHESES 
10 
2.3. 
NATURE OF STANDARD CARES EVALUATED IN THE RESEARCH 
10 
2.4. 
JUSTIFICATION OF METHODOLOGIC CHOICES 
10 
3. 
OBJECTIVES 
10 
3.1. 
PRIMARY OBJECTIVE 
10 
3.2. 
SECONDARY OBJECTIVES 
11 
4. 
STUDY DESIGN 
11 
4.1. 
METHODS 
11 
5. 
ELIGIBILITY CRITERIA 
11 
5.1. 
INCLUSION CRITERIA 
11 
5.2. 
NON-INCLUSION CRITERIA 
12 
5.3. 
PATIENT RECRUITMENT 
12 
6. 
NATURE OF ROUTINE CARE ASSESSED IN THE RESEARCH 
12 
6.1. 
ACT(S) IN STUDY 
12 
7. 
EVALUATION CRITERIA 
13 
7.1. 
PRIMARY ENDPOINT 
13 
7.2. 
SECONDARY ENDPOINTS 
14 
7.3. 
ESTIMATED TIMELINES OF THE RESEARCH 
14 
7.4. 
SUMMARY TABLE OF PATIENT FOLLOW-UP 
14 
7.5. 
SCREENING VISIT 
15 
7.5.1. 
Patient information 
15 
7.6. 
INCLUSION VISIT 
15 
7.7. 
FOLLOW-UP VISITS 
15 
7.8. 
END OF STUDY VISIT 
15 
7.9. 
SPECIAL MODALITIES OF CARE 
16 
8. 
GESTION OF SERIOUS ADVERSE EVENTS 
16 
9. 
STATISTICAL ASPECTS 
16 
9.1. 
SAMPLE SIZE CALCULATION 
16 
9.2. 
STATISTICAL METHODS 
16 
10. 
SOURCE DATA AND DOCUMENTS ACCESS RIGHTS 
17 
10.1. 
DATA ACCESS 
17 
10.2. 
SOURCE DATA 
17 

 
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10.3. 
DATA CONFIDENTIALITY 
17 
11. 
QUALITY CONTROL 
17 
11.1. 
INFORMATION FOR DATA COLLECTION 
17 
11.2. 
RESEARCH MONITORING 
18 
11.3. 
QUALITY CONTROL 
18 
11.4. 
DATA MANAGEMENT 
18 
11.5. 
AUDIT AND INSPECTION 
18 
12. 
ETHICAL AND REGULATORY CONSIDÉRATIONS 
19 
12.1. 
COMPLIANCE WITH REFERENCE TEXTS 
19 
12.2. 
PROTOCOL AMENDMENT 
19 
13. 
RESEARCH DOCUMENTS AND DATA CONSERVATION 
20 
14. 
PUBLICATION RULES 
20 
14.1. 
SCIENTIFIC COMMUNICATIONS 
20 
14.2. 
PATIENTS RESULTS COMMUNICATION 
21 
14.3. 
DATA CESSION 
21 
15. 
REFERENCES 
21 
16. 
APPENDICES 
23 
16.1. 
APPENDIX 1 
23 
16.2. 
APPENDIX 2 
24 
 
 

 
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1. PROTOCOL SYNOPSIS 
ADMINISTRATOR 
CHU de La Réunion – Site of GHSR 
RESEARCH RESPONSIBLE 
Emmanuelle De Diego 
PH Algology 
Responsible of Chronic Pain Service  
Group of Hospital South Réunion 
University Hospital Centre of Reunion 
TITLE 
Prophylactic effect of music therapy on episodic migraine patients 
under the care of chronic pain department. 
VERSION  
1.0 
JUSTIFICATION / CONTEXT 
Music therapy has been validated in the management of chronic pain 
and anxiety disorders. A program of music therapy will be proposed by 
the CHU Chronic Pain department team from GHSR. The objective of 
this study is to evaluate the effect of the music in the migraine specific 
indication. 
OBJECTIVES 
Principal objective  
To evaluate the effect of music therapy on migraine frequency, on 
patients suffering from episodic migraines and followed in chronic pain 
department of the CHU Sud Reunion. 
 
Secondary objectives   
To evaluate the effect of music therapy on migraine intensity, duration, 
and acute treatment administration. 
To evaluate the effect of music therapy on emotional effect (HAD score) 
and functional impact (HIT-6 score).  
STUDY DESIGN 
Prospective study of before-after type. It is composed of only one group 
of patients, all treated with music. The study will measure and compare 
migraine frequency in the month before the intervention with data 
collected 3 months after.  
INCLUSION CRITERIA 
- patients aged >= 18 years 
- patients with episodic migraine (<15 days / month) with at least 4 
crises per month. 
- patients with migraines with or without aura with diagnostic criteria 
per International Headache Society 
- patients with a migraine for more than one year 
- diagnosis age < 50 years 
- patients with an available internet connexion to access Music Care 
application 
- patients with minimal knowledge in informatics 
- patients who sign their inform consent  
EXCLUSION CRITERIA 
- patients aged less than 18 years 
- patients with chronic migraine 
- patients with epilepsy 
- patients with a deficiency on auditive function 
- patients with a disease that could be fatal within the study period.  

 
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STANDARD CARE NATURE 
EVALUATED IN THIS RESEARCH  
Sessions of music therapy self-directed by the patient at home, using 
Music Care software via an internet connexion. 
EVALUATION CRITERIA 
Primary evaluation criterion  
Reduction of migraine frequency of 50% after 3 months. 
 
Secondary evaluation criteria   
Reduction of migraine intensity and duration, as well as acute 
treatment administration.  
Reduction of the emotional and functional impact. 
PLANNED SAMPLE SIZE 
20 patients 
PLANNED CENTERS 
1 centre: Chronic Pain Department of CHU-GHSR site of Saint-Louis 
DURATION OF THE RESEARCH 
- Duration of inclusion period: 1 month 
- Duration of patient participation: 3 months 
- Total duration of the study: 4 months 
STATISTICAL ANALYSIS 
Analysis of the primary endpoint  
The mean number of migraine crises per month before and after music 
therapy will be compared using the Wilcoxon Paired Test. 
  
Analysis of secondary endpoints  
Quantitative variables before and after music therapy will be analysed 
using Wilcoxon Paired Test. Qualitative variables will be analyzed using 
McNemar Chi2 test. 
EXPECTED RESULTS 
To propose a new therapeutic and non-drug approach in episodic 
migraine prophylaxis. 
To improve the relationship between medical team and patients. 
To reduce the treatment consumption. 
 
 
 
 

 
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2. SCIENTIFIC JUSTIFICATION  
Migraine is a frequent pathology, it affects 20% of the French population and represents 1 milliard euros 
of direct cost. It is a research topic largely studied under non-drug approaches. The ANAES provided in its 
migraine recommendations in October 2002 to use relaxation, biofeedback and stress management 
cognitive and comportemental therapies in the care of migraine patients. 
Music therapy is a recent discipline with a trend of development in hospital services and in specialised 
ambulatory care centres. Several controlled studies allowed to validate the utilisation of music therapy in 
chronic or sharp pain, as well as in anxio-depressive disease. In this domain, the work of Stephane Guetin, 
psychologist and music therapist, helped using Music Care software to elaborate a standardised 
computerised method allowing its use by caregivers and patients themselves. 1, 2, 3 
 
Researches on music therapy effect on migraine patients are few.  
 
A first German study in 1999 evaluated the effect of Psychophonia software on migraine, informatic tool   
which build a sound sequence from EEG of the patient. This cohort study on 55 adult migraine patients 
showed a decrease of at least 50% of migraine crises in 56% of patients treated for 12 months. 4 
 
A second German study in 2008 evaluated the effect of active music therapy and the use of butterbur root 
extract (Petalodex) in the prevention of child migraine. This randomised, controlled study based on 58 
patients distributed under 3 arms (music therapy/ butterbur/placebo) demonstrated superiority of music 
therapy arm against placebo after 8 weeks, and the superiority of the 2 treatments against placebo at 6 
months. 5 
 
The demonstrated effects of music therapy on chronic pain and anxio-depressive disease allow to assume 
a benefic effect of this technique in the migraine.  
Scientific data of music therapy on migraine patients are positive and suppose its interest in this 
indication, as in chronic pain, but additional and more specific studies are needed to evaluate its indication 
on this specific pathology. A clinical study with 2 arms might be helpful.  
The standardised and validated music therapy technique named as Music care seems to be a useful tool in 
standard cares and clinical research.  
2.1. CURRENT STATE OF KNOWLEDGE 
2.1.1. ON THE PATHOLOGY 
 
Episodic migraine is defined as several days with crisis < 15 days / month. 6 
Its prevalence is equal to 12% to 20% in the general French population, so 7 million of migraine patients, 
with more women (ratio of 1/3). 
This pathology starts before 40 years with high anxio-depressive comorbidity due to possible 
pathophysiologic community.7 
It is an under-diagnosed pathology, with only 30% of migraine followed patients.  
The disease consequences are functional disability, current activities reduced in 70% of migraine patients. 
The social impact cost is estimated to 1 milliards euros / year and 15 million of loosed days of work / year. 
Fifty percent of the patients used auto medication with a risk of drug abuse and evolution to chronic 
migraine (> 15 days of crisis / month). 8 
 
2.1.2. ON THE STRATEGIES/REFERENCE PROCEDURES 
 
Recent clinical and neurophysiological studies made it possible to highlight the positive effect of music 
therapy in pain treatment 9. Causing relaxation, music decreases painful phenomena in patients with 

 
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chronic and sharp pain. By shifting the attention, music decreases muscular tension and reduces anxiety. 
In pre and postoperative pains, patients under music decreased their drug consumption up to 30%. 
The effects of music therapy are generally related to the fact that the individualized music broadcasting 
improves interactive components of pain. The impact of music therapy might be due to neurophysiologic 
effects, specific to pain, and to the music effect on sensory (attenuation of the conduction of afferent 
fibres), cognitive (memory encoding, diverts attention), affective (stimulates the production of 
endorphins) and behavioural (psychomotricity, muscular hypertonia) components. The effect of the music 
therapy is based on the impact of music on the components of the painful experience and the 
modification of pain perception.  
Psychological factors can interfere in the reduction of chronic painful phenomenon: music is chosen by the 
patient with his personal preferences, it allows to respond to an individual listening request. Listening to 
the patient after the music session allows him to evacuate their tensions.  
Several controlled studies demonstrated that receptive music therapy and more specifically psychomusical 
relaxation has an efficacy on several painful pathologies like dental, obstetrical, cancerous, chirurgical, 
neurological, rheumatic and et functional.  10, 11, 12, 13, 14 
2.2. RESEARCH HYPOTHESES  
The study is based on the hypothesis of a prophylactic effect of music therapy on migraine disease using 
its action on the 4 components: sensory, affective, behavioural and cognitive. 
2.3. NATURE OF STANDARD CARES EVALUATED IN THE RESEARCH  
Music therapy sessions are based on the use of Music Care software. It is software developed by the music 
therapist psychologist S. Guetin. Ten services in CHU GHSR will be equipped of it and their teams will be 
trained to it under the framework of the institutional training plan. This project has been proposed by Dr E 
De Diego responsible of Chronic Pain Department GHSR and supported by CLUD GHSR.  
Among concerned services, Chronic Pain Department GHSR will propose standard cares by music therapy 
for chronic migraine patients. 
2.4. JUSTIFICATION OF METHODOLOGIC CHOICES 
This study has been designed as a before-after study without control group. Intervention being realized 
under current practice, it will not be possible to propose a randomised trial with one arm is treated with 
music therapy and another one not.  
The month before inclusion will serve as reference. Effect of music therapy will be evaluated during 3 
months after inclusion, using a period of same duration of the reference one and using the same tools.  
During the 3 months, patients will be followed every month during a visit realised at Chronic Pain 
Department of GHSR in order to evaluate if the patient is compliant in completion of migraine diary, uses 
correctly Music Care and if he is compliant with his program. During the visit, migraine evaluation will be 
evaluated.  
3. OBJECTIVES 
3.1. PRIMARY OBJECTIVE  
To evaluate the effect of music therapy on migraine frequency, on patients suffering from episodic 
migraines and followed in chronic pain department of the CHU Sud Reunion. 

 
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3.2. SECONDARY OBJECTIVES 
- To evaluate the effect of music therapy on migraine intensity, duration, and acute treatment 
administration. 
- To evaluate the effect of music therapy on emotional effect (HAD score) and functional impact (HIT-6 
score). 
4. STUDY DESIGN 
4.1. METHODS 
Monocentric, prospective before-after study.  
It comprises of only one group of patients and all of them will receive the intervention. 
The study will measure and compare migraine frequency during the month before inclusion with migraine 
frequency 3 months after the inclusion. 
 
- Entry in the study: based on proposition of algologist doctor involved in the patient care and after 
patient receives information and signs inform consent. 
 
- Inclusion period: the month before the initiation of music session will serve as reference period. Patient 
will fill migraine diary, complete questionnaires on functional and emotional impact used usually in the 
department. 
 
The following endpoints will be evaluated:  
- migraine severity (number of days with migraine, duration, intensity, treatment)  
- questionnaire HAD to evaluate emotional impact  
- questionnaire HIT to evaluate functional impact  
 
- Music therapy session implementation 
Each patient will be asked to follow 1 to 2 sessions per day for 3 months, to be done at home, using music 
care software via internet connexion. 
They will complete the migraine diary during the 3 months of the study. 
They will have a visit at the Chronic Pain Department every month, so at Month 1, 2 and 3, realised by an 
intern of general medicine. 
 
- Final evaluation at Month 3 
Diary data of the third month will serve for this evaluation according to the guidelines of the International 
Headache Society: 
- number of days with migraine (primary endpoint) 
- duration and intensity of migraine 
- medication consumption 
- emotional impact: score HAD  
- functional impact: score HIT. 
5. ELIGIBILITY CRITERIA 
5.1. INCLUSION CRITERIA 
- patients aged of 18 to 65 years 
- patients with episodic migraine (<15 days / month) with at least 4 attacks per month 

 
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- patients with migraines with or without aura with diagnostic criteria per International Headache Society 
- patients with a migraine for more than one year 
- diagnosis age < 50 years 
- patients with an available internet connexion to access Music Care application 
- patients with minimal knowledge in informatics 
- patients who sign their inform consent 
5.2. NON-INCLUSION CRITERIA 
- patients aged less than 18 years 
- patients with chronic migraine 
- patients with epilepsy 
- patients with a deficiency on auditive function 
- patients with a disease that could be fatal within the study period. 
5.3. PATIENT RECRUITMENT 
The recruitment of the patients will be done at Chronic Pain Department of GHSR site of Saint-Louis during 
their standard ambulatory care.  
Inclusion and exclusion criteria will be checked by the responsible of the study during the inclusion visit.  
This study will enrol around 20 patients during a short period of time. 
6. NATURE OF ROUTINE CARE ASSESSED IN THE RESEARCH  
6.1. ACT(S) IN STUDY 
The Music Care app is a receptive music intervention self-directed by the patient at home, allowing the 
patient to freely adjust the length of and choose the preferred style between different sequences of 
instrumental music. All musical pieces were recorded in high-quality recording studios with professional 
musicians. After a formation on how to use the application, the patient will have the possibility to choose, 
according to his musical preferences, between different music therapy sequences based « U » technique. 
Music Care utilizes the “U” technique (Figure 1), designed to gradually relax the listener. In the current 
study, music sequences during patients’ sessions were based on the mount “U”, and instrumental musical 
works were selected for a varying numbers styles (classical, jazz, world music, etc.) and adapted to the 
patient's style via patient request. The “U” technique is implemented using a musical sequence of 20 
minutes that was divided into 5 different musical pieces at 3 to 4 minutes each. Initially, the objective is to 
represent the patient's state of tension by stimulating musical rhythm (80-95 beats per minute (bpm). 
From there, the remaining 4 sub-pieces are presented in a blended fashion in an attempt for the patient to 
gradually fall into a relaxed state via a gradual reduction in musical tempo (40-80 bpm), orchestral size, 
frequencies, and volume (descending arm of the “U”). The music session then reaches a phase of 
maximum relaxation (downward phase of the "U”) before a phase that gradually returns to baseline 
dynamics (ascending arm of the “U”).  

 
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Figure 1: The “U” sequence 
 
Headphones were required (provided at time of treatment), and patient were instructed to lay down (to 
promote muscle relaxation) with their eyes closed and lighting to a minimum. Participants answered 
questions related the frequency, duration, and other migraine related questions throughout the 
treatment. At the end of the 3-month of treatment, participants underwent the same assessment as at 
baseline. 
 
The objective of 1 to 2 daily sessions will be suggested to the patients according to their availability.  
Migraine crisis frequently implies a phonophobia, so it will be recommended to realise the sessions 
outside migraine crisis. As patient will manage his sessions as he wants, this information will be given 
without contraindicating music therapy during crisis if patient wants to do it.  
 
The training to Music care software for the doctors in charge of the study will be done by a music therapist 
from AM-ARC, with a validated diploma and experience in clinical research, under the framework of the 
institutional training plan of the CHU.  
 
7. EVALUATION CRITERIA 
Primary and secondary endpoints are defined according to the last recommendations related to 
the evaluation of prophylactic migraine treatment of ANAES October 2002 15: « Treatment is 
considered as efficient if crisis frequency is reduced of at least 50 %. It is also important to 
consider the reduction of medication consumption, intensity and duration of crisis. Evaluation is 
done after 3 months. ». The methodology is consistent with guidelines of International Headache 
Society for clinical research on migraine.16                 
7.1. PRIMARY ENDPOINT 
Reduction of migraine crisis frequency of at least 50% after 3 months of treatment. 
 
The studied variable will be the monthly frequency of migraine crisis. Data collection will be done using a 
migraine agenda (annex 1), starting the month before inclusion and music therapy initiation. This agenda 

 
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should then be completed usually during study period under music therapy. During each monthly visit, a 
control will be done by the intern of general medicine associated to the study.  
 
The primary endpoint will be obtained using the difference between mean crisis frequency during the 
month before music therapy initiation and the one obtained during the 3rd month of treatment.  
A reduction of at least 50% at month 3 will be considered as music therapy efficacy on episodic migraine 
prevention. 
7.2. SECONDARY ENDPOINTS 
- 
Reduction of crisis intensity and duration, as well as medication consumption. 
Crisis intensity (mild, moderate, severe), duration in hour, and the number of treatments taken will be 
collected in the migraine agenda (annex 1) filled by the patient. These variables will be compared between 
the month before music therapy initiation and the 3rd month of treatment. 
 
- 
Reduction of functional and emotional impact. 
Questionnaires HAD and HIT (annex 2) will be completed with the investigator during the inclusion visit 
before initiation of music therapy, and at Month 3 visit.  
• 
Questionnaire HAD to evaluate emotional impact (national reference HAS « chronic pain: 
recognize chronic pain syndrome, evaluate it and guide the patient ») 17 
• 
Questionnaire HIT to evaluate functional impact (guideline of the International Headache 
society) 18 
7.3. ESTIMATED TIMELINES OF THE RESEARCH 
- Start of inclusion: November 2018 
- Duration of retrospective observational period: 1 month 
- Duration of patient participation: 3 months 
- Total duration of the study: 4 months 
7.4. SUMMARY TABLE OF PATIENT FOLLOW-UP 
 
Screening 
visit M-1  
Inclusion visit 
Day 0  
Month 1 visit 
 
Month 2 visit 
 
Month 3 visit 
Patient information 
✓ 
 
 
 
 
Training on agenda migraine 
completion 
✓ 
 
 
 
 
Training on Music care use 
 
✓ 
 
 
 
Inform consent collection 
 
✓ 
 
 
 
Diagnosis questionnaire  
 
✓ 
 
 
 
Check on number of music sessions 
 
 
✓ 
 
✓ 
✓ 
Check on migraine agenda 
completion  
 
✓ 
✓ 
 
✓ 
✓ 
Questionnaires HAD et HIT 
 
✓ 
 
 
✓ 
 

 
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Screening visit will be done by the medical responsible of the study, PH algologist. Inclusion and follow-up 
visits will be also done by the investigator. 
All the visits will be performed at Chronic Pain Department of CHU-GHSR site of Saint-Louis. 
Follow-up visits will be done monthly after inclusion visit with a window of +/- 1 week. 
7.5. SCREENING VISIT 
Screening visit will be managed by the algologist responsible of the study. It will be done between 4 
months and 1 month before inclusion visit. 
7.5.1. PATIENT INFORMATION  
During screening visit and before any evaluation or data collection, the investigator will inform the patient 
of the study and propose him to participate. The following points will be described: 
- 
Objectives and design of the study,  
- 
Data collection and processing, access rights. 
 
Migraine agenda (usually used by the team) will be provided to the patient in order to complete the 1-
month observational period. 
 
During this visit, inclusion and exclusion criteria will be verified. If the patient agrees to participate, oral 
consent will be provided.  
7.6. INCLUSION VISIT 
During this visit, a complete information on objectives and course of the study is provided to the patient. 
Informed consent is collected by the algologist investigator of the study. 
Diagnosis questionnaire, and HAD and HIT questionnaires HAD et HIT are completed with the investigator.  
Migraine agenda to be filled during the next 3 months is provided to the patient. 
A training to Music care, music therapy software, is realized by the study responsible. Details on 
methodology, objectives of the technique, as well as the optimal conditions of use are given to the 
patient. During this visit, the first music session is done at the hospital under medical control. A 
questionnaire is filled in order to have a better knowledge of migraine patient about music preferences 
likely to bring him to relaxation.  
A secure account is created to allow patients to have a free internet access and use Music care during the 
study.  
At the end of this visit, the patient should be able to use at home by himself the software and to realize 
music therapy sessions using Music care. 
7.7. FOLLOW-UP VISITS 
Follow-up visits will be monthly done by the investigator, at Month 1, Month 2 and Month 3 after 
inclusion. During these visits, checks will be done regarding agenda migraine completion, patient 
motivation will be evaluated, and the number of music sessions done will be collected. 
Impressions and feeling of the patient regarding music sessions will be collected.  
7.8. END OF STUDY VISIT 
This final visit corresponds to the follow-up visit at Month 3. Final data collection on migraine agenda will 
be realized as well as HAD and HIT questionnaires filled with the algologist.  

 
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7.9. SPECIAL MODALITIES OF CARE 
Music therapy use does not require special modalities of care. 
8. GESTION OF SERIOUS ADVERSE EVENTS 
No procedure for serious adverse events is imposed by the research. Nevertheless, declaration of serious 
adverse events to the regional center of pharmacovigilance is mandatory for all doctor and health 
professional. 
9. STATISTICAL ASPECTS 
9.1. SAMPLE SIZE CALCULATION 
Primary endpoint is the reduction on migraine crisis frequency before and after music therapy.  
In the population of patients corresponding to inclusion criteria, mean number of migraine crisis per 
month can be estimated to 8 (standard deviation = 4) before intervention.  
A reduction clinically significant would be a reduction of at least 50% of mean monthly number of 
migraine crisis after 3 months of care. 
Under these conditions, 20 patients are needed to have this difference of 50% with a statistical power of 
90% and an alpha equal to 5%. 
9.2. STATISTICAL METHODS 
Baseline characteristics 
Baseline characteristics will be summarized. Qualitative variables will be described using number of 
patients, percentage and 95% confidence interval (IC95%). Quantitative variables will be described as 
number of patients, mean, standard deviation, confidence interval of the mean, median, Q1, Q3, 
minimum and maximum.  
 
Analysis of primary endpoint  
Monthly mean number of migraine crisis before music therapy will be compared to the one obtained at 
Month 3 using Wilcoxon signed rank test for paired (dependent samples). The analysis will be performed 
in intent-to-treat. 
 
Analysis of secondary endpoints 
Quantitative variables measured before music therapy will be compared with the ones collected after 
music therapy using the same statistical method as for primary endpoint.  
Qualitative variables (proportions) measured before music therapy will be compared with the ones 
collected after music therapy using McNemar Chi² test. 
 
All the tests will be realized with SAS 9.2 software with α =5%. A statistical analysis plan will be prepared 
and will detailed the different analyses.  

 
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10. SOURCE DATA AND DOCUMENTS ACCESS RIGHTS  
10.1. 
DATA ACCESS 
The administrator is in charge to obtain the agreement of all the parties implicated in the research in 
order to guarantee direct access to source data, reports and documents everywhere the study is 
conducted in case of quality control and audit. 
Corresponding people will provide documents and individual data if requested to the person authorized to 
access them to follow laws and regulations in place. 
10.2. 
SOURCE DATA 
Source data or document is defined as any original document which allow to demonstrate the existence, 
or the accuracy of a data collected during the research. 
 
Source documents come from:  
 
- 
Case Report Form  
- 
Questionnaires filled during inclusion visit: diagnosis, HAD and HIT impact 
- 
Migraine diary, filled the month before inclusion and during 3 months under intervention 
- 
End of study questionnaires: HAD and HIT 
10.3. 
DATA CONFIDENTIALITY 
In accordance with the law in force, persons with direct access to the source data shall take all necessary 
precautions to ensure the confidentiality of the information relating to the search, the persons to whom 
they belong, as regards their identity and the results obtained. These individuals, along with those who 
direct and oversee the research, are subject to solicitor-client privilege. 
 
During or at the conclusion of the research, data collected on those who are suitable for it and transmitted 
to the administrator by those who direct and supervise the research (or any other specialized 
stakeholders) will be codified. Under no circumstances should the names of the persons concerned, or 
their addresses be clearly indicated. 
 
Procedures for coding patients: 
- only the first letters of the patient’s name and first name will be recorded, accompanied by a number 
indicating the order of inclusion of patients from 01 for the first patient to 20 for the twentieth patient. 
 
The administrator will ensure that each person who is suitable for research has been informed about 
access to the individual data about them and strictly necessary for the quality control of the research. 
11. QUALITY CONTROL 
11.1. 
INFORMATION FOR DATA COLLECTION 
All information required by the protocol shall be recorded on the observation books and an explanation 
shall be provided for each missing data. Data should be collected as they are obtained and transcribed into 
these books in a neat and legible manner. 

 
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Incorrect data found on the observation books will be clearly crossed out and the new data will be copied, 
next to the crossed-out information, accompanied by initials, the date and possibly justification by the 
person who is directing and monitoring the research or the authorized person who made the correction. 
 
Data are collected on a paper CRF. 
The data to be collected directly in the CRF will be: 
- age, sex 
- migraine diagnosis according to International Headache Society criteria 
- number of days with headache per month 
- duration and intensity of crises 
- headache treatment medication per month 
- HAD and HIT 
11.2. 
RESEARCH MONITORING 
The research will be monitored by a clinical research technician. He or she will be responsible for: 
- research logistics and monitoring, 
- reporting on its progress, 
- checking the update of the CRF (request for additional information, corrections, etc.), 
He will work in accordance with standard operating procedures, in collaboration with the Clinical Research 
Associate delegated by the administrator. 
11.3. 
QUALITY CONTROL 
A clinical researcher appointed by the administrator regularly visits each center, when the research is set 
up, once or more in the course of the research according to the pace of inclusions and at the end of the 
research. During these visits, the following elements will be reviewed: 
- compliance with the research protocol, the procedures defined therein and the legal instruments in 
force, 
- quality of the data collected in the CRF: accuracy, missing data, consistency of the data with the source 
documents (medical records, appointment books, original laboratory results, etc.). 
 
All visits will be subject to a written monitoring report. 
11.4. 
DATA MANAGEMENT 
The data will be entered in Excel (or epidata for example). They will be managed by the investigator and 
stored on the computer server of the CHU de la Réunion, which will safeguard them. The data will be 
coded and frozen by the Principal Investigator before being forwarded to the Statistical Processing 
Methodological Support Unit. 
11.5. 
AUDIT AND INSPECTION 
An audit may be carried out at any time by persons appointed by the manager and independent of the 
research managers. Its objective is to ensure the quality of the research, the validity of its results and 
compliance with the law and regulations in force. 
 
The persons who direct and supervise the research agree to comply with the requirements of the 
administrator and the competent authority for an audit or inspection of the research. 
 

 
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The audit may apply to all stages of research, from the development of the protocol to the publication of 
results and the classification of data used or produced in the research. 
12. ETHICAL AND REGULATORY CONSIDÉRATIONS 
12.1. 
COMPLIANCE WITH REFERENCE TEXTS 
Since the techniques and methods used in this research are usually carried out, it can be used as part of 
research to evaluate routine care as defined by Law No. 2004-806 of 9 August 2004 (Article L1121-1, 
paragraph 2 and Article R1121-3 of the Public Health Code). 
 
The administrator and the person(s) who directs and supervises the research undertake that this research 
will be carried out in accordance with Law No. 2004-806 of 9 August 2004, as well as in accordance with 
Good Clinical Practice (I.C.H. version 4 of 1 May 1996) and the Helsinki Declaration (which can be found in 
its full version on the website http://www.wma.net/en/30publications/10policies/b3/).  
 
The research shall be conducted in accordance with this Protocol. Except in emergency situations 
requiring specific therapeutic procedures, the person(s) who directs and monitors the research 
undertakes to comply with the protocol in every respect. 
 
This research received the favorable opinion of the Committee for the Protection of Persons (CPP) of 
Bordeaux. This research is covered by the civil liability insurance of the CHU of The Reunion. 
 
The data recorded during this research are computerized at the CHU de la Réunion in compliance with the 
law no. 78-17 of 6 January 1978 on information technology, files and freedoms as amended by Law 2004-
801 of 6 August 2004. The CHU of The Reunion will send a request for an opinion to the Advisory 
Committee on the Processing of Information in the Field of Health Research (CCTIRS) and a request for 
authorization to the National Commission of Informatics and Liberties (CNIL). 
 
12.2. 
PROTOCOL AMENDMENT  
Any substantial change, that is to say any change likely to have a significant impact on the protection of 
persons, on the conditions of validity and on the results of the research, on the interpretation of scientific 
documents that support the conduct of the research or on the manner in which it is conducted-This is the 
subject of a written amendment that is submitted to the Manager and the Data Management and 
Methodology Centre, if applicable, and the latter must obtain, prior to its implementation, a favorable 
opinion from the CPP. 
Substantive changes, that is, those that have no significant impact on any aspect of the research, are 
provided to the CPP for information purposes. 
All amendments are validated by the administrator, and by all research stakeholders involved in the 
amendment, prior to submission to the CPP. This validation may require the Scientific Committee meeting. 
 
All amendments to the protocol must be brought to the attention of all health professionals who are 
involved in the research and who are committed to respecting its content. 

 
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13. RESEARCH DOCUMENTS AND DATA CONSERVATION 
The following documents related to this research are archived in accordance with Good Clinical Practice: 
- By the people who realize the research: 
- for a duration of 15 years following the completion of the research (research on drugs, 
medical devices or in vitro diagnostic medical devices or research not related to a product 
referred to in section L.5311-1 of the Public Health Code) 
• Protocol and potential amendments 
• CRF (copies) 
• Source data of the patients  
• All other documents or papers related to the research. 
- where applicable, for a period of 30 years following the completion of the research  
• Original copy of signed informed consent from participants 
All these documents are the responsibility of the person conducting the search during the 
statutory archiving period.  
 
- By the project manager: 
- for a duration of 15 years following the completion of the research (research on drugs, 
medical devices or in vitro diagnostic medical devices or research not related to a product 
referred to in section L.5311-1 of the Public Health Code), 
• Protocol and potential amendments 
• CRF (original) 
• All other documents or papers related to the research. 
- where applicable, for a period of 30 years following the completion of the research 
• A copy of the signed informed consent of the participants 
• Documents related to serious adverse events 
All these documents are under the responsibility of the project manager for the statutory 
archiving period. 
 
No movement or destruction shall be carried out without the approval of the manager. At the end of the 
statutory archiving period, the manager will be consulted for destruction. All data, documents and reports 
will be subject to audit or inspection. 
14. PUBLICATION RULES 
14.1. 
SCIENTIFIC COMMUNICATIONS 
Analysis of the data provided by the centers is carried out by the Methodological Support Unit. This 
analysis results in a written report that is submitted to the project manager. This report allows the 
preparation of one or more publications. 
 
Any written or oral communication of the results of the research must receive the prior consent of the 
person who directs and monitors the research. 
The publication of the main results mentions the name of the project manager, of all health professionals 
who have included or monitored patients in the research. International rules for writing and publishing 
will be considered (Vancouver Convention, February 2006). 

 
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14.2. 
PATIENTS RESULTS COMMUNICATION 
In accordance with Law No. 2002-303 of 4 March 2002, patients are informed, at their request, of the 
overall results of the research. 
14.3. 
DATA CESSION 
Data collection and management are carried out by the University Hospital Centre. The conditions for the 
transfer of all or part of the research database shall be decided by the research manager and shall be the 
subject of a written contract. 
15. REFERENCES 
1. Guétin S, Giniès P, Siou DK, Picot MC, Pommié C, Guldner E, Gosp AM, Ostyn K, Coudeyre 
E, The effects of music intervention in the management of chronic pain: a single-blind, 
randomized, controlled trial.” Touchon J. Clinical Journal of Pain. 2012 May;28(4):329-37. 
 
2. Guétin S., Graber-Duvernay B., Blayac J.P., Calvet, Hérisson C., Effets de la musicothérapie 
sur les douleurs rhumatismales chroniques rachidiennes, Douleurs, ed. Masson, 2003, 4; 
37-40. 
 
3. Guétin S, Portet F, Messaoudi M, Pose C, Picot M.C, Touchon J. Effets de la 
musicothérapie sur l'anxiété, la dépression des patients atteints de la maladie d'Alzheimer 
et sur la charge ressentie par l'accompagnant principal   Revue: L'Encéphale 2008  
 
4. « Psychofonia--a neurophysiologic music therapy in migraine »  Meister M, Einsle R, 
Brunner J, Rhyner K  Revue : Praxis 1999 
 
5. « Butterbur root extract and music therapy in the prevention of childhood migraine: an 
explorative study » Rieke Oelkers-Ax, Anne Leins, Peter Parzer, Thomas Hillecke, Hans V. 
Bolay c, Jochen Fischer, Stephan Bender, Uta Hermanns, Franz Resch. Eur J Pain. 2008 
Apr;12(3):301-13.  
 
6. Headache classification subcommittee of the International Headache Society (2004) The 
international classification of headache disorders, 2nd edition. Cephalalgia 24(supl1) : 1-
43. 
 
7. Lantéri-Minet M, Radat F, Chautard MH et al (2005) Anxiety and depression associated 
with migraine : influence on migraine subjects disability and quality of life, and acute 
migraine management. Pain 118 : 3189-326. 
 
8. Lantéri-Minet M, Valade D, Géraud G et al (2005) Migraine and probable migraine-results 
of FRAMIG 3, a French nationwide survey carried out according to the 2004 IHS 
classification. Cephalalgia. 25(12) : 1146-1158. 
 
9. Aderson J., Music and pattern change in chronic pain. Adv. Nurs. Sci., 1993, 15; 27-36. 
 

 
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10. Beck S.L., The therapeutique use of music for cancer related pain, Oncol. Nursing Forum, 
1991, 18;1327-1337. 
 
11. Zimmerman L., Effects of music in patients who had chronic cancer pain. West J. Nursing 
Res., 1999, 11; 298-309. 
 
12. Kullich W, Bernatzky G, Hesse HP, Wendtner F, Likar R, Klein G. Music therapy, impact on 
pain, sleep, and quality of life in low back pain. Wien Med Wochensch 2003; 153: 217-22. 
 
13. Mc Caffrey R, Freeman E. Effect of music on chronic osteoarthritis pain in older people.   J 
Adv Nurs 2003; 44: 517-24. 
 
14. Tanabe P., Thomas R.et al., The effect of standard care, Ibuprofen, and Music on pain 
Relief and patient satisfaction in adults with musculoskeletal Trauma. Journal of 
Emergency Nursing, 2001; 27; 124-131. 
 
15. Haute Autorité de la santé. Recommandations. Prise en charge diagnostique et 
thérapeutique de la migraine chez l’adulte et l’enfant, 2002. www.has.fr 
 
16. Guidelines for controlled trials of drugs in migraine: third edition. A guide for 
investigators. Tfelt-Hansen P, Pascual J, Ramadan N, Dahlöf C, D'Amico D, Diener HC, 
Hansen JM, Lanteri-Minet M, Loder E, McCrory D, Plancade S, Schwedt T; International 
Headache Society Clinical Trials Subcommittee. Cephalalgia. 2012 Jan;32(1):6-38. 
 
17. Giniès P., Draussin M., Evaluation de la qualité des soins dans la prise en charge de la 
douleur chronique en France, Douleur et Analgésie, 2002,1, 3-44. 
 
18. De Diego E, Lanteri-Minet M (2005) Recognition and management of migraine in primary 
care: influence of functional impact measured by the headache impact test (HIT). 
Cephalalgia 25(3):184-90. 
 
 
 
 
 
 

 
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16. APPENDICES 
16.1. 
APPENDIX 1 
MIGRAINE DIARY 
 
Please fill in the migraine calendar daily and specify each day: 
Migraine 
Headache intensity: mild, moderate or severe 
Duration in hours of headache 
Migraine treatments used 
 
Date 
Migraine/tension 
headache 
Intensity 
Duration 
Treatments  
D1 
 
 
 
 
D2 
 
 
 
 
D3 
 
 
 
 
D4 
 
 
 
 
D5 
 
 
 
 
D6 
 
 
 
 
D7 
 
 
 
 
D8 
 
 
 
 
D9 
 
 
 
 
D10 
 
 
 
 
D11 
 
 
 
 
D12 
 
 
 
 
D13 
 
 
 
 
D14 
 
 
 
 
D15 
 
 
 
 
D16 
 
 
 
 
D17 
 
 
 
 
D18 
 
 
 
 
D19 
 
 
 
 
D20 
 
 
 
 
D21 
 
 
 
 
D22 
 
 
 
 
D23 
 
 
 
 
D24 
 
 
 
 
D25 
 
 
 
 
D26 
 
 
 
 
D27 
 
 
 
 
D28 
 
 
 
 
D29 
 
 
 
 
D30 
 
 
 
 
D31 
 
 
 
 
 
 
 

 
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16.2. 
APPENDIX 2 
Please fill the 2 questionnaires below: 
 
HAD QUESTIONNAIRE 
 
 
 
 

 
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QUESTIONNAIRE HIT