Determining the Optimal Treatment Strategy for Patients Who Have Chronic Migraine With Medication Overuse
Phase: NA
Conditions: Migraine
Sponsor: Mayo Clinic

 
 
Determining the Optimal 
Treatment Strategy for Patients 
who have Chronic Migraine 
with Medication Overuse 
 
 NCT02764320 
 
August 1, 2020 

The MOTS Trial 
 
Protocol Version 4 
 
1 
Determining the Optimal Treatment Strategy for 
Patients who have Chronic Migraine with 
Medication Overuse 
 
 
The MOTS Trial  
(Medication Overuse Treatment Strategy) 
 
 
 
 
 
 
 
 
 
Study Protocol 
Version 4 
August 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

The MOTS Trial 
 
Protocol Version 4 
 
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Signature Page 
 
The signature below constitutes the approval of this protocol and the 
attachments, and provides the necessary assurances that this trial will 
be conducted according to all stipulations of the protocol, including all 
statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable US federal regulations and ICH 
guidelines.  
 
 
 
 
Site Number: ______________ 
 
Printed Name of Site Investigator:___________________________________ 
 
 
Signature of Site Investigator: ______________________________________ 
 
 
Date: ______________________  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

The MOTS Trial 
 
Protocol Version 4 
 
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Determining the Optimal Treatment Strategy 
for Patients who have Chronic Migraine with Medication Overuse 
 
The  MOTS Trial  
 
Table of Contents 
 
1. Leadership and Contact Information 
2. Signature Page 
3. Supporting and Collaborating Organizations 
4. Funding 
5. Study Background and Overview 
6. Study Objective  
7. Study Design 
8. Subject Eligibility 
9. Study Procedures 
a. Baseline Visit 
i. Case Report Forms 
ii. Randomization 
iii. Migraine Prophylactic Therapy 
iv. Discontinuation of the Overused Medication 
v. Symptomatic Therapy for Patients Randomized to Discontinuation of 
the Overused Medication 
vi. Symptomatic Therapy for Patients Randomized to Prophylactic Therapy 
Along 
vii. Headache Diary 
b. Twelve Week Follow-Up Visit 
i. Case Report Forms 
c. Other Follow-Up Visits and Telephone Contacts 
i. Case Report Forms’ 
ii. Telephone Calls 
iii. Changes in Therapy 
10. Study Outcomes 
a. Primary Outcome 
b. Secondary Outcomes 
c. Heterogeneity of Treatment Effects Analyses 
11. Sample Size and Data Analyses Plans 
a. Sample Size 
b. Data Analyses Plans 
12. Potential Risks and Protection of Human Subjects 
13. Informed Consent 
a. Informed Consent Personnel 
b. Location and Privacy 
c. Storage of Consent Documents 
d. Withdrawal of Consent 
14. Subject Retention 

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15. Data Management 
16. Adverse Events Reporting 
17. Protocol Maintenance 
18. Study Website 
19. Study Registration 
20. References/Citations 
21. Appendices 
a. Case Report Forms 
b. Adverse Events Form 
c. Headache Treatment Form 
 
 

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Leadership and Contact Information 
 
Principal Investigators:  
Todd J. Schwedt, MD 
Professor of Neurology 
Mayo Clinic 
Phoenix, Arizona 
 
 
 
David W. Dodick, MD 
Professor of Neurology 
Mayo Clinic 
Phoenix, Arizona 
 
 
 
Co-Investigator: 
Teri Robert, PhD 
Patient Advocate and Educator 
 
Project Manager: 
Michael Leonard 
Mayo Clinic  
Phoenix, AZ 
 
 
 
 
 
Supervisory Statistician: 
Joseph Hentz 
Supervisory Statistician 
Mayo Clinic 
Phoenix, Arizona 
 
 
Steering Committee: Todd Schwedt, MD; David Dodick, MD; Teri Robert, PhD; Larry Newman, MD; 
Bray Patrick-Lake, MFS; Morris Levin, MD; Cathy Glaser, JD; William Young, MD;, Patti Shank, Anita 
DeSilva 
 
 

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3. Supporting/ Collaborating Organizations 
 
• American Headache and Migraine Association (AHMA) 
• American Headache Society (AHS) 
• National Headache Foundation (NHF) 
• Migraine Research Foundation (MRF) 
• American Migraine Foundation (AMF) 
• American Academy of Neurology (AAN) Headache and Facial Pain Section 
• Alliance for Headache Disorders Advocacy (AHDA) 
• International Headache Society (IHS) 
• One Mind for Research 
• Mayo Clinic Health Solutions 
• Migraine Again 
• The Daily Migraine 
• Migraine.com 
 
 
4. Funding 
 
This study is funded by a contract from the Patient Centered Outcomes Research Institute (PCORI); 
Application ID: PCS-1504-30133. 
 
 
5. Study Background and Overview 
 
Migraine has a one-year prevalence of 12% in the general population, including 18% of women and 
6% of men. [Lipton 2007; Rasmussen 1995; Lipton 2001] The lifetime prevalence of migraine is 
33% in women and 13% in men. [Launer 1999] One in four households in the United States has at 
least one member with migraine. [Lipton 2001] Thus, a large proportion of the general population 
is personally impacted by migraine at some point in their life, either due to having migraine 
themselves or supporting family members or friends who are suffering with migraine. The World 
Health Organization ranks migraine as the 3rd most prevalent medical disorder in the world. [Vos 
2012] Migraine results in substantial suffering for individuals with migraine and their families. The 
World Health Organization considers migraine to be the 4th most disabling medical condition in 
women and the 8th most disabling medical condition overall. [Vos 2012] Migraine is associated 
with disabling pain, hypersensitivities to sensory stimuli, and reduced quality of life within several 
domains. [Lipton 2000; Lipton 2007; Terwindt 2000] Annual costs from migraine are estimated at 
$20 billion in the United States and €27 billion in Europe. [Stovner 2008; Stewart 2003]  
 
Two percent of the United States population (approximately 7 million people) and 8% of the 
migraine population has chronic migraine, meaning that they have at least 15 days with headache 
per month including at least 8 days per month on which they have full-blown migraine attacks (Box 
- International Classification of Headache Disorders 3 beta diagnostic criteria for chronic migraine). 
[Natoli 2010; Buse 2012; ICHD 2013] Compared to patients with episodic migraine, patients with 
chronic migraine have more severe pain, more frequent pain, higher rates of comorbid disorders, 

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more migraine-related disability, lower income, and poorer quality of life. [Buse 2010; Bigal 2008; 
Buse 2012; Blumenfeld 2011] Compared to people with episodic migraine, people with chronic 
migraine also have greater healthcare utilization, including more frequent visits to their primary 
care physician, to specialists, to emergency departments, and are more frequently hospitalized and 
undergo more diagnostic tests. [Stokes 2011;Blumenfeld 2011] Annual total medical expenses are 
4.4 times greater for patients with chronic migraine compared to patients with episodic migraine. 
[Munakata 2009] Each year, about 1 million people with episodic migraine transform to chronic 
migraine. Several factors associated with an increased risk for transforming to chronic migraine 
have been identified, including overuse of medications used to abort migraine attacks (i.e. 
“medication overuse”), female sex, obesity, presence of cutaneous allodynia, excessive caffeine 
intake, snoring, sleep disorders, major life changes, head or neck injury, lower socioeconomic 
status, and presence of comorbid pain disorders. [Schwedt 2014] [Bigal 2006] [Scher 2008a] 
[Louter 2013] [Scher 2008b] 
 
The excessive use of medications intended to abort a migraine attack, “medication overuse”, is a 
common, strong, and modifiable risk factor for transforming to chronic migraine. The one-year 
prevalence of medication overuse headache is approximately 2%-3% in the general population. 
[Westergaard 2014; Steiner 2014] Patients with chronic daily headache (i.e. at least 15 headache 
days/month) account for 70% of patients seen in headache specialty centers and the vast majority 
of these patients have chronic migraine. [Bigal 2004] Approximately 50% of patients seen in 
headache specialty medical centers have medication overuse and at least 50% of people with 
chronic migraine in the general population have medication overuse. [Natoli 2010; Davies 2012; 
Westergaard 2014] Overused medications include opioids, butalbital-containing medications (e.g. 
aspirin-butalbital-caffeine; acetaminophen-butalbital-caffeine), triptans, ergots, caffeine-containing 
medications (e.g. aspirin-acetaminophen-caffeine) and non-steroidal anti-inflammatory 
medications. The risk of transforming from episodic to chronic migraine is mediated by the specific 
medication that is being overused and the frequency with which that medication is used. Opioids 
and butalbital-containing medications are thought to be associated with the highest risk for 
transformation (odds ratios 1.4 and 1.7, respectively). [Bigal 2008] People who have chronic 
migraine and medication overuse have even poorer quality of life, greater disability, and greater 
losses in productivity compared to people who have chronic migraine without medication overuse. 
[Lanteri-Minet 2011; Steiner 2014] One-half of people who have chronic migraine with medication 
overuse have greater than 20 lost days from work, household work, and social activities each 3 
months. [Steiner 2014] Amongst people who have chronic migraine with medication overuse, the 
mean number of days per 90 lost to headache is 14.2 workdays, 21.4 housework days, and 9 days 
of social activity. [Steiner 2014] Compared to people who have chronic headaches without 
medication overuse, people who have medication overuse have lower educational attainment, 
lower incomes, and are less likely to maintain full employment. [Westergaard 2014] The definition 
for medication overuse according the International Classification of Headache Disorders 3 beta is 
found in the Box.  
 
The main treatment goals for patients who have chronic migraine with medication overuse are to 
reduce the frequency and severity of migraine attacks and to reduce the burden that the condition 
places on the daily lives of its sufferers. However, despite the high prevalence of medication 
overuse in the migraine population and the undeniable importance of treating medication overuse, 
the best treatment strategy for patients who have chronic migraine with medication overuse is 

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uncertain and is passionately debated in academic and clinical communities. Since medication 
overuse is a common condition that is associated with more frequent headaches, more severe pain, 
greater comorbidity, and toxicities related to taking too much of the overused medication, there is 
great need for determining the best treatment approach. While there is general agreement that 
patients who have chronic migraine with medication overuse should substantially reduce and limit 
the consumption of the overused medication to avoid systemic, renal, gastrointestinal and 
cardiovascular toxicities, accomplishing this objective in patients with frequent severe headache 
presents a major challenge for the patient and for the clinician. There is also agreement that a non-
pharmacologic approach that includes adjustments in lifestyle factors are indicated for the 
treatment of chronic migraine with medication overuse. However, there is disagreement and 
clinical equipoise regarding the timing for discontinuing the overused medication in relation to 
using migraine prophylactic medications. [Hagen 2009] [Smith 2014] [Tassorelli 2014] [Zeeberg 
2006]  There are arguments for two commonly used treatment strategies: 1) early discontinuation 
of the overused medication plus migraine prophylactic therapy; and 2) migraine prophylactic 
therapy without early discontinuation of the overused medication. The argument for early 
discontinuation of the overused medication with initiation/optimization of migraine prophylactic 
therapy (e.g. beta-blockers, antidepressants, anticonvulsants) is based upon the following points: 
1) migraine prophylactic medication is necessary to reduce migraine frequency and severity in 
patients who have very frequent headaches; 2) migraine prophylactic medications are ineffective 
when medication overuse persists; 3) medication overuse is partially a behavioral condition that 
has a component of medication dependence and thus patients will not necessarily reduce their 
usage of headache abortive medications on their own, even if the long-term outcome would be a 
reduction in headache frequency with concomitant prophylactic medications; 4) the reductions in 
headache frequency, severity, and duration that result from migraine prophylactic therapy will 
minimize the suffering associated with early discontinuation of the overused medication strategy, 
in which patients are unable to treat all of their withdrawal headaches and/or acute migraine 
attacks.  However, other experts argue that early discontinuation of the overused medication is not 
necessary as long as migraine prophylactic therapy is initiated or optimized. Reasons for this 
argument include: 1) early discontinuation of the overused medication results in a period of more 
severe headaches and greater migraine-related functional impairment and this period of suffering 
is unnecessary if the prophylactic therapy is effective despite continued use of the overused 
medication; 2) prophylactic therapy works even in the presence of medication overuse and 
patients will naturally reduce their use of migraine abortive medications once their headache 
frequency declines; 3) medication overuse is the consequence of having high frequency headaches 
and not the cause of the increased headache frequency. If early discontinuation of the overused 
medication is not a necessary treatment component for patients who have chronic migraine with 
medication overuse, then patients could continue their abortive medications while optimizing 
migraine prophylactic therapy. This strategy would likely enhance rates of adherence to the 
treatment plan, optimize treatment outcomes, and avoid the period of unnecessary pain and 
suffering from inadequately treated headaches. To date, there are inadequate data and opposing 
expert opinions on this critical and pragmatic treatment issue that arises very frequently in clinical 
practice.  
 
This study takes on even more importance given the widespread current undertreatment of 
chronic migraine, with or without medication overuse, in the population. In a recent epidemiologic 
web-based study of persons with migraine, only 40.8% reported currently consulting with a 

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healthcare professional. [Dodick 2014] Among those consulting a healthcare professional, 24.6% 
received an accurate diagnosis of CM and only 44.4% of this group received both acute and 
prophylactic pharmacologic treatments. Thus, among the sample of chronic migraine sufferers, 
only 4.5% (n=1254) successfully traversed all 3 barriers to migraine care (i.e., consulted a 
healthcare professional for migraine, received an accurate diagnosis, and were prescribed acute 
and prophylactic pharmacologic treatments). This study demonstrated that there is a large unmet 
need for improved treatment of patients with chronic migraine. 
 
During the development of this research, patient stakeholders were engaged from the inception. 
The research question was confirmed to be of exceptional interest to the patient community and 
patient experts have actively participated in grant development and study design. We also 
administered a survey to 92 clinician members of the American Headache Society and results 
further demonstrate the importance of the clinical question at hand and the clinical equipoise that 
currently exists. Results showed: 1) 96% felt that migraine exerts a substantial burden on their 
patients; 2) 98% felt that medication overuse is an important issue for many people with migraine; 
3) 93% answered that treating chronic migraine with medication overuse is often difficult; 4) 88% 
believed that there are different strategies for treating patients who have chronic migraine with 
medication overuse and that the most effective strategy is not known; and 5) 97% thought that a 
well-designed clinical trial that compares different treatment strategies for patients who have 
chronic migraine with medication overuse is needed. Determining the best treatment strategy for 
patients who have chronic migraine with medication overuse will directly impact the clinical 
approach to such patients and optimize patient outcomes. 
 
6. Study Objective 
 
The objective of this study is to compare two real-world methods of treating patients who have 
chronic migraine with medication overuse:  
• migraine prophylactic therapy with immediate discontinuation of the overused 
medication  
• migraine prophylactic therapy without immediate discontinuation of the overused 
medication. 
 
 
7. Study Design 
 
This is a prospective, parallel group, simple randomized trial during which patients will be 
randomized 1:1 to one of two treatment strategies: 
 
• migraine prophylactic therapy with immediate discontinuation of the overused 
medication  
• migraine prophylactic therapy without early discontinuation of the overused 
medication. 
 
 
 

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8. Subject Eligibility 
 
Inclusion Criteria 
• Adults, at least 21 years of age 
• Chronic Migraine – diagnosed according to ICHD3beta criteria 
• Medication Overuse – diagnosed according to ICHD3beta criteria 
• Willingness to be randomized to either of the two treatment arms 
• Willingness to maintain a headache diary 
• Plan for follow-up care with the clinician 
• No changes to migraine prophylactic therapy within the 4 weeks prior to randomization 
 
Exclusion Criteria 
• Younger than 21 years of age 
• Headache diagnoses other than chronic migraine with medication overuse; episodic tension-
type headache on 3 or fewer days per month is allowed 
• Not willing to be randomized to either of the treatment arms 
• Not willing to maintain a daily headache diary 
• Not planning on follow-up care with the clinician 
• In the opinion of the clinician, randomization to either treatment arm would be considered 
unsafe (Ex pregnancy, immediate discontinuation). 
• Prisoners 
• Diminished decision-making capacity which in the investigator’s opinion would interfere 
with the person’s ability to provide informed consent and complete study procedures. 
 
ICHD3beta Diagnostic Criteria for Chronic Migraine 
 
 
ICHD3beta Diagnostic Criteria for Medication Overuse 
 
 
 
Medication Overuse Diagnostic Criteria 
A. Regular intake of ergotamine, triptans, opioids, combination analgesics, or a 
combination of drugs from different classes on ≥10 days per month for >3 months
or
B. Regularintakeofsimpleanalgesics(e.g.acetaminophen,NSAIDs)on≥15 days 
per month for >3 months

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9. Study Procedures 
 
Consecutive patients presenting to the investigator’s clinic, whether in-person or via telehealth 
methods, who meet inclusion/exclusion criteria should be offered enrollment. As a pragmatic study, 
potential participants will not be excluded based upon measures of clinical severity or based upon 
preconceived notions of their likelihood to respond to the study interventions. Chronic migraine 
patients with medication overuse will be identified just as they are in daily clinical practice – 
according to the patient’s report of headache frequency, headache symptoms, acute medications 
used and their frequency of use. Patients with excessive use of opioids and butalbital containing 
medications such that immediate discontinuation, in the opinion of the investigator, will pose an 
unacceptable risk of withdrawal syndrome and a serious risk to patient safety will be excluded (this 
is expected to be a very small proportion of patients who have chronic migraine with medication 
overuse). We anticipate that about 90% of patients who are screened for this study will be eligible 
and 40% of eligible patients will agree to participate in this study. Thus, in order to meet enrollment 
targets we estimate that headache specialty centers will have to screen approximately 5-6 patients 
per month, while general neurology and primary care clinics will have to screen about 2 patients 
per month. In total, each headache specialty clinic is expected to enroll 24 patients per year, while 
general neurology and primary care clinics are expected to enroll 8 patients per year. 
 
 
Recruitment Plan 
# patients screened each month 
# patients enrolled each year 
Headache Specialty 
Clinic 
6 
                              24 
General Neurology 
Clinic 
2 
8 
Primary Care Clinic 
2 
8 
 
Study Visits 
 
Each subject must have a research visit at baseline/randomization and at 12 weeks post-
randomization. These research visits can occur in-person or using IRB-approved telehealth 
methods, such as, but not limited to telephone, video, e-mail, and regular mail. Other follow-up visits 
will occur according to the clinician’s usual follow-up patterns (these are clinical visits, not study 
specified visits). 
 
Baseline/Randomization Visit 
 
a. Case Report Forms:  The following case report forms and questionnaires are to be completed at 
the baseline visit: 
 
• Inclusion/Exclusion Criteria 
• Subject Contact Information 
• Subject Demographics 
• Headache Characteristics 

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• Medication Use 
• Headache Impact Test 6 (HIT-6) 
• PROMIS Pain Interference questionnaire 
• Generalized Anxiety Disorder 7 (GAD-7) 
• Patient Health Questionnaire 9 (PHQ-9) 
• EuroQol 5D (EQ-5D-3L) 
• Change in Migraine Therapy 
• Migraine Functional Impact Questionnaire (MFIQ) 
 
b. Randomization:  Participants are to be randomized within the Medidata Rave online system. 
(see Appendix for instructions on how to use Medidata Rave) Randomization will be 1:1 to one of 
the two treatment strategies using a simple randomization technique. Randomization is to occur at 
the time when migraine prophylactic therapy is to be initiated or optimized. For example, if a 
patient is to receive a new prophylactic migraine medication, randomization would occur on the 
same day that the prescription is provided and the patient will start the medication. If it is known 
that there will be a delay between providing the patient with a preventive prescription and that 
patient receiving/starting the preventive medication, then randomization should occur at the time 
the patient will start the preventive. If a patient is going to be started on onabotulinumtoxinA, 
randomization is to occur on the day of the injections.  
 
c. Migraine Prophylactic Therapy:  Prophylactic therapy will be initiated or optimized for all 
participants. Participants who are not taking a migraine prophylactic medication at the time of 
study enrollment will be initiated on prophylactic medication. Participants who are already taking a 
migraine prophylactic medication will either have their dose optimized (if the dose was suboptimal 
at baseline), will be switched to a different prophylactic medication, or will be started on an 
additional prophylactic medication. Clinicians will be provided with guidance regarding their 
recommendations for migraine prophylactic therapy. Prophylactic medications have been divided 
into three tiers based upon the American Headache Society, American Academy of Neurology, and 
Canadian Headache Guidelines, safety profiles, and side effect profiles. (Silberstein 2012; 
Pringsheim 2012) The total number of medications in each tier has been reduced by not including 
more than one medication with the same presumed mechanism of action within each tier (e.g. not 
listing more than one beta-blocker within a tier). Clinicians will be instructed to first consider tier I 
medications, followed by tier II medications, followed by tier III medications. As is the case in typical 
clinical practice, clinicians will choose amongst the available medications within a tier based upon 
whether or not the patient has already tried and failed the medication, contraindications to taking 
the medication, drug-to-drug interactions, patient co-morbidities, likelihood of tolerating potential 
side effects, and cost. Target therapeutic doses and recommended titration schedules, assuming that 
the therapy is new for the patient, are provided. If a patient is already taking a prophylactic 
medication, the clinician may determine that a dosage increase for that medication is the preferred 
treatment recommendation. Patients can be included in the MOTS trial even when the clinician 
decides to use a preventive therapy that is not included in the “tiered” list below.  
 
Tier 1:  
• amitriptyline; target dose 30-150 mg; 10 mg qhs x 1 week, then increase by 10 mg each 
week  

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• propranolol; target dose  80-240mg; 80 mg daily x 1 week, then 120 mg daily; if using 
short acting form then dose twice daily (e.g. 40 mg bid; 60 mg bid); use long acting form 
once daily 
• topiramate; target dose 50-200 mg; 15-25 mg qhs x 1 week, then increase by 15-25 mg 
each week  
• onabotulinumtoxinA; 150-200 units 
• any medication that receives FDA approval for the prevention of migraine (the approval 
must include the treatment of individuals with chronic migraine) during the conduction 
of the MOTS trial (e.g. CGRP monoclonal antibodies) 
 
Tier 2:   
• venlafaxine; target dose 75-225 mg; 37.5 mg qd x 1 week, then increase by 37.5 mg each 
week. Use short acting form twice daily; use long-acting form once daily 
• valproic acid and derivatives; target dose 500-2000 mg; 250 mg bid x 1 week, then 500 
mg bid. Use both short-acting and long-acting forms twice daily. Maximum dosage is 
60mg/kg/day 
• candesartan; target dose 16-32 mg; 4 mg bid x 1 week, then 8 mg bid. Increase by 4-
8mg per week  
• gabapentin; target dose 600-3600 mg; 200mg tid x 1 week; 300 mg tid x week 2, 
increase by 300-900 per day weekly.  
 
Tier 3:  
• lisinopril; target dose 10-40 mg; 10 mg qd x 1 week, increase by 10mg per week 
• verapamil; target dose 120-480 mg; 40 mg tid x 1 week, then 80 mg tid; then 120mg tid week 3; 
then 160mg tid. If using regular form, continue tid dosing; if sustained release form, then use 
once daily 
• nortriptyline; target dose 30-150 mg; 10 mg qhs x 1 week, then increase each week by 
10 mg 
 
Adjunctive non-pharmacologic interventions will be documented and limited during the first 12 
weeks to those with levels of evidence sufficient to be recommended in prophylactic treatment 
guidelines. These include cognitive-behavioral therapy and biofeedback-assisted relaxation therapy. 
While two devices have recently been approved by the Food and Drug Administration for the acute 
treatment of migraine with aura (single pulse transcranial magnetic stimulation) or prevention of 
episodic migraine (supraorbital transcutaneous nerve stimulation [Cefaly®]), neither has been 
evaluated for the treatment of chronic migraine or medication overuse and they cannot be initiated 
during the randomization phase (12 weeks) of this study. Initiation of physical therapy, nerve 
blocks, acupuncture, chiropractic, and other non-pharmacological techniques sometimes employed 
by patients and/or clinicians in practice, have not been evaluated in this patient population and will 
not be permitted during the first 12 weeks of this study.  
 
d. Discontinuation of Overused Medication: For participants who are randomized to the group 
in which early discontinuation of the overused medication is indicated, discontinuation of the 
overused medication will be performed in the outpatient setting, will not involve the use of 

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“bridging therapy”, and will be immediate. Several studies have shown that outpatient 
discontinuation is effective and is similarly effective when compared to inpatient strategies for 
discontinuation. [Creac’h 2011] [Munksgaard 2012] [Rossi 2006] Since several studies have 
demonstrated a lack of benefit from prescribing transitional or “bridging” therapy, such as steroid 
tapers or occipital nerve blocks, during the discontinuation period, this protocol will not call for 
patients to be prescribed transitional therapy. [Dilli 2014] [Halker 2013] [Rabe 2013] [Boe 2007] 
If a patient requires inpatient detoxification (according to the opinion of the treating clinician) due 
to excessive use of opioids or butalbital-containing analgesics or if immediate discontinuation of 
the overused medication is not possible due to safety concerns, that potential participant will be 
excluded from this study. Otherwise, there will not be eligibility restrictions based on the 
medications that patients overuse.  
 
Discontinuing the Overused Abortive Medication(s) (RQ-2) (RQ-5) 
• Discontinuation is to be achieved in the outpatient setting 
• No “bridging therapy” is to be prescribed (e.g. corticosteroids, extracranial nerve 
injections, daily NSAID use, ambulatory infusion therapy) 
• The overused abortive medication(s) is/are to be immediately stopped and restricted 
use (< 2 days per week) of an alternative abortive medication will be recommended 
 
e. Symptomatic Therapy for Patients Randomized to Discontinuation of the Overused 
Medication: Clinicians will also be provided with instructions regarding the methods of prescribing 
alternative abortive medications to patients randomized to prophylactic therapy plus 
discontinuation of medication overuse. The specific medications from which the clinician can 
choose are detailed below and are based upon the American Headache Society, American Academy 
of Neurology, and Canadian Headache Society guidelines for abortive therapy of migraine. 
(Marmura 2015; Silberstein 2000; Worthington 2013) Although these patients will not continue to 
overuse abortive medications, they will be allowed to treat their most severe migraines within the 
limits imposed by this study protocol. We have chosen not to recommend complete cessation of all 
abortive therapies since that strategy would not be patient-centered, would likely result in many 
patients seeking emergency therapy (e.g. emergency department visits), and would increase the 
rates of patient non-adherence and study dropout. 
 
• Avoid use of medications from the same class as the overused medication 
• Up to 2 days per week: 
o Metoclopramide 10-20 mg or  
o Prochlorperazine 10 mg or 25 mg suppository  
o Odansetron 4mg-8mg (For patients with a history of extrapyramidal side effects 
or sensitivity to dopamine antagonists, or a personal or family history of a 
bradykinetic or hyperkinetic movement disorder)  
• Up to 2 days per week 
o Triptans 
▪ almotriptan 12.5 mg 
▪ eletriptan 40 mg 
▪ frovatriptan 2.5 mg  
▪ naratriptan 2.5 mg 

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▪ rizatriptan 5-10 mg 
▪ sumatriptan 
• oral 50-100 mg 
• nasal spray 10-20 mg 
• patch 6.5 mg 
• subcutaneous 4-6 mg 
▪ zolmitriptan 
• oral 2.5-5 mg 
• nasal spray 5 mg  
OR 
o Dihydroergotamine 
▪ nasal spray 2 mg 
▪ intravenous, intramuscular, or subcutaneous 1 mg 
OR 
o Ketorolac intramuscular 30 mg 
  
   OR 
o Diphenhydramine intramuscular 25-50 mg 
  
   OR 
o Non-steroidal anti-inflammatory drugs  
▪ aspirin 500 mg 
▪ diclofenac 50-100 mg 
▪ ibuprofen 400-600 mg 
▪ naproxen 400-550 mg 
OR 
o Combination analgesics 
▪ acetaminophen/aspirin/caffeine 500/500/130 mg 
▪ sumatriptan/naproxen 85/500 mg 
  
 
  OR 
o Ergotamine tartrate 2 mg 
  
  OR 
o Gepants 
▪ rimegepant 75 mg 
▪ ubrogepant 50-100 mg 
OR 
o Lasmiditan 50-200 mg 
 
f. Symptomatic Therapy for Patients Randomized to Prophylactic Therapy Without 
Discontinuation: 
• 
New abortive medications are not to be recommended 
• 
Clinicians will be instructed to discuss the following with the patient: 1) prophylactic 
medication is being initiated or current prophylactic medication(s) is/are being adjusted; and 
2) as a result, it is expected that migraine frequency will reduce and thus abortive medications 
will be required less frequently.  
 
 

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g. Headache Diary: Patients will maintain a daily headache diary during the following post-
randomization weeks:  
• 1-12 (days 1-84) 
• 21-24 (days 141-168) 
• 45-48 (days 309-336) 
 
At the baseline visit, patients will need to receive instructions on the use of the electronic/internet 
based headache diary that is within the Medidata Rave system. Patients may choose to use either 
the online or app version of the diary (or a combination of both). Sign-in information needs to be 
obtained. A paper headache diary is also to be given to patients along with instructions for use.  
 
This migraine and medication diary will require participants to record whether or not they had a 
headache on a given day, the maximum severity of headache pain during that day, whether the 
headache caused no, mild, moderate or severe functional impairment, whether or not they took 
migraine abortive medications that day (and which medication), whether or not they took 
migraine prophylactic medication that day, and any changes to their treatment regimen. 
 
 
Twelve Week Follow-Up Visit 
All subjects are to be seen for follow-up at 12 weeks post-randomization (+/- 1 week). This 12-week 
visit can be accomplished in-person (i.e. in the office) or using IRB-approved telehealth methods, 
such as, but not limited to telephone, video, e-mail, regular mail, and by completing internet-based 
questionnaires. 
 
Subjects are to remain in the treatment group to which they were randomized through this 12-week 
visit. Subjects will remain in this study through week 48, but treatment recommendations starting 
with week 13 will be according to the clinician’s usual clinical practice.  
 
h. Case Report Forms:  The following case report forms and questionnaires are to be completed at 
the 12-week visit: 
 
• Follow-up Visit Headache Characteristics 
• Medication Use 
• Headache Impact Test 6 (HIT-6) 
• PROMIS Pain Interference questionnaire 
• Generalized Anxiety Disorder 7 (GAD-7) 
• Patient Health Questionnaire 9 (PHQ-9) 
• EuroQol 5D (EQ-5D-3L) 
• Change in Migraine Therapy 
• Migraine Functional Impact Questionnaire (MFIQ) 
 
Other Follow-Up Visits and Telephone Contacts 
 
The timing of these follow-up visits is left to the discretion of the clinician. However, consistent with 
good clinical care of patients who have chronic migraine with medication overuse, follow-up visits 

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are expected to occur approximately each 2-3 months. These visits can be accomplished in-person 
(i.e. in the office) or using IRB-approved telehealth methods, such as, but not limited to telephone, 
video, e-mail, regular mail, and by completing internet-based questionnaires. 
 
 
i. Case Report Forms: At each follow-up visit, the following case report forms are to be completed: 
 
• Follow-up Visit Headache Characteristics 
• Medication Use 
• Headache Impact Test 6 (HIT-6) 
• PROMIS Pain Interference questionnaire 
• Generalized Anxiety Disorder 7 (GAD-7) 
• Patient Health Questionnaire 9 (PHQ-9) 
• EuroQol 5D (EQ-5D-3L) 
• Change in Migraine Therapy 
• Migraine Functional Impact Questionnaire (MFIQ) 
 
 
j. Headache Diary Adherence Monitoring: 
Monitoring patient adherence to diary keeping and sending reminders to each participant will be 
necessary for improving adherence to daily diary keeping. The research team should monitor each 
patient’s completion of the headache diary on a weekly basis. If non-adherence is noted, the study 
team should contact the patient via telephone, e-mail, text messages, and/or regular mail. In these 
communications, participants should be reminded to keep their daily headache diary and provided 
with further instructions if the participant is having any difficulty with the diary. No clinical 
recommendations should be made during these research communications. In addition, telephone 
calls, e-mails, text messages, or regular mail will be necessary at the beginning of the 21-24 week 
period and 45-48 week period to remind the patient to once again start maintaining the headache 
diary.  
 
• 1-4 weeks post randomization 
o Day 1 after the baseline visit 
o Day 7-9 after the baseline visit 
o Day 14-16 after the baseline visit 
o Day 21-23 after the baseline visit 
 
• 5-8 weeks post randomization 
o Day 28-30 after the baseline visit 
o Day 35-37 after the baseline visit 
o Day 42-44 after the baseline visit 
o Day 49-51 after the baseline visit 
 
• 9-12 weeks post randomization 
o Day 56-58 after the baseline visit 
o Day 62-64 after the baseline visit 

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o Day 69-71 after the baseline visit 
o Day 76-78 after the baseline visit 
 
• 21-24 weeks post randomization 
o Day 139-141 after the baseline visit 
o Day 146-148 after the baseline visit 
o Day 153-155 after the baseline visit 
o Day 160-162 after the baseline visit 
 
• 45-48 weeks post randomization: 
o Day 307-309 after the baseline visit 
o Day 314-326 after the baseline visit 
o Day 321-333 after the baseline visit 
o Day 328-340 after the baseline visit 
 
k. Changes in Therapy: Changes in the subject’s migraine treatment that might occur outside of the 
follow-up visits (e.g. via a telephone call with the patient) should be documented in the 
“Medications and Treatments” case report form within Medidata Rave. 10. Study Outcomes 
 
a. Primary Outcome: The primary outcome measure for this study will be frequency of moderate 
to severe headache days (i.e. days on which a headache lasts for at least 2 hours and at any time 
peaks at moderate or severe intensity) per 4 weeks measured during 9-12 weeks post-
randomization. If non-inferiority is demonstrated for the primary outcome, then a test of 
superiority will be performed for the frequency of moderate to severe headache days during the 
first 2 weeks post-randomization. 
 
b. Secondary Outcomes frequency of headaches associated with moderate to severe functional 
impairment, frequency of days taking abortive medications, headache frequency, treatment 
adherence rates, and rates of subject dropout. (RQ-2) (RQ-6) (PC-3) In addition, relapse rates 
(i.e. the proportion of subjects who stopped overusing the abortive medication but then 
returned to the overuse pattern) will be measured using the 21-24 week and 45-48 week data. 
• Frequency of headaches associated with moderate to severe functional impairment 
• Frequency of days taking symptomatic medications 
• Headache Frequency 
• Treatment Adherence Rates 
• Subject Study Dropout Rates 
• Relapse Rates (i.e. the proportion of subjects who stopped overusing the abortive medication 
but then returned to the overuse pattern) 
• Quality of Life 
• Disability 
 
c. Heterogeneity of Treatment Effects Analyses 
• Class of overused medication 
• Baseline frequency of taking the overused medication 
• Duration of medication overuse 

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• Years with migraine 
• Years with chronic migraine 
• Type of provider managing the patient (i.e. headache specialist, general neurologist, primary 
care physician) 
• Frequency of follow-up visits 
• Class of prophylactic therapy(s) used 
• Baseline headache frequency 
• Baseline anxiety and depression scores 
• Patient age 
• Patient sex 
• Type of visit (in person vs. virtual) 
• Calendar period (before or after initiation of virtual visits) 
 
 
 
 

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11. Sample Size and Data Analyses Plans 
 
a. Sample Size 
 
The sample size was calculated based upon showing non-inferiority of prophylactic therapy alone 
compared to prophylactic therapy with early discontinuation of overused medication. An effective 
sample of 288 per group (80% of 360) has 80% power (two-sided α .05) to determine that the mean 
difference is less than 1.5 moderate to severe headache days per four weeks, assuming a population 
difference of 0.0 moderate to severe headache days per four weeks (pooled SD 6.4 from Silberstein 
2013). 
 
b. Data Analyses Plans 
 
Patients will be included in the primary analysis on the basis of intention-to-treat. The frequency of 
moderate to severe headache days during the 9-12 week post-randomization period will be 
compared among the two treatment groups by using a two-sample t test. The primary test will be a 
test of noninferiority. The noninferiority margin will be defined as a mean difference of 1.5 
moderate to severe headache day per four weeks. A second primary measure will be assessed by 
using a fixed sequence gatekeeper strategy. If noninferiority is demonstrated for the frequency of 
moderate to severe headache days during the 9-12 week period, then a test of superiority will be 
performed for the frequency of moderate to severe headache days during the first 2 weeks post-
randomization. Missing values will be handled by multiple imputation. Pattern mixture modeling 
will be used if the pattern of missing data differs between groups. In addition, baseline 
characteristics for subjects with missing primary outcome data will be compared to those without 
missing data. An interim analysis will be performed using data from 12 weeks after the 360th subject 
has been randomized. Interim analyses will be performed by using the alpha spending function 
method with a Haybittle-Peto boundary function. Results will be considered statistically significant 
if the nominal significance level is less than 0.001 at the interim analyses, or less than 0.049 at the 
final analysis.  Per-protocol analyses will be performed in addition to the intention-to-treat analyses 
because the primary hypothesis is based on noninferiority. The intention-to-treat and per-protocol 
analyses would both have to demonstrate non-inferiority to consider the trial positive. 
 
A confirmatory heterogeneity of treatment effect analysis for type of overused medication will be 
performed if the primary analysis demonstrates noninferiority. (HT-3) Patients will be classified 
into whether or not the overused medication was an opioid or barbiturate vs. another abortive 
medication. The frequency of moderate to severe headache days during the 9-12 week period will 
be compared among the two treatment groups by using a general linear model with terms for 
group, overused medication category (opioid or barbiturate versus other), and group by category 
interaction. Descriptive heterogeneity of treatment effect analyses will be performed for duration 
of overuse, baseline headache frequency, number of years with migraine, number of years with 
chronic migraine, the type of provider managing the patient (e.g. headache specialist vs. 
neurologist vs. primary care provider), patient sex, patient age, baseline anxiety and depression 
scores, the class of prophylactic therapy used, the frequency of follow-up visits with the clinician, 
type of visit, and calendar period. Analyses concerning prophylactic medications will focus on the 
therapy that was the change in treatment at the baseline visit. For example, if a participant is 

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taking medication A at baseline and the clinician adds medication B, it is medication B that would 
be considered the treatment of interest.  
 
12. Potential Risks and Protection of Human Subjects 
 
The study will be conducted according to Good Clinical Practice guidelines, the Declaration of 
Helsinki, U.S. 21 Code of Federal Regulations for Protection of Human Subjects, and Institutional 
Review Boards, and pursuant to state and federal HIPAA regulations. Institutional Review Boards 
for each participating center must provide unconditional approval prior to that centers 
participation in this study. Documents proving IRB-approvals will be submitted to the Principal 
Investigators prior to each center’s participation. All protocol amendments will require IRB 
approvals and documents confirming approval of such amendments will be submitted to the 
Principal Investigators.  Each participating center’s IRB and the IRB at the principal investigators’ 
center (Mayo Clinic) will be informed of all serious or unexpected adverse events that occur during 
the study. Adverse events will also be reported to PCORI, if such reporting of adverse events is 
consistent with PCORI policy. 
 
Written informed consent will be obtained from all potential subjects prior to their participation in 
this research. The informed consent process will be based upon principles discussed in the 
Declaration of Helsinki and in accordance with US 21CFR. Applicable HIPAA privacy notifications 
will be included. Participants will be given ample time and opportunities to ask questions about this 
study prior and following consent. All consent forms will require IRB approval prior to their use.  
 
Patients will always have the right and will be informed of their right to withdraw from the study at 
any time. Enrolling clinicians will be made aware that the needs of their patients come first and thus 
the safety and wellbeing of study participants is of primary concern. 
 
A Data and Safety Monitoring Board (DSMB) will review safety data on a quarterly basis through the 
first year of enrollment and then twice per year. A detailed data and safety monitoring plan will be 
submitted and approved by the Mayo IRB and by the funding entity (PCORI) prior to accrual of 
human subjects. Based upon the results of this review, the DSMB will make recommendations 
regarding study methods and continuation of the research. 
 
The benefits of this proposed research study far outweigh the risks. As discussed in detail in the 
main body of this grant application, chronic migraine with medication overuse is a very common 
problem and one that exerts substantial negative impacts on the lives of people suffering with this 
condition. Despite its high prevalence, the significant burden that it causes, and the undeniable need 
for treating patients who have chronic migraine with medication overuse, the best treatment 
strategy is currently unknown. For the benefit of patients who have chronic migraine with 
medication overuse and their family members, it is essential that we move past this clinical 
equipoise and clarify the best treatment strategy. Given the design of this proposed study, the risks 
associated with participation are similar to those that a patient is exposed to during routine clinical 
care. Both treatment strategies used in this proposed research are commonly used in routine 
clinical practice. Each patient participant’s enrolling clinician is also his or her treating clinician. 
Within the confines of the treatment strategy that an individual participant is randomized to, the 
clinician will utilize their best clinical skills for making treatment decisions, as would be done in 

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typical clinical practice. Adverse events will be managed just as they would be in typical clinical 
practice. 
 
In all research involving human subjects, the loss of confidentiality is a principal concern. Therefore, 
steps will be taken to minimize this risk. All information collected from study participants will be 
locked in a secure location. Identifying information will be removed from the data forms and 
replaced by unidentifiable codes. Electronic databases/spreadsheets will be password protected 
and only accessible to those with access rights. (DN-1) Only de-identified data will be made widely 
available to other researchers. Data will be entered into Medidata Rave. Medidata Rave is the 
information technology system endorsed by Mayo Clinic’s Clinical Trial Management System. The 
Medidata Rave system is compliant with 21 Code of Federal Regulations (CFR) Part 11 Food and 
Drug Administration (FDA) requirements. Edit checks, electronic queries, and audit trails are built 
into the system to ensure accurate and complete data collection and security. The Medidata Rave 
database access model is role based and fully auditable at the study, form, and field levels. Access is 
managed by the Mayo Clinic’s Clinical Trial Management System Service and Solution Center, under 
a controlled and monitored access request system. Data will be transmitted via the Internet from 
investigational sites to the Mayo Clinic via state-of-the-art encryption mechanisms, thus ensuring 
security and confidentiality.  
Women and minorities will be included in this study in proportions that represent the populations 
from which they are enrolled. Based upon the propensity of chronic migraine with medication 
overuse to impact women disproportionately more than men, we expect that 3.5 to 4 women will be 
enrolled into this study for every one man enrolled into this study. We anticipate that minorities will 
be enrolled in proportions that reflect the U.S. population, with approximately 35.6% of participants 
being of a race/ethnicity other than non-Hispanic white or European American. According to the 
2010 U.S. Census of the total population (Hispanic and Non-Hispanic), 78.4% of the population is 
White, 13% of the population is Black or African American, 1.2% is American Indian or Alaska 
Native, 4.9% is Asian, 0.2% is Native Hawaiian and Other Pacific Islander, and 2.3% is two or more 
races. Hispanics accounted for 16.3% of the total U.S. population according to the 2010 Census. 
Thus, we anticipate that of the 720 enrolled patient participants, 576 will be women, 117 will be 
Hispanic, 564 will be White, 94 will be Black or African American, 9 will be American Indian or 
Alaska Native, 35 will be Asian, 1 will be Native Hawaiian or Other Pacific Islander, and 17 will be 
two or more races.  
 
Children and adolescents under the age of 21 will not be included in this study. Although we 
considered including children and adolescents, their exclusion from this proposed study is based 
upon the facts that: 1) although little is known about the prevalence of medication overuse in the 
pediatric chronic migraine population, medication overuse is thought to be much less frequent 
among children and adolescents compared to adults; 2) the medications overused amongst children 
with medication overuse differ compared to the medications overused in adults; 3) the treatment 
strategies for treating children and adolescents who have chronic migraine with medication overuse 
differ from the strategies used when treating adults (e.g. onabotulinumtoxinA is approved for adult 
patients with chronic migraine but not for children or adolescents). Although additional 
investigations into chronic migraine with medication overuse in children and adolescents are 
needed, such investigations will be better performed in studies separate from this proposed PCORI 
study. 

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This study will not enroll participants from “vulnerable populations” (i.e. prisoners, pregnant 
women, children). 
 
All investigators who participate in this trial will have to complete or demonstrate prior completion 
of education on the protection of human research participants. (DN-1) The principal investigators 
will require documentation that such training has been completed prior to investigators enrolling 
subjects into this study.  
 
13. Informed Consent 
 
Informed consent procedures will be performed according to the requirements and 
recommendations of each participating centers Institutional Review Board.  
 
Written consent will be obtained from all subjects. Written consent can be obtained from the patient 
in the office, by using internet-based document software (e.g. DocuSign), by scanning paper 
documents and submitting them by e-mail, and by sending signed documents through regular mail. 
Only those methods that are IRB-approved will be used.Copies of consent forms will be submitted to 
the Mayo Clinic.  
 
a. Informed Consent Personnel 
 
Any member of the research team who obtains informed consent from a subject will need to be 
approved by their local IRB to do so. 
 
b. Location and Privacy 
 
The informed consent process will occur in a location that is approved by the local IRB.  
 
c. Storage of Consent Documents 
 
Consent documents will be stored at each participating center for a minimum of 3 years after 
conclusion of the study. The subject will be provided with a copy of the consent document.  
Copies of the consent documents will also be sent to the Mayo Clinic. 
 
d. Withdrawal of Consent 
 
Subjects will have the right to withdraw their consent at any time. After a participant withdraws 
from the study, they will not be contacted and their data will not be used moving forward.  
 
14. Subject Retention 
 
Telephone calls, e-mails, and other telehealth methods of communication with patients will help 
retain subjects and improve adherence rates. Only those methods that are IRB-approved will be 
used. The contact schedule can be seen above in section 9j.  
 

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Subjects will receive compensation of $30 per research visit, including the baseline visit and 12-
week follow-up visit. Including these two mandatory research visits, subjects can receive 
compensation for up to 6 research visits maximum during their 48 weeks of participation with this 
study. 
 
After two days of not entering diary data, subjects will receive e-mails and/or text messages 
reminding them to record their data in the internet-based or mobile app headache diary. Subjects 
will receive $50 compensation per 4-week period during which they are at least 80% compliant 
with providing headache diary data (i.e. provide diary data on at least 80% of days). Since subjects 
are asked to maintain the diary for five 4-week periods during the study (weeks 1-4, 5-8, 9-12, 21-
24, and 45-48), the maximum compensation for diary compliance is $250 per subject. 
 
15. Data Management 
 
Data will be entered into a Medidata Rave electronic database capture system. Medidata Rave is the 
information technology system endorsed by Mayo Clinic’s Clinical Trial Management System. Study 
sites will enter data into electronic case report forms using Medidata Rave. Case report forms are 
automatically presented to site investigators based on a predetermined, visit based schedule in 
order to improve study staff workflow and data quality. The Medidata Rave system is compliant 
with 21 Code of Federal Regulations (CFR) Part 11 Food and Drug Administration (FDA) 
requirements. Edit checks, electronic queries, and audit trails are built into the system to ensure 
accurate and complete data collection and security. During the course of the data entry into 
Medidata Rave, the system provides real-time within case report form and inter-case report form 
data consistency verification. Medidata Rave is flexible in nature so that all data can be entered even 
if “required” fields and other consistency checks requirements are not satisfied. The system uses an 
internal “flagging” or “query” system to distinguish the valid from the invalid data thereby ensuring 
compliance with the Food and Drug Administration guidance document “Computerized Systems 
Used in Clinical Trials”. The Medidata Rave database access model is role-based and fully auditable 
at the study, form, and field levels. Access is managed by the Mayo Clinic’s Clinical Trial 
Management System Service and Solution Center, under a controlled and monitored access request 
system. Data will be transmitted via the Internet from investigational sites to the Mayo Clinic via 
state-of-the-art encryption mechanisms, thus ensuring security and confidentiality. 
 
16. Adverse Events Reporting 
 
The adverse event process flow from the National Institutes of Health National Institute on Aging 
will be used for this study. (see appendix) Investigators will immediately report all serious adverse 
events to their local Institutional Review Board and to the Principal Investigators. The Principal 
Investigators will immediately report all serious adverse events to the Data and Safety Monitoring 
Board and to the Mayo Clinic Institutional Review Board. All serious and non-serious adverse events 
will be recorded and submitted to the Data and Safety Monitoring Board. Adverse events will be 
recorded using the Adverse Event forms created by the National Institutes of Health National 
Institute on Aging (see appendix).   
 
17. Protocol Maintenance 
 

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All protocol changes will be tracked within a Protocol Change Log and the revised protocol will 
receive a new version number and date. A description of the revision and the most recent protocol 
will be sent to each of the investigative sites. Investigators will be required to confirm receipt and 
review of the revised protocol. 
 
 
 
18. Study Website 
 
The study website is available at: www.motstrial.org 
 
The website hosts the study protocol, updates on study progress, participating centers and links to 
presentations and publications that relate to this study. 
 
 
19. Study Registration 
 
The study has been registered with clinicaltrials.gov (NCT02764320; 5/4/16) and results will be 
reported to clinicaltrials.gov. 
 
 
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Bigal ME, Lipton RB. Obesity is a risk factor for transformed migraine but not chronic tension-
type headache. Neurology 2006;67:252-257. 
 
Bigal ME, Rapoport AM, Sheftell FD, Tepper SJ, Lipton RB. Transformed migraine and medication 
overuse in a tertiary headache centre – clinical characteristics and treatment outcomes. 
Cephalalgia 2004;24:483-490. 
 
Boe MG, Mygland A, Salvesen R. Prednisolone does not reduce withdrawal headache: a 
randomized, double-blind study. Neurology 2007;69:26-31. 
 
Blumenfeld AM, Varon SF, Wilcox TK, Buse DC, Kawata AK, Manack A, et. al. Disability, HRQoL 
and resource use among chronic and episodic migraineurs: results from the International 
Burden of Migraine Study (IBMS). Cephalalgia 2011;31:301-315. 
 
Buse D, Manack A, Serrano D, Reed M, Varon S, Turkel C, et. al. Headache impact of chronic and 
episodic migraine: results from the American Migraine Prevalence and Prevention study. 
Headache 2012;52:3-17. 
 
Buse DC, Manack AN, Fanning KM, Serrano D, Reed ML, Turkel CC, et. al. Chronic migraine 
prevalence, disability, and sociodemographic factors: results from the American Migraine 
Prevalence and Prevention Study. Headache 2012;52:1456-1470. 

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Buse DC, Manack A, Serrano D, Turkel C, Lipton RB. Sociodemographic and comorbidity profiles 
of chronic migraine and episodic migraine sufferers. J Neurol Neurosurg Psychiatry 
2010;81:428-432. 
 
Classification Committee of the International Headache Society. The International Classification 
of Headache Disorders, 3rd edition (beta version). Cephalalgia 2013;33:629-808. 
 
Creac’h C, Frappe P, Cancade M, Laurent B, Peyron R, Demarquay G, Navez M. In-patient versus 
out-patient withdrawal programmes for medication overuse headache: a 2-year randomized 
trial. Cephalalgia 2011;31:1189-1198. 
 
Davies P. Medication overuse headache: a silent pandemic. Pain 2012;153:7-8. 
 
Dilli E, Halker R, Vargas B, Hentz J, Radam T, Rogers R, Dodick D. Occipital nerve block for the 
short-term preventive treatment of migraine: a randomized, double-blinded, placebo-controlled 
study. Cephalalgia 2014;epub ahead of print. 
 
Dodick DW, Lipton RB, Serrano D, Reed ML, Fanning KM, Manack AN, Holden A. Effects of 
demographic and socioeconomic characteristics on barriers to chronic migraine consultation, 
diagnosis, and treatment: results from the CaMEO (Chronic Migraine Epidemiology & Outcomes) 
Study. Headache 2014;S1:23-24. 
  
Hagen K, Albretsen C, Vilming ST, Salvesen R, Gronning M, Helde G, et. al. Management of 
medication overuse headache: 1-year randomized multicentre open-label trial. Cephalalgia. 
2009; 29: 221-32. 
 
Halker RB, Dilli E. A role for steroids in treating medication overuse headache? Cephalalgia 
2013;33:149-151. 
 
Lanteri-Minet M, Duru G, Mudge M, Cottrell S. Quality of life impairment, disability and economic 
burden associated with chronic daily headache, focusing on chronic migraine with or without 
medication overuse: a systematic review. Cephalalgia 2011;31:837-850. 
 
Launer LJ, Terwindt GM, Ferrari MD. The prevalence and characteristics of migraine in a 
population-based cohort: the GEM study. Neurology 1999;53:537-542. 
 
Lipton RB, Bigal ME, Diamond M, Freitag F, Reed ML, Stewart WF. Migraine prevalence, disease 
burden, and the need for preventive therapy. Neurology 2007;68:343-349. 
 
Lipton RB, Stewart WF, Diamond S, Diamond ML, Reed M. Prevalence and burden of migraine in 
the United States: data from the American Migraine Study II. Headache 2001;41:646-657. 
 
Lipton RB, Hamelsky SW, Kolodner KB, Steiner TJ, Stewart WF. Migraine, quality of life, and 
depression: a population-based case-control study. Neurology 2000;55:629-635. 
 

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Louter MA, Bosker JE, van Oosterhout WP, van Zwet EW, Zitman FG, Ferrari MD, et. al. Cutaneous 
allodynia as a predictor of migraine chronification. Brain 2013;136:3489-3496. 
 
Marmura MJ, Silberstein SD, Schwedt TJ. The acute treatment of migraine in adults: the American 
Headache Society evidence assessment of migraine pharmacotherapies. Headache 2015;55:3-20. 
 
Munakata J, Hazard E, Serrano D, Klingman D, Rupnow MF, Tierce J, et. al. Economic burden of 
transformed migraine: results from the American Migraine Prevalence and Prevention (AMPP) 
study. Headache 2009;49:498-508. 
 
Munksgaard SB, Bendtsen L, Jensen RH. Detoxification of medication-overuse headache by a 
multidisciplinary treatment programme is highly effective: a comparison of two consecutive 
treatment methods in an open-label design. Cephalalgia 2012;32:834-844. 
 
Natoli JL, Manack A, Dean B, Butler Q, Turkel CC, Stovner L, et. al. Global prevalence of chroinc 
migraine: a systematic review. Cephalalgia 2010;30:599-609. 
 
Pringsheim T, Davenport W, Mackie G, Worthington I, Aube M, Christie SN, et. al. Canadian 
Headache Society guideline for migraine prophylaxis. Can J Neurol Sci 2012;39(Suppl 2):S1-59. 
 
Rabe K, Pageler L, Gaul C, Lampi C, Kraya T, Foerderreuther S, Diener HC, Katsarava Z. 
Prednisone for the treatment of withdrawal headache in patients with medication overuse 
headache: a randomized, double-blind, placebo-controlled study. Cephalalgia 2013;33:202-207. 
 
Rasmussen BK. Epidemiology of headache. Cephalalgia 1995;15:45-68. 
 
Rossi P, Di Lorenzo C, Faroni J, Cesarino F, Nappi G. Advice alone vs. structured detoxification 
programmes for medication overuse headache: a prospective, randomized, open-label trial in 
transformed migraine patients with low medical needs. Cephalalgia 2006;26:1097-1105. 
 
Scher AI, Midgette LA, Lipton RB. Risk factors for headache chronification. Headache 
2008;48:16-25. 
 
Scher AI, Stewart WF, Buse D, Krantz DS, Lipton RB. Major life changes before and after the onset 
of chronic daily headache: a population-based study. Cephalalgia 2008;28:868-76. 
 
Schwedt TJ. Chronic Migraine. BMJ 2014;348:g1416. 
 
Silberstein SD, Blumenfeld AM, Cady RK, Turner IM, Lipton RB, Diener HC, et. al. 
OnabotulinumtoxinA for treatment of chronic migraine: PREEMPT 24-week pooled subgroup 
analysis of patients who had acute headache medication overuse at baseline. J Neurol Sci 
2013;331:48-56. 
 
Silberstein SD, Holland S, Freitag F, Dodick DW, Argoff C, Ashman E. Evidence-based guideline 
update: pharmacologic treatment for episodic migraine prevention in adults. Neurology 
2012;78:1337-1345. 

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Silberstein SD. Practice parameter: evidence-based guidelines for migraine headache (an 
evidence-based review): report of the Quality Standards Subcommittee of the American 
Academy of Neurology. Neurology 2000;55:754-762. 
 
Smith JH, Schwedt TJ. Consensus treatment of medication overuse headache in Latin America 
and Europe. Cephalalgia. 2014;34:643-644. 
 
Steiner TJ, Stovner LJ, Katsarava Z, Lainez JM, Lampl C, Lanteri-Minet M, et. al. The impact of 
headache in Europe: principal results of the Eurolight project. The Journal of Headache and Pain 
2014;15:31. 
 
Stewart WF, Ricci JA, Chee E, Morganstein D, Lipton R. Lost productive time and cost due to 
common pain conditions in the US workforce. JAMA 2003;290:2443-2454. 
 
Stokes M, Becker WJ, Lipton RB, Sullivan SD, Wilcox TK, Wells L, et. al. Cost of health care among 
patients with chronic and episodic migraine in Canada and the USA: results from the 
International Burden of Migraine Study (IBMS). Headache 2011;51:1058-1077. 
 
Stovner LJ, Andree C. Impact of headache in Europe: a review for the Eurolight project. J 
Headache Pain 2008;9:139-146. 
 
Tassorelli C et al. A consensus protocol for the management of medication-overuse headache: 
Evaluation in a multicentric, multinational study. Cephalalgia. 2014;online early. 
 
Terwindt GM, Ferrari MD, Tijhuis M, Groenen SM, Picavet HS, Launer LJ. The impact of migraine 
on quality of life in the general population: The GEM study. Neurology 2000;55:624-629. 
 
Vos T, Flaxman AD, Naghavi M, Lozano R, Michaud C, Ezzati M, et. al. Years lived with disability 
(YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: a systematic analysis for the 
Global Burden of Disease Study 2010. Lancet 2012;380:2163-2196. 
 
Westergaard ML et. al. Prevalence of chronic headache with and without medication overuse: 
associations with socioeconomic position and physical and mental health status. Pain 
2014;155:2005-13. 
 
Worthington I, Pringsheim T, Gawel MJ, Gladstone J, Cooper P, Dilli E, et. al. Canadian Headache 
Society Guideline: acute drug therapy for migraine headache. Can J Neurol Sci 2013;40(Suppl 
3):S1-S80. 
 
 
 
 
 

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21. Appendices 
 
a) Case Report Forms 
 
• Inclusion/Exclusion Criteria 
• Subject Contact Information 
• Subject Demographics 
• Headache Characteristics 
• Medication Use 
• Headache Impact Test 6 (HIT-6) 
• PROMIS Pain Interference questionnaire 
• Generalized Anxiety Disorder 7 (GAD-7) 
• Patient Health Questionnaire 9 (PHQ-9) 
• EuroQol 5D (EQ-5D-3L) 
• Change in Migraine Therapy 
• Migraine Functional Impact Questionnaire (MFIQ) 
 
 
 

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Determining the Optimal Treatment Strategy for Patients who have Chronic 
Migraine with Medication Overuse 
 
Inclusion and Exclusion Criteria 
 
 
Instructions: Place a mark in each bubble as you confirm the subject meets enrollment criteria. 
 
 
Inclusion Criteria: 
 
o At least 21 years of age at the time of enrollment 
o Chronic Migraine diagnosed according to ICHD3 beta criteria (see criteria) 
o Medication Overuse diagnosed according to ICHD 3 beta criteria (see criteria) 
o Willing to be randomized to either of the two treatment arms 
o Willing to maintain a headache diary 
o Plans for follow-up care with the enrolling clinician 
o No changes to migraine prophylactic therapy within the last 4 weeks prior to randomization 
 
 
Exclusion Criteria: 
o Younger than 21 years of age 
o Headache diagnosis other than migraine (with or without aura), probable migraine, chronic 
migraine with medication overuse; episodic tension type headaches on 3 or fewer days per 
month are allowed. 
o Not willing to be randomized to either of the treatment arms 
o Not willing to maintain a daily headache diary 
o Not planning on follow-up care with the clinician  
o In the opinion of the clinician, randomization to either treatment arm would be considered 
unsafe (Example: Pregnancy, immediate discontinuation, etc.) 
o Prisoner 
o Diminished decision-making capacity that in the investigator’s opinion interferes with the 
ability to provide informed consent and complete study procedures 
 
 
 

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Medication Overuse Diagnostic Criteria 
A. Regular intake of ergotamine, triptans, opioids, combination analgesics, or a 
combination of drugs from different classes on ≥10 days per month for >3 months
or
B. Regularintakeofsimpleanalgesics(e.g.acetaminophen,NSAIDs)on≥15 days 
per month for >3 months

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Determining the Optimal Treatment Strategy for Patients who have 
Chronic Migraine with Medication Overuse 
 
Contact Information 
 
 
Name: ___________________________            _______________________________ 
 
        (First) 
 
 
 
 
      (Last) 
 
 
 
 
Home:  (_____) ______-___________    
 
 Work:   (_____) ______-___________ 
 
 
Mobile: (_____) ______-___________      
 
Email:  ________________________ 
 
 
Address:  
 
________________________________________ Unit/Apt#_______________ 
 
(Street)   
  
City_________________________ State_____________ Zip_______________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Determining the Optimal Treatment Strategy for Patients who have 
Chronic Migraine with Medication Overuse 
 
Subject Demographics 
 
 
DOB:     ___   ___ / ___   ___ / ___   ___  ___  ___ 
                  Month         Day                  Year 
 
 
Current age (years): __________ 
 
 
Sex at birth (circle one):   1 = Male                     2 = Female 
 
 
Race (circle all that apply): 
 
      
1 = American Indian/Alaska Native  
2 = Asian 
 
      
3 = Black/African American  
 
4 = Native Hawaiian/Other Pacific Islander 
 
      
5 = White/Caucasian  
 
 
6 = Other ___________________ 
 
 
Ethnicity:    1 = Hispanic       2 = Non-Hispanic         
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Determining the Optimal Treatment Strategy for Patients who have Chronic 
Migraine with Medication Overuse 
 
Headache Characteristics 
 
 
On average over the last 3 months, how many days per month (30 days) with headache of any kind/severity:         
days 
 
On average over the last 3 months, how many days per month (30 days) with complete headache freedom:            
days 
 
How many days over the last 30 days with headache that at any time during the day became moderate or severe 
intensity:         days 
 
On those days when headache intensity became moderate or severe, on average how many hours did the pain 
remain moderate or severe?  
 
hours 
 
How many days in the last 30 days did the headache remain mild intensity all day long?  
days 
 
 
How many days in the last 30 days have acute (as needed) medications  (e.g. triptans, analgesic) been taken for 
headache?        
days 
 
How many days in the last 30 days have analgesic (pain) medications been taken for conditions other than 
headache (e.g. other pain, fever)?              days 
 
How many days in the last 30 days have no analgesic or acute medications been taken?              days 
 
How many days in the last 30 days did the patient take a daily migraine preventive therapy(ies)?        days 
 
On average, how long do headaches last if successfully treated:   
hours 
 
On average, how long do headaches last if untreated or inadequately treated:   
hours 
 
 
Where is headache pain usually located (circle all that apply): 
 
Right   
Left 
 
Front  
Back   
Side 
 
 
Is headache typically unilateral (circle one):  
 

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35 
 
Yes 
 
No 
 
 
Headache quality (circle all that apply):  
 
Pulsating/Throbbing          Pressure/Aching          Stabbing          Burning 
 
Headache intensity: 
 
Average on 0 (no pain) to 10 (most severe pain) scale:         /10 
 
Maximum on 0 (no pain) to 10 (most severe pain) scale:      /10 
 
 
With headaches/migraine attacks is there ever:  
 
Worsening of headache with physical activity: 
 
Yes 
 
No 
 
Nausea: 
 
 
 
 
 
 
Yes 
 
No 
 
Vomiting: 
 
 
 
 
 
 
Yes 
 
No 
 
Sensitivity to light: 
 
 
 
 
 
Yes 
 
No 
 
Sensitivity to sound:   
 
 
 
 
Yes 
 
No 
 
Conjunctival injection on same side of headache: 
 
Yes 
 
No 
 
Tearing on same side of headache: 
 
 
 
Yes 
 
No 
 
Nasal congestion/rhinorrhea on same side of headache 
Yes 
 
No 
 
Eyelid drooping on same side of headache 
 
 
Yes 
 
No 
 
 
Are there ever auras with migraine attacks:   
 
 
Yes 
 
No 
 
If yes, then what aura types are experienced: 
 
Visual:  
 
 
 
 
 
Yes 
 
No 
 
Sensory: 
 
 
 
 
 
Yes 
 
No 
 
Motor:  
 
 
 
 
 
Yes 
 
No 
 

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Language: 
 
 
 
 
 
Yes 
 
No 
 
Other:   
 
 
 
 
 
Yes 
 
No 
 
What percentage of headaches are accompanied by auras:   
_______________% 
 
 
When was the patient’s first migraine (month and year):                   __ __ / __ __ __ __ 
 
 
When was the onset of the chronic migraine pattern (month, year):  __ __ / __ __ __ __ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Determining the Optimal Treatment Strategy for Patients who have Chronic 
Migraine with Medication Overuse 
 
Follow-Up Visit: Headache Characteristics 
 
 
How many days over the last 30 days with headache of any kind/severity:          days 
 
How many days over the last 30 days with complete headache freedom:              
 
days 
 
How many days over the last 30 days with headache that at any time during the day became moderate or severe 
intensity:         days 
 
On those days when headache intensity became moderate or severe, on average how many hours did the pain 
remain moderate or severe?  
 
hours 
 
How many days in the last 30 days did the headache remain mild intensity all day long?  
days 
 
On average, how long do headaches last if successfully treated:   
hours 
 
On average, how long do headaches last if untreated or inadequately treated:   
hours  
Headache intensity over the last 30 days: 
 
Average on 0 (no pain) to 10 (most severe pain) scale:         /10 
 
Maximum on 0 (no pain) to 10 (most severe pain) scale:      /10 
 
 
How many days in the last 30 days have acute (as needed) medications  (e.g. triptans, analgesic) been taken for 
headache?  
 
days 
 
How many days in the last 30 days have analgesic (pain) medications been taken for conditions other than 
headache (e.g. other pain, fever)?  
 
days 
 
How many days in the last 30 days have no analgesic or acute medications been taken?              days 
 
How many days in the last 30 days did the patient take a daily migraine preventive therapy(ies)?        Days 
 
 
 
 
 
 
 
 

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Determining the Optimal Treatment Strategy for Patients who have Chronic 
Migraine with Medication Overuse 
 
Current Treatments – Baseline Visit 
 
On average over the last 3 months, how many days/month is the patient taking abortive/analgesic 
medications? (Include prescription and non-prescription medications; include all medications, 
regardless of the indication (e.g. count days taking an analgesic for pain other than migraine)? 
 
____ ____ days per month 
 
Medication 
Name 
(generic) 
Dose 
(include 
units) 
Dosing 
Schedule 
(e.g. once 
daily, twice 
daily) 
Days per 
Month 
Taking 
Medication 
Duration that 
patient has been 
taking medication 
(include units; e.g. 
weeks, months) 
Indication for 
medication 
(e.g. headache, 
back pain, etc) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
How long has the patient been in a medication overuse pattern:      ___________ months  
 
 

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Is the patient currently taking medications to prevent headaches/migraines (include 
medications that are considered migraine preventives regardless of the reason the patient is taking 
the medication; e.g. patient takes a beta-blocker for hypertension):   
 
  
 Yes  
 
No 
 
 If yes, complete the following table. 
 
Medication 
Name (generic) 
Dose 
(include units) 
Dosing Schedule 
(e.g. once daily, 
twice daily) 
Duration that 
patient has been 
taking 
medication 
(include units; e.g. 
weeks, months) 
Indication for 
medication (e.g. 
migraine, 
depression, 
hypertension) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Is the patient currently using non-medicinal treatments (e.g. acupuncture, nerve stimulation, 
cognitive behavioral therapy) for headaches/migraine?  
 
 Yes 
 
No 
 
 If yes, complete the following table. 
 
Treatment Name/ 
Description 
Dosing Schedule 
(e.g. once daily, 
twice daily, once 
weekly) 
Duration that 
patient has been 
using this 
treatment 
(include units; e.g. 
weeks, months) 
Indication for 
treatment (e.g. 
migraine, back 
pain, etc) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Determining the Optimal Treatment Strategy for Patients who have Chronic 
Migraine with Medication Overuse 
 
Headache Impact Test -6 (HIT-6) 
 
 
Instructions: Choose one answer for each question. 
 
 
1. When you have headaches, how often is the pain severe? 
 
Never                        Rarely                    Sometimes               Very Often                    Always 
 
 
2. How often do headaches limit your ability to do usual daily activities including household work, 
work, school, or social activities? 
 
Never                        Rarely                    Sometimes               Very Often                    Always 
 
 
3. When you have a headache, how often do you wish you could lie down? 
 
Never                        Rarely                    Sometimes               Very Often                    Always 
 
 
4. In the past 4 weeks, how often have you felt too tired to do work or daily activities because of 
your headaches? 
 
Never                        Rarely                    Sometimes               Very Often                    Always 
 
 
5. In the past 4 weeks, how often have you felt fed up or irritated because of your headaches? 
 
Never                        Rarely                    Sometimes               Very Often                    Always 
 
 
6. In the past 4 weeks, how often did headaches limit your ability to concentrate on work or daily 
activities? 
 
Never                        Rarely                    Sometimes               Very Often                    Always 
  
 
  
 
 
 

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Determining the Optimal Treatment Strategy for Patients who have Chronic 
Migraine with Medication Overuse 
 
PROMIS Pain Interference 
 
Instructions: Mark one box per row. 
 
In the past 7 days… 
 
 
 
Not at 
all 
A little 
bit 
Somewhat 
Quite a 
bit 
Very 
much 
How much did pain interfere with your 
enjoyment of life? 
 
 
 
 
 
How much did pain interfere with your 
ability to concentrate? 
 
 
 
 
 
How much did pain interfere with your 
day to day activities? 
 
 
 
 
 
How much did pain interfere with your 
enjoyment of recreational activities? 
 
 
 
 
 
How much did pain interfere with 
doing your tasks away from home (e.g. 
getting groceries, running errands)? 
 
 
 
 
 
 
Never 
Rarely 
Sometimes Often  
Always 
How often did pain keep you from 
socializing with others? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Determining the Optimal Treatment Strategy for Patients who have Chronic 
Migraine with Medication Overuse 
 
Generalized Anxiety Disorder 7 (GAD-7) 
 
 
Instructions: choose one answer for each question. 
 
 
Over the last 2 weeks, how often have you been bothered by the following problems? 
 
 
Not at all 
Several 
days 
More than 
half the 
days 
Nearly 
every day 
Feeling nervous, anxious or on edge 
0 
1 
2 
3 
Not being able to stop or control 
worrying 
0 
1 
2 
3 
Worrying too much about different 
things 
0 
1 
2 
3 
Trouble relaxing 
0 
1 
2 
3 
Being so restless that it is hard to sit still 
0 
1 
2 
3 
Becoming easily annoyed or irritable 
0 
1 
2 
3 
Feeling afraid as if something awful 
might happen 
0 
1 
2 
3 
 
 
Add the score for each column  
 
 
 
 
+  
 
+  
 
  
Total Score (add your column scores) = 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Determining the Optimal Treatment Strategy for Patients who have Chronic 
Migraine with Medication Overuse 
 
Patient Health Questionnaire 9 (PHQ-9) 
 
 
Instructions: choose one answer for each question. 
 
 
Over the last 2 weeks, how often have you been bothered by any of the following problems? 
 
 
Not at all 
Several 
days 
More than 
half the days 
Nearly 
every day 
Little interest or pleasure in doing things 
0 
1 
2 
3 
Feeling down, depressed, or hopeless 
0 
1 
2 
3 
Trouble falling or staying asleep, or sleeping 
too much 
0 
1 
2 
3 
Feeling tired or having little energy 
0 
1 
2 
3 
Poor appetite or overeating 
0 
1 
2 
3 
Feeling bad about yourself – or that you are a 
failure or have let yourself or your family 
down 
0 
1 
2 
3 
Trouble concentrating on things, such as 
reading the newspaper or watching 
television 
0 
1 
2 
3 
Moving or speaking so slowly that other 
people could have noticed? Or the opposite – 
being so fidgety or restless that you have 
been moving around a lot more than usual 
0 
1 
2 
3 
Thoughts that you would be better off dead 
or hurting yourself in some way 
0 
1 
2 
3 
 
Column totals  
 
______ 
 
+ 
____
 
+________________Add totals together: ________________________ 
 

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45 
 
 
 
 
 
 
The Migraine Functional Impact Questionnaire (MFIQ) 
(Version 2.0) 
 
• The following questions are about your ability to function in the past 7 days. 
 
• We would like to understand how a migraine affects your day-to-day activities. 
 
• Symptoms of migraine can include headache pain, nausea, vomiting, or sensitivity to light or noise. 
 
• We want you to think about the symptoms that you experience and how they impact your day-to-
day activities. 
• Please answer all questions by selecting the one option that best describes your experience. 
.  
1. In the past 7 days, how often did a migraine limit your ability to move your head? 
 
□ Never 
 
□  Rarely 
 
□  Sometimes 
 
□  Often 
 
□  Always 
 
2.  In the past 7 days, how often did a migraine limit your ability to move your body?  
(For example, standing up, walking, bending) 
 
□ Never 
 
□  Rarely 
 
□  Sometimes 
 
□  Often 
 
□  Always 
 
3. In the past 7 days, how often did a migraine limit your usual activities that required  
physical effort? 
 
□ Does not apply; do not usually do activities that require physical effort 
 
□ Never 
 
□  Rarely 
 
□  Sometimes 
 
□  Often 
 
□  Always 
4. In the past 7 days, how often did you feel that you needed to rest or lie down during the  
day because of your migraine? 
 
□ Never 

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46 
 
□  Rarely 
 
□  Sometimes 
 
□  Often 
 
□  Always 
5. In the past 7 days, how often did you feel too tired to do things because of your migraine? 
 
□ Never 
 
□  Rarely 
 
□  Sometimes 
 
□  Often 
 
□  Always 
6. In the past 7 days, how difficult was it to get yourself ready for the day? 
 
□ Not difficult 
 
□ A little difficult 
 
□ Moderately difficult  
 
□  Very difficult 
 
□  Extremely difficult 
7, In the past 7 days, how often did you have difficulty completing specific personal grooming  
activities? (For example, brushing hair, shaving, applying make-up) 
 
□ Never 
 
□  Rarely 
 
□  Sometimes 
 
□  Often 
 
□  Always 
8. In the past 7 days, how often did a migraine affect your daily routine or schedule? 
 
□ Never 
 
□  Rarely 
 
□  Sometimes 
 
□  Often 
 
□  Always 
9. In the past 7 days, how often did you have to change your plans because of a migraine? 
 
□ Never 
 
□  Rarely 
 
□  Sometimes 
 
□  Often 
 
□  Always 
10. In the past 7 days, how difficult was it to do your usual chores at home?  
(For example, tidying up,  cleaning up, preparing a meal, doing minor repairs) 
 
□ Not difficult 
 
□ A little difficult 
 
□ Moderately difficult  
 
□  Very difficult 
 
□  Extremely difficult 
11. In the past 7 days, how much did a migraine limit your ability to do your usual chores outside the  
home? (For example, shopping or running errands) 
 
□ Not at all 
 
□ Slightly 

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47 
 
□ Moderately  
 
□  Very much 
 
□  Extremely 
12. In the past 7 days, how much did a migraine affect your ability to do your usual work  
or study-related activities?  
 
□ Does not apply; I have not worked* or studied at all during the past week for reasons  
unrelated to the disorder. *Work includes paid or unpaid work. 
 
 
□ Not at all 
 
□ Slightly 
 
□ Moderately  
 
□  Very much 
 
□  Extremely 
13. In the past 7 days, how much did a migraine affect your ability to take care of your  
family? 
 
□ Does not apply; I do not live with family. 
 
□ Not at all 
 
□ Slightly 
 
□ Moderately  
 
□  Very much 
 
□  Extremely 
14. In the past 7 days, how difficult was it for you to do activities that required you to  
concentrate? 
 
□ Not difficult 
 
□ A little difficult 
 
□ Moderately difficult  
 
□  Very difficult 
 
□  Extremely difficult 
15. In the past 7 days, how difficult was it to do activities in the presence of loud noises,  
strong smells, or bright lights? 
 
□ Does not apply; I do not need to do activities in the presence of loud noises, strong  
smells, or bright lights. 
 
□ Not difficult 
 
□ A little difficult 
 
□ Moderately difficult  
 
□  Very difficult 
 
□  Extremely difficult 
16. In the past 7 days, overall, how much did a migraine affect your usual activities? 
 
□ Not at all 
 
□ Slightly 
 
□ Moderately  
 
□  Very much 
 
□  Extremely 
17. In the past 7 days, how much did a migraine affect your usual social interactions?  
(For example, with family, friends or coworkers) 
 
□ Not at all 

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48 
 
□ Slightly 
 
□ Moderately  
 
□  Very much 
 
□  Extremely 
18. In the past 7 days, how often did you avoid being around other people because of a 
migraine? 
 
□ Never 
 
□  Rarely 
 
□  Sometimes 
 
□  Often 
 
□  Always 
19. In the past, 7 days how much did you have to limit your social activities because of a  
migraine? 
 
□ Not at all 
 
□ Slightly 
 
□ Moderately  
 
□  Very much 
 
□  Extremely 
20. In the past 7 days, how often did a migraine interfere with your relationship with your  
partner or spouse? 
 
□ Does not apply; do not have a partner or spouse 
 
□ Never 
 
□  Rarely 
 
□  Sometimes 
 
□  Often 
 
□  Always 
21. In the past 7 days, how often did a migraine limit your usual leisure activities? 
 
□ Never 
 
□  Rarely 
 
□  Sometimes 
 
□  Often 
 
□  Always 
22. In the past 7 days, how frustrated did you fell about being unable to do what you needed  
to do because of a migraine? 
 
□ Not at all 
 
□ Slightly 
 
□ Moderately  
 
□  Very much 
 
□  Extremely 
23. In the past 7 days, how often did you worry about your migraines? 
 
□ Never 
 
□  Rarely 
 
□  Sometimes 
 
□  Often 
 
□  Always 
24. In the past 7 days, how often did you feel like a burden on others because of a  

The MOTS Trial 
 
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49 
migraine? 
 
□ Never 
 
□  Rarely 
 
□  Sometimes 
 
□  Often 
 
□  Always 
25. In the past 7 days, how often did you feel you lacked control of your life because of a  
migraine? 
 
□ Never 
 
□  Rarely 
 
□  Sometimes 
 
□  Often 
 
□  Always 
26. In the past 7 days, how disappointed did you feel about having a migraine? 
 
□ Not at all 
 
□ Slightly 
 
□ Moderately  
 
□  Very much 
 
□  Extremely 
© Amgen. Used with permission. 
 
 
 
 

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Determining the Optimal Treatment Strategy for Patients who have Chronic 
Migraine with Medication Overuse 
EuroQol 5D (EQ-5D-3L)
 

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Determining the Optimal Treatment Strategy for Patients who have Chronic 
Migraine with Medication Overuse 
 
Headache Diary 
 
Did you have a headache/migraine today? 
 
Yes 
 
No 
 
How long did the headache last (choose one)? 
 
1-30 mins 
31-60 mins 
61 – 120 mins 
2-4 hours 
4-6 hours 
6-12 hours 
12-24 hours 
 
What was the peak headache pain intensity (choose one)? 
 
Mild 
 
Moderate 
 
Severe 
 
If pain reached moderate or severe intensity, how long did it remain at that intensity (choose one)? 
 
1-30 mins 
31-60 mins 
61 – 120 mins 
2-4 hours 
4-6 hours 
6-12 hours 
12-24 hours 
 
 
How disabling was the headache/migraine (choose one)? 
 
Able to function normally 
Function somewhat reduced 
Function severely reduced 
Not able to function at all (e.g. bedbound) 
 

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Did you take your migraine PREVENTIVE  medication today? (i.e. Prescription or over-the-counter 
medication/treatment that is used daily with the intent of reducing your migraine/headache frequency; these 
treatments are used regardless of whether or not a headache/migraine is present on that day)  
 
Yes 
 
 
No 
 
 
Did you take migraine ABORTIVE treatments today? (i.e. prescription or over-the-counter 
medication/treatment that is used to lessen or get rid of headache/migraine pain)?     
 
Yes 
 
 
No 
 
(If answered Yes the system will present a table for patients to enter their medications from a drop 
down list and how many times that day they took it.  There will also be an option for the patient to 
write in other meds. 
 
Did you take any PAIN  medications today for reasons other than to treat a headache/migraine  
(prescription or over-the-counter)? 
 
Yes 
 
 
No 
 
(If answered Yes the system will present a table for patients to enter their medications from a drop 
down list and how many times that day they took it.  There will also be an option for the patient to 
write in other meds.) 
 
 
In the past 24 hours, overall, how difficult was it to do your usual activities? 
□ Not difficult 
□ A little difficult 
□ Moderately difficult 
□ Very difficult 
□ Extremely difficult 
 
In the past 24 hours how much of the time did you have difficulty moving your head?  
□ None of the time 
□ A little of the time 
□ Some of the time 
□ Most of the time 
□ All of the time 
 
In the past 24 hours how much of the time did you have difficulty moving your body? 
□ None of the time 
□ A little of the time 
□ Some of the time 

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54 
□ Most of the time 
□ All of the time 
 
In the past 24 hours were you able to get out of bed?  
□ Without any difficulty 
□ With a little difficulty 
□ With some difficulty 
□ With much difficulty 
□ Unable to do 
 
In the past 24 hours were you able to bend over? 
□ Without any difficulty 
□ With a little difficulty 
□ With some difficulty 
□ With much difficulty 
□ Unable to do 
 
In the past 24 hours were you able to do your usual activities that required physical effort? 
□ Without any difficulty 
□ With a little difficulty 
□ With some difficulty 
□ With much difficulty 
□ Unable to do 
 
 
 
 
 

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b) Adverse Event Form 
 
c) Headache Treatment Form  

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