Chronic Migraine
Conditions
Keywords
headache, migraine
Brief summary
The purpose of this study is to determine if milnacipran taken twice daily is effective in reduction of headache pain.
Detailed description
Milnacipran is a serotonin norepinephrine reubtake inhibitor (SNRI) approved for the management of fibromyalgia in the United States. Migraine and fibromyalgia have significant co-morbidity. Of 100 patients with fibromyalgia, 76% had chronic headaches, of whom 63% had migraine. Interestingly, general measures of pain, disability, sleep quality, and psychological distress were similar in individuals with fibromyalgia with and without headache. Conversely, the prevalence of fibromyalgia in women with migraine was reported as 22%, and at a headache referral center, 36% of headache patients had fibromyalgia. Because of significant co-morbidity, as well as the likelihood of shared pathophysiologic mechanisms, there is reason to believe that a medication effective for fibromyalgia might reduce migraine pain, especially where the pain has taken on the nature of a chronic pain disorder, as in chronic migraine. The current study evaluated the benefits of milnacipran in individuals with chronic migraine. Patients with chronic migraine were randomized to either Milnacipran or Placebo. Patients completed 30 days of baseline followed by 90 days of headache diaries while taking assigned medication. Primary outcomes were reduction in pain severity and improvement in migraine specific quality of life (MSQ) while secondary outcomes included reduction in migraine and non-migraine headache days and symptomatic use of medication for migraine. Independent sample t-tests were used to evaluate the changes in primary and secondary measures between the two groups.
Interventions
DRUGMilnacipran
titration schedule starting with 12.5mg per day increasing to 50mg twice a day, starting with day 1 to day 90 and then taper down as appropriate for dose.
DRUGPlacebo
Placebo dosing schedule was Day 1-2, 1 tablet daily, Day 3-6 BID, Day 7-14 BID, Day 15 an on through day 90 BID and taper down
Sponsors
Timothy Smith
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Individuals between the age of 18 and 65 * Headache fulfills ICHD-2 criteria for: chronic migraine, or probable medication overuse headache where individual headaches meet criteria for migraine * At least 15 headache days/month and at least 8 migraine or probable migraine days/month for the past 3 months, by patient report (including days of headache relieved with a triptan or related compound). * Age at onset of chronic migraine \< 60 years old
Exclusion criteria
* Pregnancy or attempting conception * Unable to read or write English * Use of Opiates \>/= 10 days per month * Subject has failed \>/= 4 adequate preventive trials of antidepressant medications due to lack of efficacy; at least one trial included another SNRI.(An adequate preventive trial defined as at least 6 weeks on therapeutic dose \[150mg of amitriptyline or nortriptyline or other tricyclic, 150mg of venlafaxine, 60mg of duloxetine\]) * Subjects on antidepressant medications, including SNRIs who cannot safely withdraw from those medications, in the assessment of the PI. Subjects on other headache preventives (beta blockers, antiepileptic drugs), at stable dose for at least three months, will be allowed to participate. A. Subjects on other headache preventives may be included in the study if the medication has been at a stable dose for 3 months. * Presence of fibromyalgia or another pain or medical disorder that would make it difficult for patient to distinguish headache-related quality of life from overall health related quality of life. * Uncontrolled or unstable psychiatric disorder (PHQ-9 score or GAD-7 score \>15 with sentinel questions \>/=4, or in opinion of examiner), or anticipated need for change in psychotropic medications during duration of study period; or suicidality. * Chronic kidney disease, liver disease, or any poorly controlled medical condition
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in VAS Pain Severity | Baseline and 90 days | On headache days, patients were instructed to complete a Visual Analog Scale (VAS) to rate their pain intensity. Their response (the scale was 100 cm long) was measured and assigned a score (0-100) with higher numbers indicating more severity. Scores were averaged over a 30 day period to create the score for a time period (baseline and 90 days). Change in Pain score = Score\[Baseline\] - Score\[90 days\]. Higher scores indicate greater pain reduction. |
| Change in Migraine Specific Quality of Life - Restrictive | Baseline and 90 days | The Migraine Specific Quality of Life measures the impact Migraine has on the patient's Quality of Life. The Restrictive subscale assesses the extent to which migraine restricts the patient's function. The subscale is measured on a standard scale from 0-100, where higher scores indicate better quality of life. For the outcome assessing change, higher positive scores indicate better outcomes. |
| Change in Migraine Specific Quality of Life - Preventive | Baseline and 90 days | The Migraine Specific Quality of Life measures the impact Migraine has on the patient's Quality of Life. The Preventive subscale assesses the extent to which migraine prevents the patient's function. The subscale is measured on a standard scale from 0-100, where higher scores indicate better quality of life. For the outcome assessing change, higher positive scores indicate better outcomes. |
| Change in Migraine Specific Quality of Life - Emotional | Baseline and 90 days | The Migraine Specific Quality of Life measures the impact Migraine has on the patient's Quality of Life. The Emotional subscale assesses the extent to which migraine influences the patient's emotional function. The subscale is measured on a standard scale from 0-100, where higher scores indicate better quality of life. For the outcome assessing change, higher positive scores indicate better outcomes. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Days With Non-Migraine Headache Per Month From Baseline to 90 Days | Baseline and 90 days | On days where the patient indicated they had a headache, patients were instructed to complete the diary questions regarding headache characteristics using International Headache Classification Diagnostics. This was information was used to calculate non-migraine headache days days per month. Days with migraine over a 30 day period were summed to generate a number for each time frame (baseline and 90 days). For the outcome measure, higher positive numbers indicate higher reduction of days with non-migraine headache. Change in days with non-migraine headache = Score\[Baseline\] - Score\[90 days\] |
| Change in Days Using Headache Medication Per Month From Baseline to 90 Days | Baseline and 90 days | On days where the patient indicated they had a headache (i.e., migraine or non-migraine headache), patients were instructed to complete the diary questions regarding whether they used medication to treat headache pain and related symptoms. This was used to calculate days using headache medication days per month. Days with migraine over a 30 day period were summed to generate a number for each time frame (baseline and 90 days). For the outcome measure, higher positive numbers indicate higher reduction of days using headache medication per month. Change in days using headache medication = Score\[Baseline\] - Score\[90 days\] |
| Change in Days With Migraine Per Month From Baseline to 90 Days | Baseline and 90 days | On days where the patient indicated they had a headache, patients were instructed to complete the diary questions regarding headache characteristics using International Headache Classification Diagnostics. This information was used to calculate migraine days per month. Days with migraine over a 30 day period were summed to generate a number for each time frame (baseline and 90 days). For the outcome measure, higher positive numbers indicate higher reduction of days with migraine. Change in days with migraine = Score\[Baseline\] - Score\[90days\] |
Countries
United States
Participant flow
Recruitment details
Patients were recruited from two Headache focused ambulatory clinics. From Q2, 2011 until Q2, 2013. Recruitment involved printed flyers placed in the examination rooms of both sites as well as clinical staff informing patients about the study opportunity.
Pre-assignment details
Patients completed a 30 day run-in period prior to randomization to ensure that they were accurate and compliant in completing diaries and experiencing sufficient headaches. Specifically they were required to have \> 15 headache days and 8 (probable) migraine days . Patients below this threshold but met other headache criteria could be eligible.
Participants by arm
| Arm | Count |
|---|---|
| Milnacipran Milnacipran: titration schedule starting with 12.5mg per day increasing to 50mg twice a day, starting with day 1 to day 90 and then will taper down. | 19 |
| Placebo Placebo: Tablet will be titrated 1 tablet once a day increased per protocol to 2 tablets twice a day, with a starting dose of 12.5mg per day to 50 mg twice a day | 18 |
| Total | 37 |
Baseline characteristics
| Characteristic | Placebo | Total | Milnacipran |
|---|---|---|---|
| Age, Continuous | 37.39 years STANDARD_DEVIATION 15.07 | 38.01 years STANDARD_DEVIATION 12.33 | 38.63 years STANDARD_DEVIATION 9.59 |
| Blood Pressure - Diastolic | 76.83 mmHg STANDARD_DEVIATION 8.84 | 75.72 mmHg STANDARD_DEVIATION 10.29 | 74.67 mmHg STANDARD_DEVIATION 11.66 |
| Blood Pressure - Systolic | 114.47 mmHg STANDARD_DEVIATION 13.34 | 117.74 mmHg STANDARD_DEVIATION 13.39 | 120.83 mmHg STANDARD_DEVIATION 13.43 |
| BMI | 28.32 kg/m^2 STANDARD_DEVIATION 5.93 | 29.01 kg/m^2 STANDARD_DEVIATION 6.8 | 29.67 kg/m^2 STANDARD_DEVIATION 7.62 |
| Days Using Medication for Headache Per Month | 14.63 Days per Month STANDARD_DEVIATION 7.22 | 15.12 Days per Month STANDARD_DEVIATION 5.17 | 15.59 Days per Month STANDARD_DEVIATION 3.22 |
| GAD-7 | 3.74 units on a scale STANDARD_DEVIATION 3.94 | 3.30 units on a scale STANDARD_DEVIATION 3.78 | 2.89 units on a scale STANDARD_DEVIATION 3.63 |
| MIgraine Days Per Month | 11.26 Number of Days with Migraine per Month STANDARD_DEVIATION 5.35 | 10.98 Number of Days with Migraine per Month STANDARD_DEVIATION 6.09 | 10.72 Number of Days with Migraine per Month STANDARD_DEVIATION 6.79 |
| MSQ-Emotional | 30.53 Standard Score STANDARD_DEVIATION 26.14 | 34.44 Standard Score STANDARD_DEVIATION 23.21 | 38.15 Standard Score STANDARD_DEVIATION 20.43 |
| MSQ- Preventive | 47.78 Standard Score STANDARD_DEVIATION 22.83 | 50.92 Standard Score STANDARD_DEVIATION 21.91 | 53.89 Standard Score STANDARD_DEVIATION 21.04 |
| MSQ- Restrictive | 33.68 Standard Score STANDARD_DEVIATION 18.58 | 35.79 Standard Score STANDARD_DEVIATION 16.04 | 37.78 Standard Score STANDARD_DEVIATION 13.63 |
| Non-Migraine Headache Days | 10.65 Days w/ Non-Migraine Headache per Month STANDARD_DEVIATION 5.8 | 11.04 Days w/ Non-Migraine Headache per Month STANDARD_DEVIATION 6.94 | 11.41 Days w/ Non-Migraine Headache per Month STANDARD_DEVIATION 8.02 |
| Pain Severity | 61.87 units on a scale STANDARD_DEVIATION 17.95 | 59.71 units on a scale STANDARD_DEVIATION 14.69 | 57.67 units on a scale STANDARD_DEVIATION 11.6 |
| PHQ-9 | 5.05 units on a scale STANDARD_DEVIATION 4.18 | 4.40 units on a scale STANDARD_DEVIATION 3.64 | 3.78 units on a scale STANDARD_DEVIATION 3.12 |
| Pulse | 75.47 Beats Per Minute STANDARD_DEVIATION 9.62 | 74.94 Beats Per Minute STANDARD_DEVIATION 10.61 | 74.44 Beats Per Minute STANDARD_DEVIATION 8.26 |
| Race/Ethnicity, Customized Caucasian_Non Hispanic | 15 participants | 32 participants | 17 participants |
| Race/Ethnicity, Customized Non_Caucasian | 3 participants | 5 participants | 2 participants |
| Region of Enrollment United States | 18 participants | 37 participants | 19 participants |
| Sex: Female, Male Female | 16 Participants | 33 Participants | 17 Participants |
| Sex: Female, Male Male | 2 Participants | 4 Participants | 2 Participants |
| Years with Headache | 17.89 years STANDARD_DEVIATION 9.69 | 19.20 years STANDARD_DEVIATION 11.65 | 20.44 years STANDARD_DEVIATION 13.51 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 5 / 19 | 1 / 18 |
| serious Total, serious adverse events | 0 / 19 | 0 / 18 |
Outcome results
Primary
Change in Migraine Specific Quality of Life - Emotional
The Migraine Specific Quality of Life measures the impact Migraine has on the patient's Quality of Life. The Emotional subscale assesses the extent to which migraine influences the patient's emotional function. The subscale is measured on a standard scale from 0-100, where higher scores indicate better quality of life. For the outcome assessing change, higher positive scores indicate better outcomes.
Time frame: Baseline and 90 days
Population: Intent to treat population (all participants who were randomized to one of the conditions and treated at least one migraine with Milnacipran or Placebo).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Milnacipran | Change in Migraine Specific Quality of Life - Emotional | 29.89 units on a scale |
| Placebo | Change in Migraine Specific Quality of Life - Emotional | 37.99 units on a scale |
p-value: 0.41t-test, 2 sided
Primary
Change in Migraine Specific Quality of Life - Preventive
The Migraine Specific Quality of Life measures the impact Migraine has on the patient's Quality of Life. The Preventive subscale assesses the extent to which migraine prevents the patient's function. The subscale is measured on a standard scale from 0-100, where higher scores indicate better quality of life. For the outcome assessing change, higher positive scores indicate better outcomes.
Time frame: Baseline and 90 days
Population: Intent to treat population (all participants who were randomized to one of the conditions and treated at least one migraine with Milnacipran or Placebo).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Milnacipran | Change in Migraine Specific Quality of Life - Preventive | 21.61 units on a scale |
| Placebo | Change in Migraine Specific Quality of Life - Preventive | 31.26 units on a scale |
p-value: 0.16t-test, 2 sided
Primary
Change in Migraine Specific Quality of Life - Restrictive
The Migraine Specific Quality of Life measures the impact Migraine has on the patient's Quality of Life. The Restrictive subscale assesses the extent to which migraine restricts the patient's function. The subscale is measured on a standard scale from 0-100, where higher scores indicate better quality of life. For the outcome assessing change, higher positive scores indicate better outcomes.
Time frame: Baseline and 90 days
Population: Intent to treat population (all participants who were randomized to one of the conditions and treated at least one migraine with Milnacipran or Placebo).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Milnacipran | Change in Migraine Specific Quality of Life - Restrictive | 21.01 units on a scale |
| Placebo | Change in Migraine Specific Quality of Life - Restrictive | 35.03 units on a scale |
p-value: 0.75ANCOVA
p-value: 0.24t-test, 2 sided
Primary
Change in VAS Pain Severity
On headache days, patients were instructed to complete a Visual Analog Scale (VAS) to rate their pain intensity. Their response (the scale was 100 cm long) was measured and assigned a score (0-100) with higher numbers indicating more severity. Scores were averaged over a 30 day period to create the score for a time period (baseline and 90 days). Change in Pain score = Score\[Baseline\] - Score\[90 days\]. Higher scores indicate greater pain reduction.
Time frame: Baseline and 90 days
Population: Intent to treat population (all participants who were randomized to one of the conditions and treated at least one migraine with Milnacipran or Placebo).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Milnacipran | Change in VAS Pain Severity | 3.23 units on a scale |
| Placebo | Change in VAS Pain Severity | 5.36 units on a scale |
p-value: 0.1ANCOVA
p-value: 0.88t-test, 2 sided
Secondary
Change in Days Using Headache Medication Per Month From Baseline to 90 Days
On days where the patient indicated they had a headache (i.e., migraine or non-migraine headache), patients were instructed to complete the diary questions regarding whether they used medication to treat headache pain and related symptoms. This was used to calculate days using headache medication days per month. Days with migraine over a 30 day period were summed to generate a number for each time frame (baseline and 90 days). For the outcome measure, higher positive numbers indicate higher reduction of days using headache medication per month. Change in days using headache medication = Score\[Baseline\] - Score\[90 days\]
Time frame: Baseline and 90 days
Population: Intent to treat population (all participants who were randomized to one of the conditions and treated at least one migraine with Milnacipran or Placebo).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Milnacipran | Change in Days Using Headache Medication Per Month From Baseline to 90 Days | 1.28 Days per Month |
| Placebo | Change in Days Using Headache Medication Per Month From Baseline to 90 Days | 2.17 Days per Month |
p-value: 0.78t-test, 2 sided
Secondary
Change in Days With Migraine Per Month From Baseline to 90 Days
On days where the patient indicated they had a headache, patients were instructed to complete the diary questions regarding headache characteristics using International Headache Classification Diagnostics. This information was used to calculate migraine days per month. Days with migraine over a 30 day period were summed to generate a number for each time frame (baseline and 90 days). For the outcome measure, higher positive numbers indicate higher reduction of days with migraine. Change in days with migraine = Score\[Baseline\] - Score\[90days\]
Time frame: Baseline and 90 days
Population: Intent to treat population (all participants who were randomized to one of the conditions and treated at least one migraine with Milnacipran or Placebo).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Milnacipran | Change in Days With Migraine Per Month From Baseline to 90 Days | 3.34 Days per Month |
| Placebo | Change in Days With Migraine Per Month From Baseline to 90 Days | 4.62 Days per Month |
p-value: 0.33t-test, 2 sided
Secondary
Change in Days With Non-Migraine Headache Per Month From Baseline to 90 Days
On days where the patient indicated they had a headache, patients were instructed to complete the diary questions regarding headache characteristics using International Headache Classification Diagnostics. This was information was used to calculate non-migraine headache days days per month. Days with migraine over a 30 day period were summed to generate a number for each time frame (baseline and 90 days). For the outcome measure, higher positive numbers indicate higher reduction of days with non-migraine headache. Change in days with non-migraine headache = Score\[Baseline\] - Score\[90 days\]
Time frame: Baseline and 90 days
Population: Intent to treat population (all participants who were randomized to one of the conditions and treated at least one migraine with Milnacipran or Placebo).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Milnacipran | Change in Days With Non-Migraine Headache Per Month From Baseline to 90 Days | 2.35 Days per Month |
| Placebo | Change in Days With Non-Migraine Headache Per Month From Baseline to 90 Days | 0.76 Days per Month |
p-value: 0.09t-test, 2 sided