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The purpose of this study is to determine if milnacipran taken twice daily is effective in reduction of headache pain.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Milnacipran | Active Comparator | Oral Milnacipran titration was Day 1-2 - 12.5mg/d; Day 3-6 - 12.5mg bid; Day 7-14 - 25mg bid; Day 15 and on - 50mg bid. After the first 30 days, patients did not continue to increase the dose beyond the dose they have achieved at 30 days. At study completion medication taper as follows: patients who at their completion visit were taking 50mg bid decreased to 25mg bid for 4 days, then decreased to 12.5mg bid for 2 days, then 12.5mg once a day for one day and then stopped. Patients on 25mg bid, decreased to 12.5mg bid for 2 days, 12.5mg once a day for one day and then stopped. |
|
| Placebo | Placebo Comparator | Sugar Pill No active ingredients |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Milnacipran | Drug | 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. |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Baseline and 90 days |
| 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. | Baseline and 90 days |
| 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. | Baseline and 90 days |
| 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. | Baseline and 90 days |
| Measure | Description | Time Frame |
|---|---|---|
| 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] |
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Inclusion Criteria:
Exclusion Criteria:
A. Subjects on other headache preventives may be included in the study if the medication has been at a stable dose for 3 months.
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| Name | Affiliation | Role |
|---|---|---|
| Timothy Smith, MD | Mercy Research | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Mercy Health Research | St Louis | Missouri | 63141 | United States | ||
| Headache Wellness Center |
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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.
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.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | 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 |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| BG001 | Placebo |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Intent to treat population (all participants who were randomized to one of the conditions and treated at least one migraine with Milnacipran or Placebo). | Posted | Mean | 95% Confidence Interval | units on a scale | Baseline and 90 days |
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| nausea | Gastrointestinal disorders | Non-systematic Assessment |
Given that the number needed to have adequate power to demonstrate differences was 38.3% higher than the number enrolled, it is difficult to make any specific conclusions about the efficacy of Milnacipran.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Timothy R. Smith, MD | Mercy Health Research | 314-251-8895 | Timothy.Smith@mercy.net |
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| ID | Term |
|---|---|
| D006261 | Headache |
| D008881 | Migraine Disorders |
| ID | Term |
|---|---|
| D010146 | Pain |
| D009461 | Neurologic Manifestations |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| D000078764 | Milnacipran |
| D000073893 | Sugars |
| ID | Term |
|---|---|
| D003521 | Cyclopropanes |
| D003516 | Cycloparaffins |
| D006840 | Hydrocarbons, Alicyclic |
| D006844 | Hydrocarbons, Cyclic |
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|
| Placebo | Drug | 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 |
|
|
| Baseline and 90 days |
| 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] | Baseline and 90 days |
| 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] | Baseline and 90 days |
| Greensboro |
| North Carolina |
| 27405 |
| United States |
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
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Number | participants |
|
| Region of Enrollment | Number | participants |
|
| Years with Headache | Mean | Standard Deviation | years |
|
| 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. | Mean | Standard Deviation | units on a scale |
|
| MIgraine Days Per Month | On days where the patient indicated they had a headache, patients were instructed to complete the diary questions with headache characteristics (using International Headache Classification criteria). This information was used to calculate migraine days per month. | Mean | Standard Deviation | Number of Days with Migraine per Month |
|
| MSQ- Preventive | 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. | Mean | Standard Deviation | Standard Score |
|
| MSQ- Restrictive | 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. | Mean | Standard Deviation | Standard Score |
|
| MSQ-Emotional | 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. | Mean | Standard Deviation | Standard Score |
|
| PHQ-9 | Patient Health Questionnaire - 9 PHQ-9 total score ranges from 0 to 27. The Patient Health Questionnaire assesses depression symptoms. The higher the score, the more symptoms of depression and more severe the depression. PHQ-9 score total of 0-4 points equals minimal depression, 5-9 points indicates mild depression, 10-14 points indicates moderate depression, 15-19 points indicates moderately severe depression, and 20 or more points indicates severe depression. | Mean | Standard Deviation | units on a scale |
|
| GAD-7 | Generalized Anxiety Disorder - 7 GAD-7 total score ranges from 0 to 21. The higher the score, the more symptoms of anxiety and more severe the anxiety. 0-4 points equals minimal anxiety, 5-9 points indicates mild anxiety, 10-14 points indicates moderate anxiety, 15-21 points indicate severe anxiety. | Mean | Standard Deviation | units on a scale |
|
| BMI | Body Mass Index | Mean | Standard Deviation | kg/m^2 |
|
| Blood Pressure - Systolic | Mean | Standard Deviation | mmHg |
|
| Blood Pressure - Diastolic | Mean | Standard Deviation | mmHg |
|
| Pulse | Mean | Standard Deviation | Beats Per Minute |
|
| Non-Migraine Headache Days | On days where the patient indicated they had a headache, patients were instructed to complete the diary questions with headache characteristics (using International Headache Classification criteria). This information was used to calculate non-migraine days per month. | Mean | Standard Deviation | Days w/ Non-Migraine Headache per Month |
|
| Days Using Medication for Headache Per Month | Patients indicated whether they took an acute medication for the treatment of headache that day. This information was used to calculate medication days per month. | Mean | Standard Deviation | Days per Month |
|
| OG001 | 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 |
|
|
|
| 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] | Intent to treat population (all participants who were randomized to one of the conditions and treated at least one migraine with Milnacipran or Placebo). | Posted | Mean | 95% Confidence Interval | Days per Month | Baseline and 90 days |
|
|
|
|
| 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. | Intent to treat population (all participants who were randomized to one of the conditions and treated at least one migraine with Milnacipran or Placebo). | Posted | Mean | 95% Confidence Interval | units on a scale | Baseline and 90 days |
|
|
|
|
| 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. | Intent to treat population (all participants who were randomized to one of the conditions and treated at least one migraine with Milnacipran or Placebo). | Posted | Mean | 95% Confidence Interval | units on a scale | Baseline and 90 days |
|
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|
|
| 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. | Intent to treat population (all participants who were randomized to one of the conditions and treated at least one migraine with Milnacipran or Placebo). | Posted | Mean | 95% Confidence Interval | units on a scale | Baseline and 90 days |
|
|
|
|
| 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] | Intent to treat population (all participants who were randomized to one of the conditions and treated at least one migraine with Milnacipran or Placebo). | Posted | Mean | 95% Confidence Interval | Days per Month | Baseline and 90 days |
|
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|
|
| 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] | Intent to treat population (all participants who were randomized to one of the conditions and treated at least one migraine with Milnacipran or Placebo). | Posted | Mean | 95% Confidence Interval | Days per Month | Baseline and 90 days |
|
|
|
|
| 0 |
| 19 |
| 5 |
| 19 |
| EG001 | 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 | 0 | 18 | 1 | 18 |
| anxiety | Psychiatric disorders | Non-systematic Assessment |
|
| dizziness | Ear and labyrinth disorders | Non-systematic Assessment |
|
| testicular discomfort | Renal and urinary disorders | Non-systematic Assessment |
|
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| D051270 | Headache Disorders, Primary |
| D020773 | Headache Disorders |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D006838 |
| Hydrocarbons |
| D009930 | Organic Chemicals |
| D002241 | Carbohydrates |
| 2-Sided |
| Superiority or Other (legacy) |