Milnacipran for Migraine Pain

• Evaluating Headache Pain Reduction [ Time Frame: Will report change from baseline after the 90 day reporting period ] [ Designated as safety issue: No ]
  To evaluate the efficacy of milnacipran in headache pain reduction in subjects with chronic migraine (CM) without fibromyalgia
• Evaluating the improvement of Quality of Life [ Time Frame: Changes from Visit 1 quality of life until study completion month 4 ] [ Designated as safety issue: No ]
  To evaluate the efficacy of milnacipran in improving quality of life in subjects with chronic migraine (CM) without fibromyalgia

• Migraine Prevention [ Time Frame: Will assess at day 30, day 60 and day 90 ] [ Designated as safety issue: No ]
  To evaluate the efficacy of milnacipran in migraine prevention in subjects with chronic migraine
• Sleep and Energy [ Time Frame: Will assess at visit 2 and again at visit 5, study completion visit ] [ Designated as safety issue: No ]
  To evaluate the impact of milnacipran on sleep and energy in subjects with chronic migraine
• Anxiety and Depression [ Time Frame: At screening visit 1, visit 2, visit 3, visit 4 and visit 5 study completion ] [ Designated as safety issue: Yes ]
  To evaluate the relationship of baseline anxiety and depression on the efficacy of milnacipran for the above outcome measures

The purpose of this study is to determine if milnacipran taken twice daily is effective in reduction of headache pain.

• Drug: 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.
• Drug: 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

• Active Comparator: Milnacipran
  Intervention: Drug: Milnacipran
• Placebo Comparator: Sugar Pill
  Intervention: Drug: Placebo

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