Study Evaluated the Effectiveness of Milnacipran to Reduce Pain Levels in Individuals With Chronic Migraine

A Randomized Double Blind Placebo Control Trial of Milnacipran for Migraine Pain

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

Study Overview

• Status: Completed
• Conditions: Chronic Migraine
• Intervention / Treatment: Drug: Milnacipran; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 37
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63141
      • Mercy Health Research
  • North Carolina
    • Greensboro, North Carolina, United States, 27405
      • Headache Wellness Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Milnacipran; 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.	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 taper down as appropriate for dose.; Other Names: Savella
Placebo Comparator: Placebo; Sugar Pill No active ingredients	Drug: Placebo; 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; Other Names: Sugar Pill

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Secondary Outcome Measures

Outcome Measure	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]	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

Collaborators and Investigators

• Sponsor: Timothy Smith
• Investigators: Principal Investigator: Timothy Smith, MD, Mercy Research

Study record dates

Study Major Dates

• Study Start: June 1, 2011
• Primary Completion (Actual): December 1, 2013
• Study Completion (Actual): December 1, 2013

Study Registration Dates

• First Submitted: July 6, 2011
• First Submitted That Met QC Criteria: July 12, 2011
• First Posted (Estimate): July 13, 2011

Study Record Updates

• Last Update Posted (Actual): August 12, 2022
• Last Update Submitted That Met QC Criteria: August 11, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Keywords: headache; migraine
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Headache Disorders, Primary; Headache Disorders; Migraine Disorders; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Antidepressive Agents; Serotonin and Noradrenaline Reuptake Inhibitors; Milnacipran; Levomilnacipran
• Other Study ID Numbers: SAV-MD-25

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided