The Effects of Milnacipran on Sleep Disturbance in Fibromyalgia

Study Overview
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Brief Summary
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Fibromyalgia is a condition of chronic widespread pain, sleep disturbance and fatigue. Most of the patients with fibromyalgia complain of either non-restorative sleep or complaints of disturbed sleep due to pain. The study aimed at examining the effects of milnacipran on sleep disturbance in patients with fibromyalgia. The study is a randomized, double-blind, placebo controlled, two way crossover polysomnography (PSG) study to explore the effects of milnacipran on sleep disturbance. Patients received either milnacipran 50 mg twice a day (BID) or matching placebo.

Detailed Description
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The sleep disturbance in fibromyalgia is characterized as non-restorative in nature, and is defined as a feeling of light sleep, independent of duration, and as non-refreshing. As such, these patients wake up in the morning and complain of stiffness and overall aching of the body. It is well known that reciprocal relationship exists between sleep and pain, with sleep disturbances being an important contributor to morbidity in fibromyalgia. Milnacipran, a selective serotonin norepinephrine receptor inhibitor (SNRI), was approved by the Food and Drug Administration (FDA) for the management of fibromyalgia. Although milnacipran has extensively been studied in fibromyalgia patients, but there is no objective measure, i.e., the use of overnight polysomnography, to determine its effects on sleep. The study was undertaken to evaluate the effects of milnacipran on PSG determined measures of sleep in patients with fibromyalgia. The study also evaluated the impact of milnacipran on subjective measures of sleep and fibromyalgia symptoms.

Official Title
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The Effects of Milnacipran on Sleep Disturbance in Fibromyalgia

Conditions
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Sleep Disorders, Fibromyalgia, Sleep

Intervention / Treatment
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* Drug: Milnacipran
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men or women at least 18 years or older Diagnosis of fibromyalgia Clinically significant sleep disturbance, defined as difficulty in maintaining sleep (wake after sleep onset and arousal index) at least three times per week for at least one month Understand and willing to cooperate with the study procedures Maintain a normal sleep schedule, with daytime-awake and nighttime-sleep schedule, with customary bedtime between 9 PM and midnight, and rise time 5 AM and 9 AM Patients who are able to speak, read, and understand English language and able to follow the study protocol, and are able to sign the informed consent Exclusion Criteria: Subject has any of the following medical conditions: Liver disease, blood disorder, autoimmune disease, endocrine, cardiovascular, hypertension, renal, hepatic, gastrointestinal, or neurological disorder, active peptic ulcer or inflammatory bowel disease Significant sleep apnea Periodic leg movement disorder (PLMD) or restless legs syndrome (RLS) Any form of severe psychiatric illness, moderate to severe depression, including significant risk of suicide Patients with uncontrolled glaucoma Inability to discontinue the prohibited medications Female of childbearing potential not using birth control measures; or lactating. History of alcohol, narcotic, benzodiazepines or other substance abuse within the past one year. Patient on prohibited medication will include but not limited to: Anxiolytics, anti-convulsants, antipsychotics, lithium, barbiturates, anti-histamines, monoamine oxidase inhibitors, or medications that affect sleep Any prescription or over the counter stimulants Medications that are contraindicated with the use of milnacipran Excessive caffeine use, defined as a consumption of more than 500 mg of caffeine or other xanthines, smoking >1/2 a pack/day or alcohol use >14 units/week History of allergy to milnacipran.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: milnacipran<br>Drug: milnacipran 7-day dose escalation, 28- day treatment with milnacipran 50 mg and 7-day taper period before or after crossover to placebo | Drug: Milnacipran<br>* 50 mg twice daily<br>* Other names: Savella;|
| Placebo Comparator: placebo<br>Drug: placebo 45-day placebo treatment before or after crossover to milnacipran | Drug: Placebo<br>* 50 mg twice daily<br>* Other names: Sugar pill;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Awakenings After Sleep Onset (NAASO) | Number of awakenings after defined sleep onset until lights on. | 4-Week maintenance treatment with milnacipran and placebo | 
| Sleep Efficiency (SE) | Percentage of time spent asleep while in bed | 4-Week maintenance treatment with milnacipran and placebo | 
| Wake After Sleep Onset (WASO) | Wake time after defined sleep onset until lights on. | 4-Week maintenance treatment with milnacipran and placebo | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Latency to Persistent Sleep Onset (LPS) | It is defined as time from lights out to the first consecutive 2 minutes of uninterrupted sleep. | 4-Week treatment with milnacipran and placebo | 
| Total Sleep Time (TST) | Total sleep of all Rapid Eye Movement (REM) and Non- Rapid Eye Movement Sleep (NTREM) from lights out to lights on. | 4-Week treatment with milnacipran and placebo | 
| Arousal Index (AI) | Number of arousals per hour of sleep | 4-Week treatment with milnacipran and placebo | 
| Slow Wave Sleep (SWS) | Time spent in stage 3 of non-rapid eye movement sleep and often referred to as deep sleep. | 4-Week treatment with milnacipran and placebo | 
| Sleep Problem Index 2, Medical Outcomes Study Sleep Scale (MOS-SS) | This is a subjective index derived from the medical outcomes study sleep scale (MOS-SS) scored on a 0-100 possible range with higher scores indicating more severe sleep disruption. The scale is a self-report instrument consisting of 12 items that assess perceived initiation and maintenance of sleep, respiratory problems during sleep, sleep duration, perceived adequacy of sleep and daytime somnolence. | 4-Week treatment with milnacipran and placebo | 
| Sleep Quality Scale | Sleep quality measure derived from daily sleep diary rating ranging from 0 (very poor) to 10 (excellent) | 4-Week treatment with milnacipran and placebo | 
| Fatigue Severity Scale (FSS) Total Score | The scale is a 9-item self-report of fatigue in the past week and scored on a 7-point scale with 1 = strongly disagree and 7 = strongly agree. Scores range from 9 to 63 with higher scores indicating higher fatigue severity. A total score greater or equal to 36 suggests fatigue. | 4-Week treatment with milnacipran and placebo | 
| Fibromyalgia Impact Questionnaire (FIQ) Total Score | The scale is composed of 10 items relating to fibromyalgia symptoms experienced in the past week. Score ranges from 0 to 100 with higher scores indicating a greater effect of fibromyalgia on a person's life. | 4-Week treatment with milnacipran and placebo | 
| Brief Pain Inventory (BPI) Mean Severity Score | The score is derived from the BPI scale and measures pain intensity in the past 24 hour. The pain severity score is derived as the average score of 4 pain items assessing pain at its worst, least, average and now and ranges from 0-10 with higher scores reflecting greater pain | 4-Week treatment with milnacipran and placebo | 
| Brief Pain Inventory (BPI) Mean Interference Score | The score is derived from the BPI scale and measures the effect of pain on functioning in the past 24 hour. It is the average score of 7 items interfering with general activity, mood, walking ability, normal work, relations with other people, sleep and enjoyment of life. Score ranges from 0-10 with higher scores reflecting greater interference. | 4-Week treatment with milnacipran and placebo | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fibromyalgia, Sleep disorders, Forest Laboratories, Milnacipran