The Effects of Milnacipran on Sleep Disturbance in Fibromyalgia

Status

Completed

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01234675

Enrollment

Registered

2010-11-04

Start date

2010-11-30

Completion date

2014-02-28

Last updated

2019-08-21

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Fibromyalgia, Sleep, Sleep Disorders

Keywords

Fibromyalgia, Sleep disorders, Forest Laboratories, Milnacipran

Brief summary

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

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.

Interventions

DRUGMilnacipran

50 mg twice daily

DRUGPlacebo

50 mg twice daily

Study design

Allocation

RANDOMIZED

Intervention model

CROSSOVER

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

1. Men or women at least 18 years or older 2. Diagnosis of fibromyalgia 3. 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 4. Understand and willing to cooperate with the study procedures 5. 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 6. 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

1. 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 2. Significant sleep apnea 3. Periodic leg movement disorder (PLMD) or restless legs syndrome (RLS) 4. Any form of severe psychiatric illness, moderate to severe depression, including significant risk of suicide 5. Patients with uncontrolled glaucoma 6. Inability to discontinue the prohibited medications 7. Female of childbearing potential not using birth control measures; or lactating. 8. History of alcohol, narcotic, benzodiazepines or other substance abuse within the past one year. 9. 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 10. 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 11. History of allergy to milnacipran.

Design outcomes

Primary

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

Secondary

Measure	Time frame	Description
Slow Wave Sleep (SWS)	4-Week treatment with milnacipran and placebo	Time spent in stage 3 of non-rapid eye movement sleep and often referred to as deep sleep.
Sleep Problem Index 2, Medical Outcomes Study Sleep Scale (MOS-SS)	4-Week treatment with milnacipran and placebo	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.
Sleep Quality Scale	4-Week treatment with milnacipran and placebo	Sleep quality measure derived from daily sleep diary rating ranging from 0 (very poor) to 10 (excellent)
Latency to Persistent Sleep Onset (LPS)	4-Week treatment with milnacipran and placebo	It is defined as time from lights out to the first consecutive 2 minutes of uninterrupted sleep.
Fibromyalgia Impact Questionnaire (FIQ) Total Score	4-Week treatment with milnacipran and placebo	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.
Brief Pain Inventory (BPI) Mean Severity Score	4-Week treatment with milnacipran and placebo	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
Brief Pain Inventory (BPI) Mean Interference Score	4-Week treatment with milnacipran and placebo	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.
Fatigue Severity Scale (FSS) Total Score	4-Week treatment with milnacipran and placebo	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.
Total Sleep Time (TST)	4-Week treatment with milnacipran and placebo	Total sleep of all Rapid Eye Movement (REM) and Non- Rapid Eye Movement Sleep (NTREM) from lights out to lights on.
Arousal Index (AI)	4-Week treatment with milnacipran and placebo	Number of arousals per hour of sleep

Countries

United States

Participant flow

Participants by arm

Arm	Count
All Study Participants 2 treatment period, with each period 6 weeks and 7 day washout period Milnacipran in treatment period 1, Placebo in treatment period 2 Placebo treatment in Period 1, and Milnacipran in Period 2	19
Total	19

Withdrawals & dropouts

Period	Reason	FG000	FG001
First Intervention (6 Weeks)	Adverse Event	0	1
First Intervention (6 Weeks)	Withdrawal by Subject	1	0

Baseline characteristics

Characteristic	All Study Participants
Age, Continuous	49.2 years
Arousal index (AI)	24.8 arousals per hour STANDARD_DEVIATION 9.8
Baseline polysomnographic sleep parameters Latency to persistent sleep (LPS)	49.4 minutes STANDARD_DEVIATION 43.4
Baseline polysomnographic sleep parameters Total sleep time (TST)	340.7 minutes STANDARD_DEVIATION 78.9
Baseline polysomnographic sleep parameters Wake after sleep onset (WASO)	97.2 minutes STANDARD_DEVIATION 70.6
Number of awakenings after sleep onset (NAASO)	31.9 awakenings STANDARD_DEVIATION 12.9
Rapid Eye Movement (REM) latency	126.5 minutes STANDARD_DEVIATION 91.3
Sex: Female, Male Female	17 Participants
Sex: Female, Male Male	2 Participants
Sleep architecture REM Sleep	18.0 percentage of total sleep time STANDARD_DEVIATION 7.3
Sleep architecture Stage N1	18.9 percentage of total sleep time STANDARD_DEVIATION 6.6
Sleep architecture Stage N2	59.0 percentage of total sleep time STANDARD_DEVIATION 13
Sleep architecture Stage N3	4.2 percentage of total sleep time STANDARD_DEVIATION 8.4
Sleep efficiency (SE)	72.3 percentage of total sleep time STANDARD_DEVIATION 15.8
Total stage shifts	147.4 Stage shifts STANDARD_DEVIATION 42.2

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	12 / 19	10 / 19
serious Total, serious adverse events	0 / 19	1 / 19

Outcome results

Primary

Number of Awakenings After Sleep Onset (NAASO)

Number of awakenings after defined sleep onset until lights on.

Time frame: 4-Week maintenance treatment with milnacipran and placebo

Population: 15 subjects completed the study

Arm	Measure	Value (MEAN)	Dispersion
Milnacipran	Number of Awakenings After Sleep Onset (NAASO)	39.5 Awakenings	Standard Error 4.5
Placebo	Number of Awakenings After Sleep Onset (NAASO)	34.9 Awakenings	Standard Error 4.2

p-value: 0.42495% CI: [-7.3, 16.6]Paired T test

Primary

Sleep Efficiency (SE)

Percentage of time spent asleep while in bed

Time frame: 4-Week maintenance treatment with milnacipran and placebo

Arm	Measure	Value (MEAN)	Dispersion
Milnacipran	Sleep Efficiency (SE)	77.1 percentage of total sleep time	Standard Error 3.8
Placebo	Sleep Efficiency (SE)	83.3 percentage of total sleep time	Standard Error 2.3

p-value: 0.04995% CI: [-12.2, -0.04]Paired T test

Primary

Wake After Sleep Onset (WASO)

Wake time after defined sleep onset until lights on.

Time frame: 4-Week maintenance treatment with milnacipran and placebo

Arm	Measure	Value (MEAN)	Dispersion
Milnacipran	Wake After Sleep Onset (WASO)	76.2 minutes	Standard Error 10.8
Placebo	Wake After Sleep Onset (WASO)	53.6 minutes	Standard Error 8.1

p-value: 0.05695% CI: [-0.6, 45.8]Paired T test

Secondary