Fibromyalgia, Neurocognition
Conditions
Keywords
Milnacipran, Fibromyalgia, Neurocognition
Brief summary
This study was designed to investigate whether milnacipran is safe and effective in improving cognitive function in fibromyalgia. In addition, this study was aimed to investigate whether improvement in neurocognitive status due to milnacipran correlates with improvements in pain, to investigate whether improvement in neurocognitive status due to milnacipran correlates with improvements in fatigue, and to determine whether treatment with improvement in neurocognitive status, pain and fatigue correlates with functional improvement.
Detailed description
Cognitive dysfunction is observed in fibromyalgia, especially for episodic memory, learning, and working memory.There is evidence for dysregulation of the attention system from low-level sensory processes up to emotional processes, and increased sensitivity to distraction.Milnacipran's balance of norepinephrine (NE) to serotonin (5-HT) of 3:1, similar to amitriptyline, a tricyclic that has demonstrated efficacy in fibromyalgia, as compared to venlafaxine which is 1:30, or duloxetine which is 1:10.7 In addition, because of milnacipran's effect on 5-HT, it should also be effective in treating other symptoms such as sleep disturbances and mood changes, which are associated to fibromyalgia, as well as other functional somatic syndromes. It is worth noting that several medications to treat fibromyalgia are sedating (e.g pregabalin, opioids, muscle relaxants) and impair neurocognition.
Interventions
DRUGMilnacipran
DRUGPlacebo
Sponsors
Forest Laboratories
Duke University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Age 18 to 65 years. * Specific diagnosis of FM by the participant's rheumatologist or physician, including written confirmation, from a physician, of the FM diagnosis. * Confirmation of the FM diagnosis by American College of Rheumatology Criteria and a physical tender point examination. * Ability to give informed consent. * If female, nonpregnant/nonlactating. * If a sexually active female of reproductive potential, must be using adequate contraception (i.e., oral contraceptives, barrier protection, or prior tubal ligation) during the trial.
Exclusion criteria
* Bipolar disorders, any psychotic disorder. * the existence of concomitant rheumatological disorders, including rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's disease, Sjogren's syndrome or scleroderma. * Substance dependence (except nicotine dependence) in the previous 3 months. * Currently suicidal or high suicide risk. * Serious or unstable medical disorders. * Any psychotropic drug treatment in the previous 2 weeks before screening. * A positive urine pregnancy test. * Screening laboratory values three times the limits of normal or judged clinically significant by the investigator. * History of hypersensitivity to milnacipran. * Seizure disorder, traumatic brain injury, any CNS disorder that affects cognitive status. * Concomitant meds: A minimum of 30 days on stable dose of analgesics and a minimum of 4 week washout from antidepressants and fibromyalgia specific medication ( e.g. pregabalin, neurontin) and supplements ( St John's wort, SAM-E). * Narrow angle glaucoma.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Visual Analogue Scale for Pain | Baseline, Week 1, 2,4, and 6 weeks | Visual Analogue Scale for Pain operationally is a 100 mm line anchored by word descriptors at each end. The patient marks a point on the line that reflects their current pain state. The distance in mm from the left anchor point is the score. Higher scores indicate more pain. |
| Changes in The Fatigue Severity Scale (FSS) | Baseline, Week 1, 2,4, and 6 weeks | The Fatigue Severity Scale (FSS) is composed of nine items with a seven-point response format. The minimum score = 9 and maximum score possible = 63. Higher scores = greater fatigue severity. Sample questions include I am easily fatigued and Exercise brings on my fatigue. In the initial validation study, internal consistency for the Fatigue Severity Scale was high for specific illness groups (MS and lupus) and healthy controls. The scale clearly distinguished patients from controls and it was moderately correlated with a single-item visual analogue scale of fatigue intensity. In all patients, clinical improvement in fatigue was associated with reductions in scores on the Fatigue Severity Scale. The Fatigue Severity Scale is also a practical measure due to its brevity and ease of administration and scoring. |
| Composite Brief Assessment of Cognition (BAC) Score | Baseline, Week 6 | The composite BAC score is calculated by scoring each of the 6 individual tests (Verbal Memory Recall, Digit Sequencing, Token Motor Task, Verbal Fluency, Symbol Coding, and Tower of London), comparing each score to a healthy control sample to create z-scores, summing the z-scores, and rescaling the sum. The composite score range is -2127.8 to 1878.8, with higher scores indicating better cognition. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| MATRICS Consensus Cognitive Battery Composite Score | Baseline, Week 6 | (MATRICS) Consensus Cognitive Battery measures cognitive functioning within 7 domains: speed of processing, attention/vigilance, working memory (non verbal and verbal), verbal learning, visual learning, reasoning and problem solving and social cognition. The composite score is calculated by the MATRICS computer program, which equally weights each of the 7 domain scores. The range of composite scores is 20-80. Higher scores indicate higher levels or cognitive functioning, while lower scores indicate lower levels of cognitive functioning. |
Countries
United States
Participant flow
Recruitment details
Patients were randomized to receiving milnacipran-washout-placebo or placebo- washout-milnacipran for 6 weeks, followed by a 1 week washout and then cross over to the other arm for another 6 weeks. The overall trial lasted 13 weeks starting on July 2011 and ending in May 2013.
Participants by arm
| Arm | Count |
|---|---|
| Subjects Who Completed the Study | 20 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention | Screen Failure | 4 | 2 |
Baseline characteristics
| Characteristic | Subjects Who Completed the Study |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 20 Participants |
| Age, Continuous | 47.6 years STANDARD_DEVIATION 9.1 |
| Region of Enrollment United States | 20 participants |
| Sex: Female, Male Female | 18 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 12 / 20 | 18 / 20 |
| serious Total, serious adverse events | 0 / 20 | 0 / 20 |
Outcome results
Primary
Changes in The Fatigue Severity Scale (FSS)
The Fatigue Severity Scale (FSS) is composed of nine items with a seven-point response format. The minimum score = 9 and maximum score possible = 63. Higher scores = greater fatigue severity. Sample questions include I am easily fatigued and Exercise brings on my fatigue. In the initial validation study, internal consistency for the Fatigue Severity Scale was high for specific illness groups (MS and lupus) and healthy controls. The scale clearly distinguished patients from controls and it was moderately correlated with a single-item visual analogue scale of fatigue intensity. In all patients, clinical improvement in fatigue was associated with reductions in scores on the Fatigue Severity Scale. The Fatigue Severity Scale is also a practical measure due to its brevity and ease of administration and scoring.
Time frame: Baseline, Week 1, 2,4, and 6 weeks
Population: Analysis employed Intent-to-Treat with Last Observation Carried Forward (LOCF) analysis. The Intent-to-Treat group (ITT) was comprised of all subjects who received at least one dose of the medication.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Milnacipran | Changes in The Fatigue Severity Scale (FSS) | Week 1 | 54.0 units on a scale |
| Milnacipran | Changes in The Fatigue Severity Scale (FSS) | Week 4 | 54.1 units on a scale |
| Milnacipran | Changes in The Fatigue Severity Scale (FSS) | Week 2 | 53.7 units on a scale |
| Milnacipran | Changes in The Fatigue Severity Scale (FSS) | Week 6 | 52.1 units on a scale |
| Milnacipran | Changes in The Fatigue Severity Scale (FSS) | Week 0 | 56.3 units on a scale |
| Placebo | Changes in The Fatigue Severity Scale (FSS) | Week 6 | 53.0 units on a scale |
| Placebo | Changes in The Fatigue Severity Scale (FSS) | Week 0 | 49.2 units on a scale |
| Placebo | Changes in The Fatigue Severity Scale (FSS) | Week 1 | 53.4 units on a scale |
| Placebo | Changes in The Fatigue Severity Scale (FSS) | Week 2 | 52.2 units on a scale |
| Placebo | Changes in The Fatigue Severity Scale (FSS) | Week 4 | 52.8 units on a scale |
Primary
Composite Brief Assessment of Cognition (BAC) Score
The composite BAC score is calculated by scoring each of the 6 individual tests (Verbal Memory Recall, Digit Sequencing, Token Motor Task, Verbal Fluency, Symbol Coding, and Tower of London), comparing each score to a healthy control sample to create z-scores, summing the z-scores, and rescaling the sum. The composite score range is -2127.8 to 1878.8, with higher scores indicating better cognition.
Time frame: Baseline, Week 6
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Milnacipran | Composite Brief Assessment of Cognition (BAC) Score | Week 6 | 42.9 units on a scale | Standard Deviation 8 |
| Milnacipran | Composite Brief Assessment of Cognition (BAC) Score | Baseline | 41.2 units on a scale | Standard Deviation 7.3 |
| Placebo | Composite Brief Assessment of Cognition (BAC) Score | Baseline | 40.9 units on a scale | Standard Deviation 10.4 |
| Placebo | Composite Brief Assessment of Cognition (BAC) Score | Week 6 | 42.9 units on a scale | Standard Deviation 7.8 |
Primary
Visual Analogue Scale for Pain
Visual Analogue Scale for Pain operationally is a 100 mm line anchored by word descriptors at each end. The patient marks a point on the line that reflects their current pain state. The distance in mm from the left anchor point is the score. Higher scores indicate more pain.
Time frame: Baseline, Week 1, 2,4, and 6 weeks
Population: Analysis employed Intent-to-Treat with Last Observation Carried Forward (LOCF) analysis. The Intent-to-Treat group (ITT) was comprised of all subjects who received at least one dose of the medication.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Milnacipran | Visual Analogue Scale for Pain | Week 1 | 58.5 mm |
| Milnacipran | Visual Analogue Scale for Pain | Week 4 | 56.9 mm |
| Milnacipran | Visual Analogue Scale for Pain | Week 2 | 55.7 mm |
| Milnacipran | Visual Analogue Scale for Pain | week 6 | 54.4 mm |
| Milnacipran | Visual Analogue Scale for Pain | Week 0 | 59.4 mm |
| Placebo | Visual Analogue Scale for Pain | week 6 | 60.4 mm |
| Placebo | Visual Analogue Scale for Pain | Week 0 | 68.6 mm |
| Placebo | Visual Analogue Scale for Pain | Week 1 | 66.2 mm |
| Placebo | Visual Analogue Scale for Pain | Week 2 | 61.5 mm |
| Placebo | Visual Analogue Scale for Pain | Week 4 | 54.4 mm |
Secondary
MATRICS Consensus Cognitive Battery Composite Score
(MATRICS) Consensus Cognitive Battery measures cognitive functioning within 7 domains: speed of processing, attention/vigilance, working memory (non verbal and verbal), verbal learning, visual learning, reasoning and problem solving and social cognition. The composite score is calculated by the MATRICS computer program, which equally weights each of the 7 domain scores. The range of composite scores is 20-80. Higher scores indicate higher levels or cognitive functioning, while lower scores indicate lower levels of cognitive functioning.
Time frame: Baseline, Week 6
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Milnacipran | MATRICS Consensus Cognitive Battery Composite Score | Baseline | 41.4 units on a scale | Standard Deviation 7.4 |
| Milnacipran | MATRICS Consensus Cognitive Battery Composite Score | Week 1 | 41.0 units on a scale | Standard Deviation 9.7 |
| Placebo | MATRICS Consensus Cognitive Battery Composite Score | Baseline | 37.8 units on a scale | Standard Deviation 9.6 |
| Placebo | MATRICS Consensus Cognitive Battery Composite Score | Week 1 | 40.6 units on a scale | Standard Deviation 10 |