Milnacipran and Neurocognition, Pain and Fatigue in Fibromyalgia : A 13-week Randomized, Placebo Controlled Cross Over Trial

Phase 3

Completed

Conditions: Fibromyalgia
Neurocognition

Interventions: Drug: Milnacipran
Drug: Placebo

Registration Number: NCT01829243

Lead Sponsor: Duke University

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 26

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Milnacipran	Placebo	Eligible subjects will receive milnacipran (12.5 mg-200 mg/day) in the forces titration schedule in flexible doses to the maximum tolerated dose starting with 12.5 mg qd for 1 day, 12.5 mg bid for 2 days, 25 mg bid for 4 days, 50 mg bid for 7 days and 100 mg bid thereafter. Patients who cannot tolerate higher doses will have a step-wise reduction in doses (e.g. 200 mg/day dose will be reduced to 100 mg/day; 100 mg/day will be reduced to 50 mg/day). Drug will be discontinued at the end of the study.
Placebo	Placebo	Eligible subjects will receive placebo (12.5 mg-200 mg/day) in the forces titration schedule in flexible doses to the maximum tolerated dose starting with 12.5 mg qd for 1 day, 12.5 mg bid for 2 days, 25 mg bid for 4 days, 50 mg bid for 7 days and 100 mg bid thereafter. Patients who cannot tolerate higher doses will have a step-wise reduction in doses (e.g. 200 mg/day dose will be reduced to 100 mg/day; 100 mg/day will be reduced to 50 mg/day). Drug will be discontinued at the end of the study.
Milnacipran	Milnacipran	Eligible subjects will receive milnacipran (12.5 mg-200 mg/day) in the forces titration schedule in flexible doses to the maximum tolerated dose starting with 12.5 mg qd for 1 day, 12.5 mg bid for 2 days, 25 mg bid for 4 days, 50 mg bid for 7 days and 100 mg bid thereafter. Patients who cannot tolerate higher doses will have a step-wise reduction in doses (e.g. 200 mg/day dose will be reduced to 100 mg/day; 100 mg/day will be reduced to 50 mg/day). Drug will be discontinued at the end of the study.
Placebo	Milnacipran	Eligible subjects will receive placebo (12.5 mg-200 mg/day) in the forces titration schedule in flexible doses to the maximum tolerated dose starting with 12.5 mg qd for 1 day, 12.5 mg bid for 2 days, 25 mg bid for 4 days, 50 mg bid for 7 days and 100 mg bid thereafter. Patients who cannot tolerate higher doses will have a step-wise reduction in doses (e.g. 200 mg/day dose will be reduced to 100 mg/day; 100 mg/day will be reduced to 50 mg/day). Drug will be discontinued at the end of the study.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.