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CompletedNCT01207453Updated Nov 17, 2014Results posted

Milnacipran in the Treatment of Widespread, Non-Joint Pain in Rheumatoid Arthritis

A Phase 4 interventional study of Milnacipran and Placebo in Arthritis, Rheumatoid, sponsored by Brigham and Women's Hospital. Completed at 1 site in United States. Open to participants aged 24 Years and older. Per ClinicalTrials.gov, last updated 2014-11-17.

Sponsored by Brigham and Women's Hospital · Phase 4, Interventional, and Treatment

Phase
Phase 4
Study type
Interventional
Enrollment
49
Allocation
Randomized
Ages
24 Years and older
Sex
All
01

Study summary

The purpose of this study is to determine whether milnacipran reduces widespread, non-joint pain in patients with rheumatoid arthritis (RA). The investigators will conduct a double-blind randomized crossover trial in subjects with RA to test the hypothesis that milnacipran improves widespread, non-joint pain. The investigators will also use data from the trial to determine whether response to milnacipran is associated with pain-modulating mechanisms from the central nervous system. The investigators hypothesize that response to milnacipran will be greater among patients with impaired central pain mechanisms than among patients with intact central pain modulating mechanisms.

Read the detailed description

Despite the development of effective medications to treat inflammation, pain remains a priority for rheumatoid arthritis (RA) patients. The pain that persists despite anti-inflammatory treatment is usually widespread and non-articular; it may lead to diminished quality of life and high medical, psychological and social costs. To develop better treatments for pain and prevent disability, it is critical to obtain a better understanding of widespread, non-joint pain in RA.

Milnacipran is a selective serotonin-norepinephrine reuptake inhibitor (SNRI). No studies have examined the effect of SNRIs on pain in RA. However, several studies have examined the role of SNRIs in fibromyalgia and related pain conditions. Treatment with milnacipran has been associated with improvements in clinical pain severity in Phase 2 and Phase 3 randomized placebo-controlled trials of fibromyalgia patients. In animal models, milnacipran appears to moderate the pain-inducing effects of inflammation and central sensitization. Thus milnacipran may be an ideal drug to treat pain in RA.

A clinical trial of an SNRI in the treatment of widespread, non-joint pain in RA will provide more information regarding pain mechanisms and may lead to more targeted, effective ways of treating pain in RA.

02

Conditions studied

  • Arthritis, Rheumatoid

Keywords

  • Arthritis, Rheumatoid
  • Milnacipran
  • Pain
03

In context

Arthritis

3,554 studies on the registry are indexed under Arthritis; 317 are open to participants now.

This study's enrollment of 49 is below the median of 90 across 2,377 interventional studies indexed under Arthritis.

Browse Arthritis studies →

Lead sponsor

Brigham and Women's Hospital is the lead sponsor of 1,236 studies on the registry; 224 are open to participants now.

Of its 116 completed or terminated interventional studies of FDA-regulated products, 64 (55%) have results posted.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
24 Years and older
Sexes eligible
All
Accepts healthy volunteers
No

Inclusion criteria

  • Age 24 years or older
  • Primary diagnosis of rheumatoid arthritis from a board-certified rheumatologist
  • Willing to maintain stable doses of concurrent non-steroidal anti-inflammatory drugs or other acceptable medications or therapies for the duration of the study
  • Brief Pain Inventory Average Pain >= 4 at the screening visit
  • Widespread Pain Index >= 5 at the screening visit
  • Able to give informed consent

Exclusion criteria

Exclusion Criteria:

  • Diagnosis of primary fibromyalgia
  • Diagnosis of cold sensitive conditions such as Raynaud's syndrome, cryoglobulinemia and paroxysmal cold hemoglobinuria
  • Diagnosis of psychotic disorders, such as schizophrenia, schizoaffective disorder, delusional disorder and shared psychotic disorder
  • Patients being treated with SSRIs, MAO inhibitors or tricyclic, tetracyclic or atypical antidepressants for pain may participate in this study if they are washed off these medications before study entry. Patients currently receiving therapy with SSRIs or tricyclic, tetracyclic or atypical antidepressants for depression may be washed off these medications before study entry pending permission of the prescribing physician and if they have never received a diagnosis of major depressive disorder or had a history of suicidal ideation.
  • Patients on thioridazine or MAO inhibitors
  • Patients taking codeine or other opioids/opiates. Patients who are taking medications such as pregabalin (Lyrica) and gabapentin (Neurontin) for pain may be enrolled in this study.
  • Known hypersensitivity to milnacipran
  • Patients with a significant risk of suicide as assessed by the Beck depression inventory form
  • Patients with a history of suicide
  • Pregnant or breast-feeding women
  • Patients with an actively pending worker's compensation claim or auto no-fault claim; patients with current worker's compensation, auto no-fault compensation, or litigation; or any patient with significant secondary gain issues per discretion of the researchers.
  • Patients with myocardial infarction within the past 12 months, active cardiac disease (chest pain or evidence of ischemia on stress test), acute congestive heart failure requiring hospitalization in the past 12 months, clinically significant cardiac rhythm or conduction abnormalities requiring hospitalization in the past 12 months

  • Patients with severe liver impairment (AST or ALT > 3 times the upper limit of normal)

    • For patients 2-3 times the upper limit of normal, we will obtain enrollment permission from the patient's hepatologist and monitor values at each study visit. If values increase above 3 times the upper limit of normal, the patient will be discontinued from the study.
    • For patients 1-2 times the upper limit of normal, we will obtain enrollment permission from the patient's physician and monitor per request of the physician.
  • Patients with severe or end stage renal disease, defined as a GFR \< 15 ml/min or on dialysis
  • Patients with a recent (≤ 12 months) history of seizures.
  • Patients with uncontrolled narrow-angle glaucoma.
  • Patients who have been treated with an experimental agent within the last three months.
05

Study design

Phase
Phase 4
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Crossover assignment
Masking
Quadruple (Participant, Care provider, Investigator, Outcomes assessor)
Enrollment
49 participants (actual)

Study arms

  • Other
    Milnacipran then placebo

    This arm of the study will contain half the study population after randomization. The participants in this arm will receive milnacipran for 6 weeks. They will undergo a one-week taper and a two week washout period and then crossover to a placebo for 6 weeks.

    Drug: Milnacipran · Drug: Placebo

  • Other
    Placebo then milnacipran

    This arm of the study will contain half the study population after randomization. The participants in this arm will receive placebo for 6 weeks. They will undergo a one-week "taper" and a two week "washout" period and then crossover to milnacipran for 6 weeks.

    Drug: Milnacipran · Drug: Placebo

Interventions

  • DrugMilnacipran

    Milnacipran comes in 50 mg tablets and is taken orally. Participants will gradually be increased to a target dose of 50 mg twice daily.

    Also known as: Savella

  • DrugPlacebo
06

What researchers measure

Primary outcomes

  1. Brief Pain Inventory (BPI) Change

    A measure of change in scores on the BPI short form, a "24-hr average pain" item, from baseline to 6 weeks, The BPI short form scores ranges from 0-10, with 10 being the worst pain.

    Time frame: Baseline to 6 weeks

Secondary outcomes

  1. Change in Conditioned Pain Modulation (CPM)

    CPM is defined as the difference between pain threshold A (measured after a conditioning stimulus activates pathways that inhibit pain) and pain threshold B (measured before the conditioning stimulus is applied). The conditioning stimulus was immersion of the hand in a cold water bath. Pressure pain threshold was assessed at the trapezius muscle initially. Subjects were then instructed to immerse their hand in a water bath for 30 seconds. At 20 seconds, pressure pain threshold at the trapezius was assessed again. We defined the magnitude of subjects' CPM as the difference in pressure pain threshold between baseline and 20 seconds after cold water immersion. This difference was compared to that measured at 6 weeks. The scale for the difference in CPM ranged from 0-11 kg/cm\^2, with 0 indicating no change in CPM between 6 weeks and baseline and 11 indicating the maximum possible change. A greater change in CPM between baseline and 6 weeks is indicative of improvements in CPM.

    Time frame: Baseline to 6 weeks

  2. Symptom Intensity Scale (SIS)

    A measure of the change in SIS score from baseline to 6 weeks. The SIS score ranges from 0-9.75, with high scores being worse indicating more widespread pain and fatigue.

    Time frame: Baseline to 6 weeks

  3. Thumbnail Pain Threshold

    A measure of the change in thumbnail pain threshold from baseline to 6 weeks. Thumbnail pain threshold was determined by applying pressure to a subjectt's thumbnail until the subject felt pain. The difference between the average thumbnail pain threshold (an average for the right and left thumbs) at baseline was compared to that at 6 months. Pain threshold was measured in kg/cm\^2. The difference in threshold could range from 0-11 kg/cm\^2. A higher difference between thresholds indicates improved pain sensitivity.

    Time frame: Baseline to 6 weeks

  4. Trapezius Pain Threshold

    A measure of the change in trapezius pain threshold from baseline to 6 weeks. Trapezius pain threshold was determined by applying pressure to a subject's trapezius muscle until the subject felt pain. The difference between the average trapezius pain threshold (an average for the right and left trapezii) at baseline was compared to that at 6 months. Pain threshold was measured in kg/cm\^2. The difference in threshold could range from 0-11 kg/cm\^2. A higher difference between thresholds indicates improved pain sensitivity.

    Time frame: Baseline to 6 weeks

  5. Wrist Pain Threshold

    A measure of the change in wrist pain threshold from baseline to 6 weeks. Wrist pain threshold was determined by applying pressure to a subject's wrist until the subject felt pain. The difference between the average wrist pain threshold (an average for the right and left wrists) at baseline was compared to that at 6 months. Pain threshold was measured in kg/cm\^2. The difference in threshold could range from 0-11 kg/cm\^2. A higher difference between thresholds indicates improved pain sensitivity.

    Time frame: Baseline to 6 weeks

  6. Knee Pain Threshold

    A measure of the change in knee pain threshold from baseline to 6 weeks. Knee pain threshold was determined by applying pressure to a subject's knee until the subject felt pain. The difference between the average knee pain threshold (an average for the right and left knees) at baseline was compared to that at 6 months. Pain threshold was measured in kg/cm\^2. The difference in threshold could range from 0-11 kg/cm\^2. A higher difference between thresholds indicates improved pain sensitivity.

    Time frame: Baseline to 6 weeks

07

Results

Posted Nov 17, 2014

Participant flow

First Intervention
Participant flow — First Intervention
MilestoneMilnacipran and Then PlaceboPlacebo and Then Milnacipran
Started2318
Completed2117
Not completed21
Withdrew: Adverse event21
Washout
Participant flow — Washout
MilestoneMilnacipran and Then PlaceboPlacebo and Then Milnacipran
Started2117
Completed1917
Not completed20
Withdrew: Adverse event10
Withdrew: Lost to follow-up10
2nd Intervention
Participant flow — 2nd Intervention
MilestoneMilnacipran and Then PlaceboPlacebo and Then Milnacipran
Started1917
Completed1715
Not completed22
Withdrew: Adverse event12
Withdrew: Lost to follow-up10

Outcome measures

PrimaryBrief Pain Inventory (BPI) Change

A measure of change in scores on the BPI short form, a "24-hr average pain" item, from baseline to 6 weeks, The BPI short form scores ranges from 0-10, with 10 being the worst pain.

Time frame:
Baseline to 6 weeks
Reported as:
Mean · units on a scale
Brief Pain Inventory (BPI) Change
units on a scalePlaceboMilnacipran
Baseline5.2 ± 2.15.6 ± 2.0
6 weeks4.9 ± 2.14.8 ± 2.2
Change-0.3 ± 2.0-0.7 ± 1.7
Statistical analysis
  • Placebo vs Milnacipran · Wilcoxon (Mann-Whitney) · p = 0.42 (Not adjusted for multiple comparisons. A priori threshold for statistical significance was \< 0.05.)
  • Placebo vs Milnacipran · Mixed Models Analysis · p = 0.37 (Linear mixed models including treatment, crossover period and treatment sequence. Not adjusted for multiple comparisons. A priori threshold for statistical significance was \< 0.05.)
SecondaryChange in Conditioned Pain Modulation (CPM)

CPM is defined as the difference between pain threshold A (measured after a conditioning stimulus activates pathways that inhibit pain) and pain threshold B (measured before the conditioning stimulus is applied). The conditioning stimulus was immersion of the hand in a cold water bath. Pressure pain threshold was assessed at the trapezius muscle initially. Subjects were then instructed to immerse their hand in a water bath for 30 seconds. At 20 seconds, pressure pain threshold at the trapezius was assessed again. We defined the magnitude of subjects' CPM as the difference in pressure pain threshold between baseline and 20 seconds after cold water immersion. This difference was compared to that measured at 6 weeks. The scale for the difference in CPM ranged from 0-11 kg/cm\^2, with 0 indicating no change in CPM between 6 weeks and baseline and 11 indicating the maximum possible change. A greater change in CPM between baseline and 6 weeks is indicative of improvements in CPM.

Time frame:
Baseline to 6 weeks
Reported as:
Mean · kg/cm^2
Change in Conditioned Pain Modulation (CPM)
kg/cm^2PlaceboMilnacipran
Baseline0.8 ± 1.00.8 ± 1.1
6 Weeks0.9 ± 1.30.9 ± 1.1
Change0.1 ± 1.20.1 ± 1.5
Statistical analysis
  • Placebo vs Milnacipran · Wilcoxon (Mann-Whitney) · p = 0.39 (Not adjusted for multiple comparisons. A priori threshold for statistical significance was \< 0.05.)
  • Placebo vs Milnacipran · Mixed Models Analysis · p = 0.96 (Linear mixed models including treatment, crossover period and treatment sequence. Not adjusted for multiple comparisons. A priori threshold for statistical significance was \< 0.05.)
SecondarySymptom Intensity Scale (SIS)

A measure of the change in SIS score from baseline to 6 weeks. The SIS score ranges from 0-9.75, with high scores being worse indicating more widespread pain and fatigue.

Time frame:
Baseline to 6 weeks
Reported as:
Mean · units on a scale
Symptom Intensity Scale (SIS)
units on a scalePlaceboMilnacipran
Baseline5.1 ± 2.15.2 ± 2.0
6 weeks4.3 ± 2.44.5 ± 8.3
Change-0.8 ± 1.9-0.7 ± 1.6
Statistical analysis
  • Placebo vs Milnacipran · Wilcoxon (Mann-Whitney) · p = 0.89 (Not adjusted for multiple comparisons. A priori threshold for statistical significance was \< 0.05.)
  • Placebo vs Milnacipran · Mixed Models Analysis · p = 0.83 (Linear mixed models including treatment, crossover period and treatment sequence. Not adjusted for multiple comparisons. A priori threshold for statistical significance was \< 0.05.)
SecondaryThumbnail Pain Threshold

A measure of the change in thumbnail pain threshold from baseline to 6 weeks. Thumbnail pain threshold was determined by applying pressure to a subjectt's thumbnail until the subject felt pain. The difference between the average thumbnail pain threshold (an average for the right and left thumbs) at baseline was compared to that at 6 months. Pain threshold was measured in kg/cm\^2. The difference in threshold could range from 0-11 kg/cm\^2. A higher difference between thresholds indicates improved pain sensitivity.

Time frame:
Baseline to 6 weeks
Reported as:
Mean · kg/cm^2
Thumbnail Pain Threshold
kg/cm^2PlaceboMilnacipran
Baseline5.8 ± 3.05.3 ± 2.7
6 weeks5.8 ± 2.86.0 ± 2.8
Change-0.02 ± 1.40.7 ± 1.4
Statistical analysis
  • Placebo vs Milnacipran · Wilcoxon (Mann-Whitney) · p = 0.04 (Not adjusted for multiple comparisons. A priori threshold for statistical significance was \< 0.05.)
  • Placebo vs Milnacipran · Mixed Models Analysis · p = 0.04 (Linear mixed models including treatment, crossover period and treatment sequence. Not adjusted for multiple comparisons. A priori threshold for statistical significance was \< 0.05.)
SecondaryTrapezius Pain Threshold

A measure of the change in trapezius pain threshold from baseline to 6 weeks. Trapezius pain threshold was determined by applying pressure to a subject's trapezius muscle until the subject felt pain. The difference between the average trapezius pain threshold (an average for the right and left trapezii) at baseline was compared to that at 6 months. Pain threshold was measured in kg/cm\^2. The difference in threshold could range from 0-11 kg/cm\^2. A higher difference between thresholds indicates improved pain sensitivity.

Time frame:
Baseline to 6 weeks
Reported as:
Mean · kg/cm^2
Trapezius Pain Threshold
kg/cm^2PlaceboMilnacipran
Baseline4.9 ± 2.85.1 ± 3.1
6 Weeks5.5 ± 3.15.5 ± 3.1
Change0.6 ± 1.50.4 ± 1.3
Statistical analysis
  • Placebo vs Milnacipran · Wilcoxon (Mann-Whitney) · p = 0.89 (Not adjusted for multiple comparisons. A priori threshold for statistical significance was \< 0.05.)
  • Placebo vs Milnacipran · Mixed Models Analysis · p = 0.44 (Linear mixed models including treatment, crossover period and treatment sequence. Not adjusted for multiple comparisons. A priori threshold for statistical significance was \< 0.05.)
SecondaryWrist Pain Threshold

A measure of the change in wrist pain threshold from baseline to 6 weeks. Wrist pain threshold was determined by applying pressure to a subject's wrist until the subject felt pain. The difference between the average wrist pain threshold (an average for the right and left wrists) at baseline was compared to that at 6 months. Pain threshold was measured in kg/cm\^2. The difference in threshold could range from 0-11 kg/cm\^2. A higher difference between thresholds indicates improved pain sensitivity.

Time frame:
Baseline to 6 weeks
Reported as:
Mean · kg/cm^2
Wrist Pain Threshold
kg/cm^2PlaceboMilnacipran
Baseline5.3 ± 2.75.0 ± 2.4
6 weeks5.9 ± 3.05.9 ± 2.9
Change0.6 ± 1.60.9 ± 1.5
Statistical analysis
  • Placebo vs Milnacipran · Wilcoxon (Mann-Whitney) · p = 0.35 (Not adjusted for multiple comparisons. A priori threshold for statistical significance was \< 0.05.)
  • Placebo vs Milnacipran · Mixed Models Analysis · p = 0.34 (Linear mixed models including treatment, crossover period and treatment sequence. Not adjusted for multiple comparisons. A priori threshold for statistical significance was \< 0.05.)
SecondaryKnee Pain Threshold

A measure of the change in knee pain threshold from baseline to 6 weeks. Knee pain threshold was determined by applying pressure to a subject's knee until the subject felt pain. The difference between the average knee pain threshold (an average for the right and left knees) at baseline was compared to that at 6 months. Pain threshold was measured in kg/cm\^2. The difference in threshold could range from 0-11 kg/cm\^2. A higher difference between thresholds indicates improved pain sensitivity.

Time frame:
Baseline to 6 weeks
Reported as:
Mean · kg/cm^2
Knee Pain Threshold
kg/cm^2PlaceboMilnacipran
Baseline7.0 ± 3.16.9 ± 3.2
6 weeks7.3 ± 3.17.3 ± 3.2
Change0.3 ± 1.80.3 ± 1.4
Statistical analysis
  • Placebo vs Milnacipran · Wilcoxon (Mann-Whitney) · p = 0.72 (Not adjusted for multiple comparisons. A priori threshold for statistical significance was \< 0.05.)
  • Placebo vs Milnacipran · Mixed Models Analysis · p = 0.82 (Linear mixed models including treatment, crossover period and treatment sequence. Not adjusted for multiple comparisons. A priori threshold for statistical significance was \< 0.05.)

Adverse events

Collected over 6 weeks for intervention with a period of 3 weeks of washout between each intervention period.. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Milnacipran—0/41 (0%)17/41 (41.5%)
Placebo—1/41 (2.4%)8/41 (19.5%)
Washout Period—0/41 (0%)1/41 (2.4%)
Most frequent serious events
Most frequent serious events
EventMilnacipranPlaceboWashout Period
Colon AbscessGastrointestinal disorders0/411/410/41
Most frequent other events
Most frequent other events
EventMilnacipranPlaceboWashout Period
NauseaGastrointestinal disorders11/413/411/41
Loss of appetiteGastrointestinal disorders4/410/410/41
Sleep ProblemsGeneral disorders3/412/410/41
VomitingGastrointestinal disorders3/410/410/41
HeadacheGeneral disorders2/412/410/41
DizzinessGeneral disorders2/411/411/41
FatigueGeneral disorders2/410/410/41
ConstipationGastrointestinal disorders2/411/410/41
Urinary HesitationRenal and urinary disorders2/410/410/41
ParathesthesiasNervous system disorders0/412/410/41

Baseline characteristics

49 individuals signed the informed consent document. Of these individuals, 8 did not meet inclusion/exclusion criteria. 41 subjects were randomized and received study drug.

Age, Continuous
Age, Continuous(Year)Milnacipran and Then PlaceboPlacebo and Then MilnacipranTotal
Age56.39 ± 12.3558.50 ± 14.7957.32 ± 13.34
Sex: Female, Male
Sex: Female, Male(Participants)Milnacipran and Then PlaceboPlacebo and Then MilnacipranTotal
Female191534
Male437
08

Study locations

1 site
  • Brigham and Women's Hospital
    Boston, Massachusetts 02115, United States
09

References and documents

Publications

  • Lee YC, Chibnik LB, Lu B, Wasan AD, Edwards RR, Fossel AH, Helfgott SM, Solomon DH, Clauw DJ, Karlson EW. The relationship between disease activity, sleep, psychiatric distress and pain sensitivity in rheumatoid arthritis: a cross-sectional study. Arthritis Res Ther. 2009;11(5):R160. doi: 10.1186/ar2842. Epub 2009 Oct 29. PubMed 19874580 ↗
  • Lee YC, Massarotti E, Edwards RR, Lu B, Liu C, Lo Y, Wohlfahrt A, Kim ND, Clauw DJ, Solomon DH. Effect of Milnacipran on Pain in Patients with Rheumatoid Arthritis with Widespread Pain: A Randomized Blinded Crossover Trial. J Rheumatol. 2016 Jan;43(1):38-45. doi: 10.3899/jrheum.150550. Epub 2015 Dec 1. PubMed 26628607 ↗
10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Nov 17, 2014, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT01207453
Lead sponsor
Brigham and Women's Hospital
Collaborators
Forest Laboratories, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Responsible party
Yvonne C. Lee (Yvonne C. Lee, MD, MMSc, Brigham and Women's Hospital) — Principal investigator
First posted
Sep 23, 2010
Start date
Jan 2011
Primary completion
Nov 2013
Completion
Nov 2013
Results posted
Nov 17, 2014
Last update
Nov 17, 2014

Study contacts

Yvonne C Lee, MD, MMSc
principal investigator · Brigham and Women's Hospital

Oversight

Data monitoring committee
Yes
View the source record on ClinicalTrials.gov ↗

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