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

Primary Purpose

Arthritis, Rheumatoid

Status

Completed

Phase

Phase 4

Locations

United States

Study Type

Interventional

Intervention

Milnacipran

Placebo

About this trial

This is an interventional treatment trial for Arthritis, Rheumatoid focused on measuring Arthritis, Rheumatoid, Milnacipran, Pain

Eligibility Criteria

24 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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:

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.

Sites / Locations

Brigham and Women's Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Other

Arm Label

Milnacipran then placebo

Placebo then milnacipran

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

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.

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.

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.

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.

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.

Full Information

NCT ID

NCT01207453

First Posted

September 21, 2010

Last Updated

November 7, 2014

Sponsor

Brigham and Women's Hospital

Collaborators

Forest Laboratories, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

1. Study Identification

Unique Protocol Identification Number

NCT01207453

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

November 2014

Overall Recruitment Status

Completed

Study Start Date

January 2011 (undefined)

Primary Completion Date

November 2013 (Actual)

Study Completion Date

November 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Brigham and Women's Hospital

Collaborators

Forest Laboratories, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief 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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Arthritis, Rheumatoid

Keywords

Arthritis, Rheumatoid, Milnacipran, Pain

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Crossover Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

49 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Milnacipran then placebo

Arm Type

Other

Arm Description

Arm Title

Placebo then milnacipran

Arm Type

Other

Arm Description

Intervention Type

Drug

Intervention Name(s)

Milnacipran

Other Intervention Name(s)

Savella

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Placebo

Primary Outcome Measure Information:

Title

Brief Pain Inventory (BPI) Change

Description

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 Outcome Measure Information:

Title

Change in Conditioned Pain Modulation (CPM)

Description

Time Frame

Baseline to 6 weeks

Title

Symptom Intensity Scale (SIS)

Description

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

Title

Thumbnail Pain Threshold

Description

Time Frame

Baseline to 6 weeks

Title

Trapezius Pain Threshold

Description

Time Frame

Baseline to 6 weeks

Title

Wrist Pain Threshold

Description

Time Frame

Baseline to 6 weeks

Title

Knee Pain Threshold

Description

Time Frame

Baseline to 6 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

24 Years

Accepts Healthy Volunteers

Eligibility Criteria

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: 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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Yvonne C Lee, MD, MMSc

Organizational Affiliation

Brigham and Women's Hospital

Official's Role

Principal Investigator

Facility Information:

Facility Name

Brigham and Women's Hospital

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02115

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

19874580

Citation

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.

Results Reference

background

PubMed Identifier

26628607

Citation

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.

Results Reference

derived

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

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