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

NCT ID: NCT01207453

Last Updated: 2014-11-17

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 49 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-01-31
• Study Completion Date: 2013-11-30

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.

Conditions

Arthritis, Rheumatoid

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

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.

Group Type: OTHER

Milnacipran

Intervention Type: DRUG

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

Placebo

Intervention Type: DRUG

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.

Group Type: OTHER

Milnacipran

Intervention Type: DRUG

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

Placebo

Intervention Type: DRUG

Interventions

Milnacipran

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

Placebo

Intervention Type: DRUG

Other Intervention Names

Savella

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.

• Minimum Eligible Age: 24 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Forest Laboratories

INDUSTRY

Sponsor Role: collaborator

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

NIH

Sponsor Role: collaborator

Brigham and Women's Hospital

OTHER

Sponsor Role: lead

Responsible Party

Yvonne C. Lee

Yvonne C. Lee, MD, MMSc

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Yvonne C Lee, MD, MMSc

Role: PRINCIPAL_INVESTIGATOR

Brigham and Women's Hospital

Locations

Brigham and Women's Hospital

Boston, Massachusetts, United States

Countries

United States

References

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.

Reference Type: BACKGROUND

PMID: 19874580 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 26628607 (View on PubMed)

Other Identifiers

K23AR057578

Identifier Type: NIH

Identifier Source: secondary_id

View Link

SAV-MD-16

Identifier Type: -

Identifier Source: org_study_id