Arthritis, Rheumatoid
Conditions
Keywords
Arthritis, Rheumatoid, Milnacipran, Pain
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.
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.
DRUGPlacebo
Sponsors
Forest Laboratories
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Brigham and Women's Hospital
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
24 Years to No maximum
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
* 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Brief Pain Inventory (BPI) Change | Baseline to 6 weeks | 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
| Measure | Time frame | Description |
|---|---|---|
| Symptom Intensity Scale (SIS) | Baseline to 6 weeks | 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 | Baseline to 6 weeks | 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. |
| Change in Conditioned Pain Modulation (CPM) | Baseline to 6 weeks | 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. |
| Wrist Pain Threshold | Baseline to 6 weeks | 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 | Baseline to 6 weeks | 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. |
| Trapezius Pain Threshold | Baseline to 6 weeks | 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. |
Countries
United States
Participant flow
Pre-assignment details
49 patients signed the informed consent document. 8 patients did not meet inclusion criteria and failed screening. 41 patients were randomized and received \>= 1 dose of the study drug/placebo. Seven patients stopped participation due to adverse events, and 2 were lost to follow-up. 32 patients completed the study and were analyzed.
Participants by arm
| Arm | Count |
|---|---|
| Milnacipran and Then Placebo Participants first received 6 weeks of milnacipran (titrated up to full dose of 50 mg twice daily). This was followed by a 3-week wash-out. Participants then received 6 weeks of placebo. | 23 |
| Placebo and Then Milnacipran Participants first received 6 weeks of placebo. This was followed by a 3-week wash-out. After the wash-out period, participants then received 6 weeks of milnacipran (titrated up to full dose of 50 mg twice daily). | 18 |
| Total | 41 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| 2nd Intervention | Adverse Event | 1 | 2 |
| 2nd Intervention | Lost to Follow-up | 1 | 0 |
| First Intervention | Adverse Event | 2 | 1 |
| Washout | Adverse Event | 1 | 0 |
| Washout | Lost to Follow-up | 1 | 0 |
Baseline characteristics
| Characteristic | Milnacipran and Then Placebo | Placebo and Then Milnacipran | Total |
|---|---|---|---|
| Age, Continuous Age | 56.39 Year STANDARD_DEVIATION 12.35 | 58.50 Year STANDARD_DEVIATION 14.79 | 57.32 Year STANDARD_DEVIATION 13.34 |
| Sex: Female, Male Female | 19 Participants | 15 Participants | 34 Participants |
| Sex: Female, Male Male | 4 Participants | 3 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 17 / 41 | 8 / 41 | 1 / 41 |
| serious Total, serious adverse events | 0 / 41 | 1 / 41 | 0 / 41 |
Outcome results
Primary
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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Brief Pain Inventory (BPI) Change | Baseline | 5.2 units on a scale | Standard Deviation 2.1 |
| Placebo | Brief Pain Inventory (BPI) Change | 6 weeks | 4.9 units on a scale | Standard Deviation 2.1 |
| Placebo | Brief Pain Inventory (BPI) Change | Change | -0.3 units on a scale | Standard Deviation 2 |
| Milnacipran | Brief Pain Inventory (BPI) Change | Baseline | 5.6 units on a scale | Standard Deviation 2 |
| Milnacipran | Brief Pain Inventory (BPI) Change | 6 weeks | 4.8 units on a scale | Standard Deviation 2.2 |
| Milnacipran | Brief Pain Inventory (BPI) Change | Change | -0.7 units on a scale | Standard Deviation 1.7 |
Comparison: The difference between the change measured during placebo versus the change during milnacipran treatment. Calculated using Wilcoxon signed rank tests.p-value: 0.42Wilcoxon (Mann-Whitney)
Comparison: The difference between the change measured during placebo versus the change during milnacipran treatment. Calculated using linear mixed models.p-value: 0.37Mixed Models Analysis
Secondary
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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change in Conditioned Pain Modulation (CPM) | Baseline | 0.8 kg/cm^2 | Standard Deviation 1 |
| Placebo | Change in Conditioned Pain Modulation (CPM) | 6 Weeks | 0.9 kg/cm^2 | Standard Deviation 1.3 |
| Placebo | Change in Conditioned Pain Modulation (CPM) | Change | 0.1 kg/cm^2 | Standard Deviation 1.2 |
| Milnacipran | Change in Conditioned Pain Modulation (CPM) | Baseline | 0.8 kg/cm^2 | Standard Deviation 1.1 |
| Milnacipran | Change in Conditioned Pain Modulation (CPM) | 6 Weeks | 0.9 kg/cm^2 | Standard Deviation 1.1 |
| Milnacipran | Change in Conditioned Pain Modulation (CPM) | Change | 0.1 kg/cm^2 | Standard Deviation 1.5 |
Comparison: The difference between the change measured during placebo versus the change during milnacipran treatment. Calculated using the Wilcoxon signed-rank tests.p-value: 0.39Wilcoxon (Mann-Whitney)
Comparison: The difference between the change measured during placebo versus the change during milnacipran treatment. Calculated using linear mixed models.p-value: 0.96Mixed Models Analysis
Secondary
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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Knee Pain Threshold | Baseline | 7.0 kg/cm^2 | Standard Deviation 3.1 |
| Placebo | Knee Pain Threshold | 6 weeks | 7.3 kg/cm^2 | Standard Deviation 3.1 |
| Placebo | Knee Pain Threshold | Change | 0.3 kg/cm^2 | Standard Deviation 1.8 |
| Milnacipran | Knee Pain Threshold | Baseline | 6.9 kg/cm^2 | Standard Deviation 3.2 |
| Milnacipran | Knee Pain Threshold | 6 weeks | 7.3 kg/cm^2 | Standard Deviation 3.2 |
| Milnacipran | Knee Pain Threshold | Change | 0.3 kg/cm^2 | Standard Deviation 1.4 |
Comparison: The difference between the change measured during placebo versus the change during milnacipran treatment. Calculated using Wilcoxon signed-rank tests.p-value: 0.72Wilcoxon (Mann-Whitney)
Comparison: The difference between the change measured during placebo versus the change during milnacipran treatment. Calculated using linear mixed models.p-value: 0.82Mixed Models Analysis
Secondary
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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Symptom Intensity Scale (SIS) | Baseline | 5.1 units on a scale | Standard Deviation 2.1 |
| Placebo | Symptom Intensity Scale (SIS) | 6 weeks | 4.3 units on a scale | Standard Deviation 2.4 |
| Placebo | Symptom Intensity Scale (SIS) | Change | -0.8 units on a scale | Standard Deviation 1.9 |
| Milnacipran | Symptom Intensity Scale (SIS) | Baseline | 5.2 units on a scale | Standard Deviation 2 |
| Milnacipran | Symptom Intensity Scale (SIS) | 6 weeks | 4.5 units on a scale | Standard Deviation 8.3 |
| Milnacipran | Symptom Intensity Scale (SIS) | Change | -0.7 units on a scale | Standard Deviation 1.6 |
Comparison: The difference between the change measured during placebo versus the change during milnacipran treatment. Calculated using Wilcoxon signed-rank tests.p-value: 0.89Wilcoxon (Mann-Whitney)
Comparison: The difference between the change measured during placebo versus the change during milnacipran treatment. Calculated using linear mixed models.p-value: 0.83Mixed Models Analysis
Secondary
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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Thumbnail Pain Threshold | Baseline | 5.8 kg/cm^2 | Standard Deviation 3 |
| Placebo | Thumbnail Pain Threshold | 6 weeks | 5.8 kg/cm^2 | Standard Deviation 2.8 |
| Placebo | Thumbnail Pain Threshold | Change | -0.02 kg/cm^2 | Standard Deviation 1.4 |
| Milnacipran | Thumbnail Pain Threshold | Baseline | 5.3 kg/cm^2 | Standard Deviation 2.7 |
| Milnacipran | Thumbnail Pain Threshold | 6 weeks | 6.0 kg/cm^2 | Standard Deviation 2.8 |
| Milnacipran | Thumbnail Pain Threshold | Change | 0.7 kg/cm^2 | Standard Deviation 1.4 |
Comparison: The difference between the change measured during placebo versus the change during milnacipran treatment. Calculated using Wilcoxon signed-rank tests.p-value: 0.04Wilcoxon (Mann-Whitney)
Comparison: The difference between the change measured during placebo versus the change during milnacipran treatment. Calculated using linear mixed models.p-value: 0.04Mixed Models Analysis
Secondary
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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Trapezius Pain Threshold | Baseline | 4.9 kg/cm^2 | Standard Deviation 2.8 |
| Placebo | Trapezius Pain Threshold | 6 Weeks | 5.5 kg/cm^2 | Standard Deviation 3.1 |
| Placebo | Trapezius Pain Threshold | Change | 0.6 kg/cm^2 | Standard Deviation 1.5 |
| Milnacipran | Trapezius Pain Threshold | Baseline | 5.1 kg/cm^2 | Standard Deviation 3.1 |
| Milnacipran | Trapezius Pain Threshold | 6 Weeks | 5.5 kg/cm^2 | Standard Deviation 3.1 |
| Milnacipran | Trapezius Pain Threshold | Change | 0.4 kg/cm^2 | Standard Deviation 1.3 |
Comparison: The difference between the change measured during placebo versus the change during milnacipran treatment. Calculated using Wilcoxon signed-rank tests.p-value: 0.89Wilcoxon (Mann-Whitney)
Comparison: The difference between the change measured during placebo versus the change during milnacipran treatment. Calculated using linear mixed models.p-value: 0.44Mixed Models Analysis
Secondary
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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Wrist Pain Threshold | Baseline | 5.3 kg/cm^2 | Standard Deviation 2.7 |
| Placebo | Wrist Pain Threshold | 6 weeks | 5.9 kg/cm^2 | Standard Deviation 3 |
| Placebo | Wrist Pain Threshold | Change | 0.6 kg/cm^2 | Standard Deviation 1.6 |
| Milnacipran | Wrist Pain Threshold | Baseline | 5.0 kg/cm^2 | Standard Deviation 2.4 |
| Milnacipran | Wrist Pain Threshold | 6 weeks | 5.9 kg/cm^2 | Standard Deviation 2.9 |
| Milnacipran | Wrist Pain Threshold | Change | 0.9 kg/cm^2 | Standard Deviation 1.5 |
Comparison: The difference between the change measured during placebo versus the change during milnacipran treatment. Calculated using Wilcoxon signed-rank tests.p-value: 0.35Wilcoxon (Mann-Whitney)
Comparison: The difference between the change measured during placebo versus the change during milnacipran treatment. Calculated using linear mixed models.p-value: 0.34Mixed Models Analysis