Sex Differences in Pain and Quantitative Sensory Testing in Patients With Rheumatoid Arthritis.

OBJECTIVE: Women with rheumatoid arthritis (RA) have higher pain and worse functional outcomes compared to men, even when treated with similar medications. The objective of this study was to identify sex differences in pain intensity, pain interference, and quantitative sensory tests (QST), which are independent of inflammation, in patients with RA. METHODS: This study is a post hoc analysis of participants in the Central Pain in Rheumatoid Arthritis cohort. Pain intensity was assessed using a 0-10 numeric rating scale. Pain interference was measured using a Patient-Reported Outcomes Measurement Information System computerized adaptive test. QST included pressure pain detection thresholds, temporal summation, and conditioned pain modulation. Women and men were compared using multiple linear regression, adjusted for age, education, race, research site, depression, obesity, RA disease duration, swollen joint count, and C-reactive protein. RESULTS: Mean ± SD pain intensity was 5.32 ± 2.29 among women with RA, compared to 4.60 ± 2.23 among men with RA (adjusted difference 0.83 [95% confidence interval (95% CI) 0.14, 1.53]). Women with RA had lower pressure pain detection thresholds at the trapezius (adjusted difference -1.22 [95% CI -1.73, -0.72]), wrist (adjusted difference -0.57 [95% CI -1.07, -0.06]), and knee (adjusted difference -1.10 [95% CI -2.00, -0.21]). No statistically significant differences in pain interference, temporal summation, and conditioned pain modulation were observed. CONCLUSION: Women reported higher pain intensity and lower pressure pain detection thresholds (higher pain sensitivity) than men. However, pain interference, temporal summation, and conditioned pain modulation did not differ between men and women.

Pain Mechanisms Associated With Disease Activity in Patients With Rheumatoid Arthritis Treated With Disease-Modifying Antirheumatic Drugs: A Regression Tree Analysis.

OBJECTIVE: Although pain affects the assessment of disease activity in patients with rheumatoid arthritis (RA), pain is not always directly related to peripheral joint inflammation. Peripheral and central nervous system regulatory mechanisms also affect pain perception. We used regression tree methodology to identify mechanisms most predictive of disease activity after disease-modifying antirheumatic drug (DMARD) treatment. METHODS: Disease activity was evaluated using the Disease Activity Score in 28 joints (DAS28) in 176 patients with RA, before and after starting a DMARD. Quantitative sensory testing (QST), including pressure pain thresholds (PPTs), temporal summation, and conditioned pain modulation (CPM), were used to assess pain mechanisms. Regression tree methodology was used to determine the QST modalities most predictive of DAS28 after DMARD treatment. RESULTS: This analysis identified 4 groups defined by baseline DAS28 category and either knee PPT (a combined measure of peripheral and central nervous system dysregulation) or CPM (a measure of descending pain inhibition). Among patients starting with low/moderate disease activity, lower knee PPT (PPT ≤ 4.65 kgf) most strongly predicted higher posttreatment disease activity (group 1 mean DAS28 2.8 [SD 1.0] vs group 2 mean DAS28 3.5 [SD 1.0]). Among patients starting with high baseline disease activity, less efficient descending pain modulation (CPM ≤ 1.55) most strongly predicted higher posttreatment disease activity (group 3 mean DAS28 3.4 [SD 1.4] vs group 4 mean DAS28 4.6 [SD 1.1]). CONCLUSION: These results highlight the importance of identifying and treating aberrant peripheral and central pain regulation in patients with RA starting or switching DMARD therapy.

Pain Sensitization as a Potential Mediator of the Relationship Between Sleep Disturbance and Subsequent Pain in Rheumatoid Arthritis.

OBJECTIVE: Many patients with rheumatoid arthritis (RA) experience sleep disturbances, commonly attributed to joint pain. Sleep disturbances could also influence pain. One mechanism may be through dysregulated pain processing, manifested by enhanced pain sensitivity. The present study was undertaken to examine the role of pain sensitization, measured by quantitative sensory testing (QST), as a mediator in the pathway of sleep disturbance leading to subsequent pain. METHODS: We used longitudinal data from 221 patients with active RA who were followed for 12 weeks after initiating a disease-modifying antirheumatic drug. Baseline QST included pressure pain thresholds at articular (wrists, knees) and nonarticular (trapezius, thumbnails) sites, temporal summation (TS) at the wrist and forearm, and conditioned pain modulation (CPM). Baseline sleep disturbance and subsequent pain intensity were assessed using the Patient-Reported Outcomes Measurement Information System (PROMIS). We evaluated correlations between sleep disturbance, QSTs, and subsequent pain intensity. Mediation analyses separately assessed each QST as a mediator, adjusting for baseline confounding factors. RESULTS: Sleep disturbance was correlated with all QST measures except wrist TS and CPM. Sleep disturbance significantly predicted subsequent pain (coefficient for a meaningful increase of 5 units in sleep disturbance = 0.32 (95% confidence interval 0.11, 0.50) in multiple regression. QST mediated 10-19% of this effect. CONCLUSION: Pain sensitization may be one mechanism through which sleep disturbance contributes to pain. The small magnitude of association indicates that unmeasured pathways may contribute to this relationship. Intervention studies are needed to establish causality and determine whether improving sleep can improve pain in patients with RA.

Correlation of Fibromyalgia Survey Questionnaire and Quantitative Sensory Testing Among Patients With Active Rheumatoid Arthritis.

OBJECTIVE: Patients with rheumatoid arthritis (RA) commonly demonstrate disordered pain processing associated with high pain sensitization. Pain sensitization is often assessed using quantitative sensory testing (QST), which is burdensome to patients. The self-administered Fibromyalgia Survey Questionnaire (FSQ) has been proposed as a low-burden, surrogate measure of central pain sensitization. We examined the correlation between FSQ and QST in patients with active RA. METHODS: Participants in the Central Pain in Rheumatoid Arthritis (CPIRA) cohort underwent FSQ and QST evaluation at enrollment. QST measures included pressure pain threshold (PPT) at the thumb, trapezius, wrist, and knee; temporal summation (TS) at the wrist and arm; and conditioned pain modulation (CPM). Partial Spearman correlation between FSQ and each QST measure was assessed, adjusted for demographic factors, study site, disease characteristics, and pain catastrophizing. Sensitivity analyses included (1) stratified analysis by sex and (2) evaluation of how each component of FSQ associates with the QST measures. RESULTS: Among 285 participants with active RA, FSQ was weakly but statistically significantly correlated with PPT (r range = -0.31 to -0.21), and TS (r range = 0.13-0.15) at all sites in unadjusted analyses. After adjustment, statistically significant correlations persisted for TS at the wrist and PPT at all sites (except the thumb). Sensitivity analyses did not identify differences in association based on sex or with individual FSQ components. CONCLUSION: FSQ and QST were correlated among participants with active RA, but the strength of association was weak. QST and FSQ are not interchangeable measures of pain sensitization.

Fibromyalgianess and glucocorticoid persistence among patients with rheumatoid arthritis.

OBJECTIVES: Over one-third of patients with RA exhibit evidence of fibromyalgianess, which is associated with higher rates of disability and inadequate responsiveness to RA treatment. Patients with RA often remain on glucocorticoids long-term, despite the known risk of dose-dependent morbidity. We undertook this study to examine the relationship between fibromyalgianess and glucocorticoid persistence among RA patients. METHODS: We followed participants with active RA on oral prednisone for ∼3 months after initiating a new DMARD. Fibromyalgianess was measured using the Fibromyalgia Survey Questionnaire (FSQ), previously shown to correlate with key FM features often superimposed upon RA. Severity of fibromyalgianess was stratified as follows: FSQ <8 low, FSQ 8-10 moderate and FSQ >10 high/very high. The association between baseline fibromyalgianess and glucocorticoid persistence, defined as prednisone use at 3-month follow-up visit after DMARD initiation, was assessed using multiple logistic regression adjusted for baseline demographics, RA duration, serostatus and inflammatory activity assessed using swollen joint count and CRP. RESULTS: Of the 97 participants on prednisone at baseline, 65% were still taking prednisone at follow-up. Fifty-seven percent of participants with low baseline fibromyalgianess had persistent glucocorticoid use, compared with 84% of participants with high or very high fibromyalgianess. After adjustment for non-inflammatory factors and inflammatory activity, participants with high/very high baseline fibromyalgianess were more likely to be taking prednisone at follow-up relative to those with low fibromyalgianess [odds ratio 4.99 (95% CI 1.20, 20.73)]. CONCLUSION: High fibromyalgianess is associated with persistent glucocorticoid use, independent of inflammatory activity.

Association of Dysregulated Central Pain Processing and Response to Disease-Modifying Antirheumatic Drug Therapy in Rheumatoid Arthritis.

OBJECTIVE: To determine the association between dysregulated central pain processing and treatment response in rheumatoid arthritis (RA). METHODS: One hundred eighty-two participants with active RA were followed up for 12 weeks after starting a disease-modifying antirheumatic drug (DMARD). To assess central pain processing, participants underwent quantitative sensory testing (QST), including assessment of pressure pain thresholds (PPTs) at the trapezius muscles, temporal summation, and conditioned pain modulation (CPM). QST measures were categorized as high central dysregulation versus low central dysregulation. The association between baseline central dysregulation and treatment response, as defined by the European League Against Rheumatism (EULAR) response criteria, was assessed using multiple logistic regression adjusted for demographic characteristics, RA-related variables, and psychosocial variables. RESULTS: A good EULAR response was achieved in fewer participants with high CPM dysregulation than participants with low CPM dysregulation (22.5% versus 40.3%; P = 0.01). A similar trend, though not significant, was noted when central dysregulation was assessed with PPT and temporal summation. The adjusted odds ratios (ORs) for the association between high central dysregulation and good EULAR response were 0.59 for PPTs (95% confidence interval [95% CI] 0.28-1.23), 0.60 for temporal summation (95% CI 0.27-1.34), and 0.40 for CPM (95% CI 0.19-0.83). In a model examining the combined effects of dysregulated temporal summation and CPM, dysregulation of both measures was associated with lower odds of achieving a good EULAR response (OR 0.23 [95% CI 0.07-0.73]). CONCLUSION: Low CPM was significantly associated with lower odds of achieving a good EULAR response, suggesting that inefficient descending inhibitory mechanisms may be a potential treatment target for further study.

Association of Pain Centralization and Patient-Reported Pain in Active Rheumatoid Arthritis.

OBJECTIVE: Pain is a significant burden for patients with rheumatoid arthritis (RA) despite advancements in treatment. We undertook this study to examine the independent contribution of pain centralization to the pain experience of patients with active RA. METHODS: A total of 263 RA patients with active disease underwent quantitative sensory testing (QST), including assessment of extraarticular pressure pain thresholds (PPTs), temporal summation (TS), and conditioned pain modulation (CPM). The pain experience was assessed by a pain intensity numeric rating scale and the Patient-Reported Outcomes Measurement Information System pain interference computerized adaptive test. We examined associations between QST measures and pain intensity and pain interference. Multiple linear regression models were adjusted for demographic and clinical variables, including swollen joint count and C-reactive protein level. RESULTS: Patients with the lowest PPTs (most central dysregulation) reported higher pain intensity than patients with the highest PPTs (adjusted mean difference 1.02 [95% confidence interval (95% CI) 0.37, 1.67]). Patients with the highest TS (most central dysregulation) had higher pain intensity than those with the lowest TS (adjusted mean difference 1.19 [95% CI 0.54, 1.84]). CPM was not associated with differences in pain intensity. PPT and TS were not associated with pain interference. Patients with the lowest CPM (most centrally dysregulated) had lower pain interference than patients with the highest CPM (adjusted mean difference -2.35 [95% CI -4.25, -0.44]). CONCLUSION: Pain centralization, manifested by low PPTs and high TS, was associated with more intense pain. Clinicians should consider pain centralization as a contributor to pain intensity, independent of inflammation.

Responsiveness of Patient-Reported Outcomes Measurement Information System Measures in Rheumatoid Arthritis Patients Starting or Switching a Disease-Modifying Antirheumatic Drug.

OBJECTIVE: The Patient-Reported Outcomes Measurement Information System (PROMIS) is a calibrated item bank used to assess patient-reported outcomes across multiple domains. The purpose of this study was to describe the performance of selected PROMIS measures in patients with rheumatoid arthritis (RA) with active disease who were initiating a disease-modifying antirheumatic drug (DMARD). METHODS: Participants in an ongoing prospective observational study completed 8 PROMIS measures before and after DMARD initiation. Linear regression models were performed to identify cross-sectional associations between baseline PROMIS measures and disease activity, measured using the Clinical Disease Activity Index (CDAI). Paired t-tests were performed to evaluate responsiveness after 12 weeks of DMARD treatment. Associations between changes in PROMIS measures and changes in the CDAI score were assessed using linear regression. RESULTS: Among the 156 participants who completed the first study visit, the mean ± SD baseline CDAI score was 25.5 ± 14.0. Baseline scores for PROMIS measures of physical health, pain, and sleep were associated with the baseline CDAI score (P ≤ 0.05). Among the 106 participants with 12-week data, all PROMIS scores improved after DMARD initiation (P ≤ 0.05). With the exception of depression, changes in all assessed PROMIS measures were correlated with changes in the CDAI score (standardized ßs from |0.23| to |0.38|). CONCLUSION: These data provide support for the utility of PROMIS measures for the assessment of physical and mental health in individuals with active RA. All PROMIS measures improved significantly after DMARD initiation, with the magnitudes of association between changes in PROMIS measures and changes in the CDAI score in the low-to-moderate range.

Pain and Catastrophizing in Patients With Rheumatoid Arthritis: An Observational Cohort Study.

BACKGROUND: The aims of this study were to define changes in catastrophizing that occur with initiation of a new disease-modifying antirheumatic drug (DMARD) and to examine the relationship between changes in Clinical Disease Activity Index (CDAI) and changes in catastrophizing. METHODS: Participants in an ongoing multisite, observational study completed the Pain Catastrophizing Scale (PCS) before and 12 weeks after DMARD initiation. We used multivariable linear regression models to examine the association between changes in CDAI as the exposure and change in pain catastrophizing as the outcome. We also assessed the relationship between changes in each component of CDAI and change in PCS, using multivariable linear regression models. RESULTS: Among the 165 rheumatoid arthritis patients with data on CDAI at both time points, CDAI decreased from 22 to 11.5 on a 76-point scale (p < 0.0001) after 12 weeks. Pain intensity decreased from a median of 5 to 3 on a 10-point numeric rating scale (p < 0.0001), and catastrophizing decreased, from 16.0 to 12.0 on the 52-point PCS (p = 0.0005). Among the 163 with complete data for the regression analysis, changes in CDAI were positively correlated with changes in catastrophizing (standardized ß = 0.19, p = 0.01). Of the components of the CDAI, change in assessor global score was most strongly associated with changes in catastrophizing (standardized ß = 0.24, p = 0.003). CONCLUSIONS: Pain catastrophizing decreases, in conjunction with disease activity, after initiation of a new DMARD. These findings provide support for catastrophizing as a dynamic construct that can be altered with treatment directed at decreasing inflammatory disease activity and pain.

Use of rheumatology-specific patient navigators to understand and reduce barriers to medication adherence: Analysis of qualitative findings.

OBJECTIVE: Adherence to medications among patients with rheumatic diseases is often suboptimal. Patient navigators, individuals trained in care coordination, motivational interviewing and basic rheumatology and pharmacology, have not been employed to explore and address this issue. We piloted a single-site, single arm intervention to determine the feasibility and acceptability of using rheumatology-specific navigators to understand and reduce barriers to adherence to oral disease modifying anti-rheumatic drugs (DMARDs). We analyzed our qualitative findings from navigator-patient interactions as well as patient satisfaction with the intervention. METHODS: We recruited patients ≥18 years with a systemic rheumatic disease who initiated an oral DMARD within the prior 6 months. Navigators conducted baseline needs assessments and 2-4 week follow-up calls to understand and address issues related to medication adherence. We analyzed patient-navigator encounters qualitatively using content analysis to identify key themes related to barriers to adherence and navigator actions performed in response to the barriers described. We also categorized intentional and unintentional nonadherent behavior and assessed satisfaction with the navigator experience (range 0-5, 5 = most satisfied). RESULTS: 107 rheumatology patients were followed for up to 6 months. Mean patient age was 55 years (+17) and 93% were female; 36% described one or more episode of intentional or unintentional nonadherence. The three most common themes identified as barriers to adherence were fear of adverse events (raised by 54%), concerns about medication effectiveness (43%), and challenges with medication acquisition (32%). 86% of participants described at least one adherence-related barrier. Frequent navigator actions included facilitation of patient-doctor communication (38%), medication and diagnosis education (27%), and development of individualized strategies to improve adherence (16%). Patients were satisfied with the navigator experience (mean 4.4 + 0.9). CONCLUSION: Navigators uncovered and addressed a number of medication adherence-related concerns and patients were satisfied with the services provided.

Identification of monosodium urate crystal deposits in patients with asymptomatic hyperuricemia using dual-energy CT.

OBJECTIVES: Dual-energy CT (DECT) scan is a sensitive and specific tool used to visualise and quantify monosodium urate (MSU) crystal deposits in the joints. Few studies have examined MSU crystal deposits in patients with asymptomatic hyperuricemia (ie, hyperuricemia in the absence of gout) using DECT. METHODS: We conducted a prospective, non-interventional cross-sectional study to detect MSU crystal deposits on DECT scans among patients with asymptomatic hyperuricemia. We also examined patient factors associated with subclinical MSU crystal deposits. Out of 130 subjects aged ≥40 years with metabolic syndrome screened for serum uric acid (sUA) levels ≥6.5 mg/dL, 46 underwent a foot/ankle DECT scan. RESULTS: The mean age of the study participants was 62 (±8) years, 41% were men and the mean sUA level was 7.8 (±1.0) mg/dL. Seven (15%) of 46 patients had MSU crystal deposits on DECT with a mean total volume of 0.13 (±0.14) cm3. In the univariable logistic regression analysis, older age had a significant association with presence of MSU crystal deposits (OR 1.20, 95% CI 1.03 to 1.39), but sUA did not (OR 1.36, 95% CI 0.63 to 2.95). In the univariable analysis, sUA levels showed a trend towards a modest linear association (ß=0.11, P=0.09) with total volume of MSU crystal deposits. CONCLUSIONS: Fifteen per cent of patients with asymptomatic hyperuricemia had subclinical MSU crystal deposits on foot/ankle DECT scans. Older age, but not sUA, was significantly associated with presence of subclinical MSU crystal deposits among patients with asymptomatic hyperuricemia. Clinical significance of these subclinical MSU crystal deposits needs to be determined.

Association Between Pain Sensitization and Disease Activity in Patients With Rheumatoid Arthritis: A Cross-Sectional Study.

OBJECTIVE: Pain sensitization may contribute to pain severity in rheumatoid arthritis (RA), impacting disease activity assessment. We examined whether pain processing mechanisms were associated with disease activity among RA patients with active disease. METHODS: The study included 139 subjects enrolled in the Central Pain in Rheumatoid Arthritis cohort. Subjects underwent quantitative sensory testing (QST), including assessment of pressure pain thresholds (PPTs) at multiple sites, conditioned pain modulation, and temporal summation. RA disease activity was assessed using the Clinical Disease Activity Index (CDAI) and its components. We examined cross-sectional associations between QST measures and disease activity using linear regression. RESULTS: Low PPTs (high pain sensitization) at all sites were associated with high CDAI scores (P ≤ 0.03) and tender joint counts (P ≤ 0.002). Associations between PPTs and patient global assessments were also seen at most sites. High temporal summation at the forearm (also reflecting high pain sensitization) was significantly associated with high CDAI scores (P = 0.02), patient global assessment scores (P = 0.0006), evaluator global assessment scores (P = 0.01), and tender joint counts (P = 0.02). Conversely, conditioned pain modulation (a measure of descending inhibitory pain pathways) was associated only with tender joint count (P = 0.03). CONCLUSION: High pain sensitization is associated with elevations in disease activity measures. Longitudinal studies are underway to elucidate the cause-effect relationships between pain sensitization and inflammatory disease activity in RA.

Asymptomatic hyperuricemia and coronary flow reserve in patients with metabolic syndrome.

BACKGROUND: Patients with metabolic syndrome (MetS) are at increased risk of asymptomatic hyperuricemia (i.e., elevated serum uric acid (SUA) level without gout) and cardiovascular disease. We conducted a cross-sectional study to examine associations between SUA levels and coronary flow reserve and urate deposits in carotid arteries in patients with asymptomatic hyperuricemia and MetS. METHODS: Adults aged ≥40 years with MetS and SUA levels ≥6.5 mg/dl, but no gout, were eligible. Using a stress myocardial perfusion positron emission tomography (PET), we assessed myocardial blood flow (MBF) at rest and stress and calculated coronary flow reserve (CFR). CFR < 2.0 is considered abnormal and associated with increased cardiovascular risk. We also measured insulin resistance by homeostatic model assessment (HOMA-IR) method and urate deposits using dual-energy CT (DECT) of the neck for the carotid arteries. RESULTS: Forty-four patients with the median age of 63.5 years underwent a blood test, cardiac PET and neck DECT scans. Median (IQR) SUA was 7.8 (7.1-8.4) mg/dL. The median (IQR) CFR was abnormally low at 1.9 (1.7-2.4) and the median (IQR) stress MBF was 1.7 (1.3-2.2) ml/min/g. None had urate deposits in the carotid arteries detected by DECT. In multivariable linear regression analyses, SUA had no association with CFR (ß = - 0.12, p = 0.78) or stress MBF (ß = - 0.52, p = 0.28). Among non-diabetic patients (n = 25), SUA was not associated with HOMA-IR (ß = 2.08, p = 0.10). CONCLUSIONS: Among MetS patients with asymptomatic hyperuricemia, we found no relationship between SUA and CFR, stress MBF, and insulin resistance. No patients had any DECT detectable subclinical urate deposition in the carotid arteries.

Can Patient Navigators Improve Adherence to Disease-Modifying Antirheumatic Drugs? Quantitative Findings From a Six-Month Single-Arm Pilot Intervention.

OBJECTIVE: Nonadherence to disease-modifying antirheumatic drugs (DMARDs) is common, worsens during the treatment course, and results in adverse outcomes. We studied whether patient navigators (laypersons trained in care coordination, motivational interviewing, basic pharmacology, and disease management) improved oral DMARD adherence. METHODS: We enrolled 107 patients ages ≥18 years with systemic rheumatic diseases who initiated an oral DMARD within 6 months. Navigators interacted with patients up to 2-4 times per week for 6 months. Patients completed validated surveys (Morisky Medication Adherence Scale [MMAS-8], Mental Health Inventory [MHI-5], Beliefs about Medicines Questionnaire, and Brief Illness Perception Questionnaire) at baseline and at 6 months. We used paired t-tests to compare baseline and 6-month outcomes. We examined the association of age, race/ethnicity, insurance, and MHI-5 with change in MMAS-8 score using multivariable linear regression. RESULTS: Among 107 patients enrolled, 69 (64%) completed baseline and 6-month MMAS-8 surveys. Mean ± SD age was 55 ± 16 years and 93% were female. The mean ± SD baseline MMAS-8 score was 6.7 ± 1.3 (indicating borderline adherence), and the mean ± SD MHI-5 score was 60.8 ± 9.1 (<68 suggests any depressive symptoms). After 6 months, there were no significant changes in MMAS-8 (P = 0.09) or MHI-5 (P = 0.83). Patients described fewer medication concerns (P = 0.03), but a more threatening perception of illness (P = 0.01). Our multivariable model demonstrated a small change in MMAS-8 for each 5-year increase in age (ß = 0.14, P = 0.02). CONCLUSION: Our intervention resulted in no significant change in adherence from baseline. A multicenter, randomized controlled trial is needed to determine whether patient navigators are effective in maintaining adherence to DMARDs over time.

Non-inflammatory Causes of Pain in Patients with Rheumatoid Arthritis.

Although pain in rheumatoid arthritis (RA) is frequently thought to be inflammatory in nature, the association between measures of inflammation and pain intensity is low. This observation is likely due to the multifactorial nature of pain. In addition to pain from joint inflammation, RA patients may also have pain due to structural damage or central etiologies, such as aberrancies in the central nervous system (CNS) pain regulatory pathways. These CNS pathways include mechanisms that facilitate pain, as well as mechanisms that inhibit pain. Other factors, such as sleep disturbances, depression, anxiety, and catastrophizing, may also impact the perception of pain in RA patients. Since pain is frequently used as a proxy for inflammation in the assessment of RA disease activity, it is important that patients and physicians recognize that not all pain is inflammatory, and alternative management strategies, other than escalating disease-modifying antirheumatic drug treatment, may need to be considered.

Effect of Milnacipran on Pain in Patients with Rheumatoid Arthritis with Widespread Pain: A Randomized Blinded Crossover Trial.

OBJECTIVE: Clinical trials have shown that serotonin norepinephrine reuptake inhibitors, such as milnacipran, decrease pain in noninflammatory pain conditions such as fibromyalgia and osteoarthritis. We examined the effect of milnacipran on self-reported pain intensity and experimental pain sensitivity among patients with rheumatoid arthritis (RA) with widespread pain and stable RA disease activity. METHODS: In this double-blind, crossover study, patients with RA with widespread pain, receiving a stable treatment regimen, were randomized (by a random number generator) to receive milnacipran 50 mg twice daily or placebo for 6 weeks, followed by a 3-week washout and crossed over to the other arm for the remaining 6 weeks. The primary outcome was change in average pain intensity, assessed by the Brief Pain Inventory short form. The sample size was calculated to detect a 30% improvement in pain with power = 0.80 and α = 0.05. RESULTS: Of the 43 randomized subjects, 41 received the study drug, and 32 completed the 15-week study per protocol. On a 0-10 scale, average pain intensity decreased by 0.39 (95% CI -1.27 to 0.49, p = 0.37) more points during 6 weeks of milnacipran treatment compared with placebo. In the subgroup of subjects with swollen joint count ≤ 1, average pain intensity decreased by 1.14 more points during 6 weeks of milnacipran compared with placebo (95% CI -2.26 to -0.01, p = 0.04). Common adverse events included nausea (26.8%) and loss of appetite (9.7%). CONCLUSION: Compared with placebo, milnacipran did not improve overall, self-reported pain intensity among subjects with widespread pain receiving stable RA medications. TRIAL REGISTRATION: ClinicalTrials.gov NCT01207453.