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9 Articles in Volume 17, Issue #3
Anxiety and Pain
Central Pain in Rheumatoid Arthritis
Imagine Dragons’ Dan Reynolds Educates People About Ankylosing Spondylitis
Letters to the Editor: Ehlers-Danlos Syndrome, Arachnoiditis
Managing Cancer-Related Pain: A Look at Alternative Approaches
Pain Management in the Elderly: Focus on Safe Prescribing
Painful Genetic Diseases
Responding to Women's Pain Early and Effectively
The 5 Most Misunderstood Terms in Pain Medicine

Central Pain in Rheumatoid Arthritis

It is important to evaluate patients for signs of central sensitization to better define a treatment protocol.

Traditionally, rheumatoid arthritis (RA) has been thought to be a peripheral inflammatory joint disease, with immune mechanisms at the local level triggering cytokine activation, which results in joint inflammation, progressive structural joint damage, and pain. However, we now recognize that central pain is an important aspect of RA.

Patients should be evaluated for signs of central sensitization to better define a treatment plan.

Central pain—which emanates from the central nervous system and does not require peripheral structural, immune, or neuropathic activation—is the primary mechanism of many chronic pain disorders, including fibromyalgia (FM), irritable bowel syndrome, chronic headaches, chronic fatigue syndrome, and pelvic/bladder pain syndromes.

Over the past 20 years, there has been a growing body of research demonstrating central pain in RA. The strong association between RA and FM also has provided clues that central pain must be considered in patients with RA. This article will review these studies and provide guidelines to best recognize and treat the central pain associated with RA.

Research Studies

Evidence for altered central pain sensitivity in RA was found more than 2 decades ago. In a small study of 4 RA patients, Jones et al observed changes in central opioid binding, as detected by significant increases in [11C] diprenorphine binding, in association with a reduction in pain.1

The investigators saw increases in 11C in most of the areas of the brain other than the occipital cortex. They then compared changes in regional cortical blood flow after painful stimuli in 6 RA patients and healthy controls.2 They found decreased cortical and subcortical pain response in the RA patients compared with the controls. They compared reduced anterior cingulate responses to heat pain with the increased cingulate responses seen in patients with psychogenically maintained pain (who had both lower pain tolerance and lower mood than the RA group).

Leffler et al found that RA patients with more than 5 years of symptoms showed generalized allodynia to pressure as well as increased sensitivity to light touch and hyperalgesia to innocuous cold.3 These patients also had pressure allodynia at the thigh, and lower pressure pain thresholds (PPTs) than healthy controls at joint and non-joint sites.

A pain model based on the recording of cortical chemo-somatosensory event-related potentials (CSSERP) after painful stimulation of the nasal mucosa demonstrated pain hypersensitivity in RA patients.4 When the investigators performed repetitive stimulation with an interval of 2 seconds, the CSSERP amplitudes were significantly greater in RA patients than controls.

In another pain study, Shenker et al found contralateral hyperalgesia and allodynia following intradermal capsaicin injections to be similar in RA subjects and controls.5 However, compared to controls, RA patients displayed general hyperalgesia to mechanical and thermal stimuli across several body sites.6

In addition, although serum cortisol levels at baseline or following pain testing did not differ in RA patients relative to controls, the RA patients tended to show elevations in serum interleukin 6 and demonstrated enhanced pain-reactivity of serum levels of tumor necrosis factor-a compared with the healthy controls. This suggests possible immune activation related to heightened pain sensitivity.

A study of inflammatory markers found that C-reactive protein (CRP) levels were inversely associated with pain thresholds at joint sites but not at non-joint sites in 59 RA patients.7 Sleep disturbances were associated with decreased pain thresholds, at both joint and non-joint sites, as well as the number of tender points and FM, suggesting a central mechanism linking pain sensitivity and sleep problems (Figure 1).

A systematic review of RA found substantial evidence for central sensitization in RA.8 The review focused on increased windup in RA, as well as generalized hyperalgesia at both articular and nonarticular sites for different kinds of stimuli.

Wartolowska et al found that RA patients had an increase in gray matter in the basal ganglia (mainly in the nucleus accumbens and caudate nucleus) compared with controls.9 The RA subjects also had a smaller intracranial volume (Figure 2). The investigators postulated that these changes may result from altered motor control or prolonged pain processing.

Incidence of FM in RA

The other evidence for central pain in RA is the common comorbidity of RA and FM. The overall prevalence of FM in patients with RA has been reported to be between 13% and 17% (Figure 3).10-12 Thirty-four percent of RA patients reported chronic widespread pain (CWP).13

Patients who have FM and RA are more likely to be female, older, higher functioning, and have longer morning stiffness compared with patients with only RA.

In addition, RA disease activity scores and poor function were significantly higher in patients with RA and FM than in patients with RA only. In a report on early-onset RA from Canada, the incidence of FM varied from 3.6 to 6.8 cases per 100 person-years, and was highest during the first year of RA.14

The Canadian investigators found that the presence of joint inflammation or seropositivity (testing positive for rheumatoid factor or anti-cyclic citrullinated peptides [anti-CCPs], or both) did not correlate with concurrent FM, but the severity of pain and the presence of poor mental health did.

These investigators15 then grouped the RA patients into 3 clusters:

  • Cluster 1 consisted of 89 individuals with low levels of inflammation, pain, fatigue, and psychosocial distress
  • Cluster 2 consisted of 57 individuals with low levels of inflammation but high levels of pain, fatigue, and psychosocial distress
  • Cluster 3 consisted of 23 individuals with active inflammatory disease, manifested by high swollen joint counts, high CRP levels, and high levels of pain and fatigue

They subsequently examined the association between the multibiomarker disease activity (MBDA) score, CRP, and clinical disease activity measures among RA patients with and without concomitant FM.16 MBDA scores frequently indicated RA disease activity when CRP did not. They found that neither MBDA nor CRP were significantly greater among patients with RA and FM versus RA alone. They concluded that most patients had low levels of inflammation and nearly 50% of those with high levels of pain and fatigue had evidence of CWP/FM rather than persistently active RA. This is an important sign that central pain should be strongly considered.

Lage-Hansen et al found that patients with concomitant FM and RA had higher 28-joint Disease Activity Score (DAS28) related to subjective symptoms and were more frequently treated with biologic agents.17 They identified 25 patients (15.4%) with concomitant FM, and found no group differences with respect to disease duration, age, gender, and serological status. They found that 64% of the RA patients with concomitant FM were treated with biologic therapy compared with 32% of RA patients without concomitant FM. How the patients responded to therapy was not part of the study. The mean DAS28 in the FM/RA group was 4.4 compared to 2.9 in the RA-only group. Elevated DAS28 in the FM group resulted from a high tender joint count and greater pain, as reported by high visual analog scale (VAS)-global score, whereas erosions were more frequent in the RA-only group.

Joharatnam et al evaluated 50 subjects with stable, long-standing RA for PPTs at the knee, tibia, and sternum, and assessed their function using the DAS28 as well as information about their FM symptoms and mental health status.18 Greater PPTs, both over the joints and distant from joints, were associated with greater reported pain, higher patient-reported DAS28 components, and poorer mental health. Nearly 50% of the RA patients satisfied classification criteria for FM.

Concurrent FM was associated with more sensitive PPTs, increased DAS28 scores, and poorer mental health. Similarly, in a study of patients recently diagnosed with RA, concomitant FM resulted in higher activity scores and similar response to treatment; however, these patients also missed the target of remission or low disease activity with treatment with both biologic agents and traditional FM therapy.19

Using the validated painDETECT questionnaire, Koop et al found 20% of RA patients to have neuropathic symptoms.20 The presence of neuropathic pain correlated with meeting the diagnostic criteria for FM, treatment with analgesics, occurrence of more tender joints, and a worse physical and mental health status.

Doss et al conducted an electronic health record review of more than 2,000 RA patients, including 63% with seropositive RA, and found a strong association of FM with seronegativity, with an odds ratio of 1.8.21

Using ultrasound of the hands and wrists, Mian et al found RA patients with concomitant FM to have fewer inflamed joints than in those without FM.22 The RA patients with FM, despite having less synovitis, had higher disease activity scores and greater depression, disability, and fatigue.

A recent prospective study of 156 RA patients found that 17% had FM, and the presence of FM was a predictor of worse functional outcomes.23 At baseline, the RA/FM group had greater disease activity (DAS28/CRP, Polysymptomatic Distress Scores [PSD, a proxy for FM]), mood disorders (HADS), and Multi-Dimensional Health Assessment Questionnaire (MDHAQ) scores (Figure 4). RA patients with FM had significantly worse disease activity scores over a 2-year period using the MDHAQ. PSD scores significantly correlated with increases in the MDHAQ score.

Clinical Implications— Recognition and Treatment

Sleep Disturbances—As noted above, sleep disturbances are more prominent in RA/FM patients than in RA patients without concomitant FM.7 Even in RA patients who do not meet criteria for FM, sleep disturbances are common and correlate with increased disease activity and with generalized pain, fatigue, and mood disturbances.24,25 The widespread heightened pain sensitivity in RA patients compared with controls, as measured by quantitative sensory testing, was linked to sleep problems, as well as to pain catastrophizing (a negative cascade of cognitive and emotional responses to actual or anticipated pain), depression, and anxiety.26

Mood Disturbances—It has been difficult to separate the influence of mood disturbances from those of sleep disturbances in RA, RA/FM, and FM. It is clear that depression and anxiety are prominent in all 3 conditions. The strong association of pain and depression, often termed the pain/depression dyad, is discussed in detail in Chapter 5 of Chronic, Widespread Pain: Lessons Learned from FM and Related Disorders.27 

Rates of depression in RA vary from 15% to 40%. RA patients are twice as likely as controls to develop depression.28 Depression has an adverse impact on all outcomqae factors in RA.29 However, most studies have not accounted for the subset of RA patients with concurrent FM. The recent studies discussed above show that the RA/FM patients have a significantly greater burden of both sleep and mood disturbances.14,15,26

Therefore, it is recommended that every RA patient be screened for sleep and mood disturbances. In RA patients reporting high levels of pain despite little evidence of worsening joint inflammation, it is likely that central pain is a prominent factor (Table 1). Patients who generally report widespread muscle and joint pain likely will have little active synovitis on physical examination, and, generally, the erythrocyte sedimentation rate (ESR) and/or CRP will not be elevated. These RA patients should be evaluated carefully for FM and concomitant sleep and mood disturbances. This may require referral to a rheumatologist, sleep specialist, and mental health professional. The treating clinician should avoid adding more medications that target RA and should consider non-pharmacologic and pharmacologic therapy recommended for FM and chronic, widespread pain (See Chapters 12-14, Chronic, Widespread Pain: Lessons Learned from FM and Related Disorders).27


In conclusion, there is strong evidence that central sensitization plays a role in RA. It is important, therefore, to screen RA patients for signs of central sensitization and concomitant FM. Central pain sensitivity impacts disease activity measures in RA and other inflammatory rheumatic conditions. Once identified, patients with signs of central sensitization and RA should be treated on an individual basis, factoring in treatment of RA and CWP, as well as sleep and mood disturbances.

Dr. Goldenberg has just completed his latest book, covering all aspects of identifying and treating FM and related diseases, titled Chronic, Widespread Pain: Lessons Learned From Fibromyalgia and Related Disorders. To purchase the  e-book, click here and use the promo code READPPM for a 15% discount.

Last updated on: June 13, 2017
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