Central Pain in Rheumatoid Arthritis
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.
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.
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: