The overall objective of this proposal is to understand the relationship between central pain regulatory mechanisms, the clinical pain experience (clinical pain intensity, pain behaviors and interference) and treatment response in rheumatoid arthritis (RA) patients with active disease. Chronic pain is a debilitating health problem, affectig over 116 million people. One of the most common causes of chronic pain is arthritis, affecting 22% of the adult population. Pain in RA, the most common systemic inflammatory arthritis, is historically thought to be due to joint inflammation. However, 70% of RA patients rate pain as their number one priority, despite treatment with disease-modifying anti-rheumatic drugs (DMARDs), and approximately one-third do not respond to immunosuppressive therapy. Compared to the general population, RA patients are more sensitive to pain in a widespread distribution, affecting joint and non-joint sites. These observations suggest that RA patients have altered central pain mechanisms. It is not known whether enhanced pain sensitivity, reflecting alterations in central mechanisms, predisposes RA patients to more intense clinical pain, beyond what is expected from joint inflammation. It is also not known whether these patients respond less well to DMARDs, which act on peripheral inflammation, compared with therapies that act on central pain mechanisms. The central hypothesis of this project is that alterations in central pain mechanisms are associated with heightened measures of clinical pain (pain intensity, pain behavior, pain interference) and poor DMARD response.
The specific aims of this proposal are to: 1) determine the associations between central pain mechanisms and pain intensity, pain behaviors and pain interference among RA patients, and 2) evaluate the effects of central pain mechanisms on treatment response. The proposed study will follow 272 RA patients starting or switching DMARD therapy over 12 weeks. To assess overall central pain mechanisms, pressure pain thresholds (the amount of pressure that causes pain) will be measured at both joint and non-joint sites. In addition, two specific types of central pain mechanisms, the descending analgesic pathways and central sensitization, will be assessed. The descending analgesic pathways dampen pain signals extending from the brain to the spinal cord, whereas central sensitization is associated with heightened excitability of the central nervous system neurons transmitting pain. Descending analgesic mechanisms will be assessed using the paradigm of conditioned pain modulation, whereby a painful conditioning stimulus (cold pressor) is used to stimulate the analgesic pathways. Central sensitization will be assessed using the paradigm of temporal summation, whereby a noxious stimulus is given repeatedly, and pain ratings are assessed at the beginning and end of each series. We will examine the association between central pain mechanisms and the primary outcomes of pain intensity and treatment response. The results of this study will have an important positive impact by identifying mechanism-based targets for pain management in systemic inflammatory diseases.

Public Health Relevance

Although pain is the most common presenting symptom of rheumatoid arthritis (RA), little is known about the role of central nervous system pathways in the clinical pain experience and drug response. This proposal examines the association between central pain mechanisms, the clinical pain experience and the assessment of treatment response in RA. The identification of central pain mechanisms associated with clinical pain and drug response will enable us to take the next step in tailoring pain management, using treatments targeted to specific pain pathways.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR064850-02
Application #
8697015
Study Section
Special Emphasis Panel (ZRG1-PSE-P (02))
Program Officer
Witter, James
Project Start
2013-07-01
Project End
2018-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
2
Fiscal Year
2014
Total Cost
$628,087
Indirect Cost
$132,015
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115