Pain A Complex Issue For Patients With Rheumatoid Arthritis

Although swelling of the joints is the most common cause of pain, even in the absence of swelling, joint pain might persist. This indicates that other, noninflammatory factors might be important contributors to pain.

AUSTIN, Texas — Rheumatoid arthritis (RA) is an inflammatory disease that affects 1% of the US population and commonly causes pain, with 90% of patients with RA rating pain as a top priority.1 Subsequently, a high number of RA patients take pain medications, but many continue to experience daily pain. Even RA patients who are in remission can continue to experience pain, with clinically significant pain reported in approximately 12% of these patients, indicating a need for additional treatment options.1

During the APS 35th Annual Scientific Meeting of the American Pain Society, Yvonne C. Lee, MD, MMSc, at the Brigham and Women’s Hospital, Harvard Medical School, provided an overview of pain in RA and described the results of a study she and her colleagues conducted that assessed a treatment of widespread pain in patients with RA.1

Pain is a complex issue in RA patients, Dr Lee noted. Although inflammation of the joints is the most common cause of pain, even in the absence of swelling, joint pain might persist. This indicates that other, noninflammatory factors might be important contributors to pain. Two such factors that have been previously identified include peripheral pain sensitization and central nervous system (CNS) pain dysregulation.

Previous studies have reported lower pain–pressure thresholds (ie, higher pain sensitivity) in patients with RA compared with healthy controls.2-5 Other studies found changes in the CNS modulation of pain in RA patients compared with matched healthy controls, including enhanced cortical responses to noxious stimulation on electroencephalography and a larger area of hyperalgesia following administration of capsaicin.7 Additionally, sleep problems have been found to contribute to impaired pain processing in RA patients, Lee said.1

The observations that alterations in central pain processing may contribute to pain in RA patients potentially opens the door to new treatment options, including the use of serotonin norepinephrine reuptake inhibitors (SNRIs), such as milnacipran.1,8 Milnacipran (Forest Labs) is considered to be the SNRI with the most balanced norepinephrine (NRI) and serotonin (SRI) ratio and, therefore, to have the most potent relative NRI action. In previous clinical trials, milnacipran has shown efficacy in decreasing pain in patients with noninflammatory conditions, such as fibromyalgia or osteoarthritis.

Dr Lee and colleagues conducted a 15-week, double-blind, crossover study (NCT01207453) in RA patients with widespread pain who were on a stable treatment regimen.1,9 Patients were randomly assigned to receive milnacipran 50 mg daily or placebo for 6 weeks and then completed a 3-week washout period before crossing over to the other study arm for the remaining 6 weeks.

Of the 41 randomized patients who received ≥1 doses of milnacipran, 32 (78%) completed the study. The effect of milnacipran on pain was assessed using self-reported pain intensity and experimental pain sensitivity.

The average pain intensity on a 10-point pain scale only decreased by 0.39 points with milnacipran vs placebo (95% confidence interval [CI], -1.27 to 0.49; P = 0.37); however, a subgroup analysis showed that patients with ≥1 swollen joints reaped greater benefits. In these patients, average pain intensity decreased by 1.14 more points than placebo over 6 weeks of milnacipran treatment (95% CI, -2.26 to -0.01; P =.04).

A challenge with milnacipran treatment was a high number of adverse effects (AEs), with 58% of patients reporting ≥1 AE. The most common AEs included nausea (26.8%), loss of appetite (9.8%), vomiting (7.3%), and sleep problems (7.3%). Fatigue, urinary hesitation, constipation, dizziness, and headache were also reported, with each of these affecting 4.9% of milnacipran-treated patients.

The  study was unique because it was the first to evaluate the therapeutic effect of a pure SNRI in RA. Although the results were not dramatic, the study provides preliminary evidence that milnacipran might be beneficial in certain subsets of patients with RA and that further investigation is warranted to better elucidate its role and that of other SNRIs in managing RA-related pain.


1. Lee YC. Pain in RA: inflammation’s ugly step sister. Presented at: 35th Annual Scientific Meeting of the American Pain Society; May 11-14, 2016; Austin, Texas.

2. Huskisson EC, Hart FD. Pain threshold and arthritis. Br Med J. 1972;4:193-195.

3. Gerecz-Simon EM, Tunks ER, Heale JA, Kean WF, Buchanan WW. Measurement of pain threshold in patients with rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, and healthy controls. Clin Rheumatol. 1989;8:467-474.

4. Konttinen YT, Honkanen VE, Gronblad M, Keinonen M, Santavirta N, Santavirta S. The relation of extraarticular tenderness to infl ammatory joint disease and personality in patients with rheumatoid arthritis. J Rheumatol. 1992;19:851-855.

5. Vladimirova N, Jespersen A, Bartels EM, et al. Pain sensitization in women with active rheumatoid arthritis: a comparative cross-sectional study. Arthritis. Published July 2015. Accessed May 10, 2016.

6. Wendler J, Hummel T, Reissinger M, et al. Patients with rheumatoid arthritis adapt differently to repetitive painful stimuli compared to healthy controls. J Clin Neurosci. 2001,8:272-277.

7. Morris VH, Cruwys SC, Kidd BL. Characterisation of capsaicin-induced mechanical hyperalgesia as a marker for altered nociceptive processing in patients with rheumatoid arthritis. Pain. 1997;71:179-186.

8. Lee YC, Nassikas NJ, Clauw DJ, et al. The role of the central nervous system in the generation and maintenance of chronic pain in rheumatoid arthritis, osteoarthritis, and fibromyalgia. Arthritis Research & Therapy 2011;13:211.

9. Lee YC, Massarotti E, Edwards RR, et al. Effect of milnacipran on pain in patients with rheumatoid arthritis with widespread pain: a randomized blinded crossover trial. J Rheumatol. 2016;43:38-45.