Studying Remaining Pain
In part one of this series on the role of pain in rheumatoid arthritis / disease, we learned that “Remaining pain” is a term for joint pain that patients experience despite treatment with DMARDs like methotrexate or Enbrel.
Today we discuss a large study about Remaining Pain in rheumatoid arthritis (RA) / rheumatoid disease (RD): Remaining pain is common in early rheumatoid arthritis patients treated with methotrexate.(1) Confusion about Remaining Pain can have devastating effects on patient treatment and on research. Let’s take a closer look.
First, why do we care about a study on Remaining Pain?
Beliefs about “Remaining Pain” are fundamental to treating and curing RD. It is crucial that patients, investigators and clinicians have a proper understanding of rheumatoid disease activity and its response to treatment. Here are three reasons.
3 Consequences of misunderstood Remaining Pain
1) People with rheumatoid disease (PRD) can receive poor care: When doctors do not recognize that disease activity is causing remaining pain, they may respond incorrectly. As a result, PRD may be treated dismissively or receive the wrong drugs for uncontrolled RD.
2) Research dollars can be wasted on flawed theories about Remaining Pain while uncontrolled RD harms more people.
3) Focus on incorrect theories can delay or derail research for better treatments or a cure.
Questions about the Remaining Pain study
The authors state that they specifically use CRP to assess inflammation and disease activity because CRP is “independent of pain.” In fact they say “CRP levels did not correlate with levels of pain or patient’s global assessment” (PGA). This disconnect is actually the most common cause of patient – physician discordance: The doctor looks at a blood test (CRP or ESR) from a single day, while a patient considers all of the painful and disabling symptoms experienced day by day.
The authors claim CRP is an “objective marker” to detect inflammation. But CRP is insufficient for that. If CRP alone is sufficient to detect disease activity / inflammation, what is the purpose of the many disease activity measurement tools? Of musculoskeletal ultrasound (MSUS)? Of numerous other blood tests commonly used in RD? Or of novel markers such as 14-3-3-eta? Or composite tests such as the Vectra DA? If a CRP were a foolproof test for inflammation, why even have joint examinations?
Remaining Pain concerns the majority of people with RD
The investigators found only 9% of those with “increased pain” were “good responders” to methotrexate, but 45% of those with increased pain were “non-responders.” It makes sense that more “non-responders” had increased pain. The question should be with the few who were called “good responders” to medication (meaning less swelling), but had increased pain.
However, the study found most patients have Remaining Pain. “Moreover, remaining pain was present in one-third of patients with a good EULAR response to therapy and in two-thirds of patients with moderate or no response.” A majority had Remaining Pain, including a third of those with a so-called “good response.” The majority of people with rheumatoid disease (PRD) treated with only methotrexate have remaining pain. The authors also quote surveys showing two-thirds of PRD are unhappy with how their pain is managed. Note well that this discussion concerns the majority of us.
THE KEY QUESTIONS ARE
- What does Remaining Pain mean?
- What should be done about it?
The study authors offer a few explanations, none of them adequate. They give nod to terms such as “maladaptive pain coping,” “fibromyalgia-like disease,” and “dysregulated pain thresholds, hyperalgesia and allodynia.” They don’t offer much hope for what they call “treatment-resistant pain conditions.”The majority of people with RD treated with only methotrexate have remaining pain. Click To Tweet
The same old ideas on Remaining Pain
In a moment, I’ll share why I know they’re wrong. And what can be done to help PRD. But first, note how similar their suggestions are to previously debunked explanations of rheumatoid pain, below. These would be great to catch up on or reread when you can.
- Over-focusing (on pain)
- Symptom intensification syndrome / Amplified pain syndrome
- Fibromyalgia syndrome
- Pain processing disorder
- Lowered pain tolerance
- Rheumatoid personality
- Secondary gains
12 Reasons these stale theories on Remaining Pain are still wrong
At one point the study authors question whether Remaining Pain could actually be “sub-clinical inflammation” from RD that’s continuing to simmer. (Yes?) No, they hastily dismiss this idea due to low CRP and low swollen joint counts in the “responders.” Here’s why they are wrong:
- When people with Remaining Pain eventually respond to a therapy, their pain is relieved. I’ve seen this in hundreds of PRD.
- Steroids almost always relieve or significantly reduce Remaining Pain. If steroids relieve pain, it’s likely tied to inflammation. The connection is strong enough that steroids are sometimes used to confirm an inflammatory diagnosis. NSAIDs in high “therapeutic” doses are also used effectively in these PRD.
- Inflammation that’s called subclinical is less obvious to a doctor (in a “clinic”), but is still enough to cause symptoms like pain and stiffness. Ultrasound studies have repeatedly documented that patients judged to be in “remission” clinically (in a clinic, by a doctor), do indeed have persisting inflammation. Subclinical joint inflammation detected by imaging explains why people in “clinical” remission continue to have disease damage.(2) See also my Swelling, Take Two article on the astonishing 2006 study on MSUS and so-called remission in RA.(3)
- Some rheumatoid pain is experienced as part of inflammation, whether or not there is obvious external swelling. Five cardinal signs can exist with inflammation, but all 5 are not required: swelling, redness, pain, heat, and loss of function.(4) The Remaining Pain study determined inflammation solely by CRP.
- RD pain is not like “phantom limb pain,” as some have suggested, coming out of “nowhere.” RD pain fluctuates in response to disease activity or circumstances such as increased usage of a joint. RD pain does not occur in isolation although it inflames some joints more than others.
- Most PRD state that RD pain is sharp, distinct, and persistent like other severe pains they experienced before RD (childbirth, broken bones, kidney stones, surgeries). It does not usually resemble the “dull ache” described in magazines. RD pain is mostly repeated acute pain, not so-called “chronic pain,” a critical distinction.
- Studies have shown damage often continues despite apparent “response” to treatment. That’s why some researchers have begun to detach “clinical disease activity” (swelling) from structural damage.(5) So, “responders” who are still at risk for damage ought not to have their pain dismissed as “not inflammatory mediated.”
- Researchers can divide PRD into subsets (phenotypes) that may impact how people respond to different treatments.(6) PRD differ in presentation (symptom) and response to therapy because of differing immune reactions, not any psychological or moral failure.
- Recent reports cast doubt on the old assumption that damage and inflammation are necessarily linked.(7) If damage and inflammation markers are not necessarily linked, it is risky to patients to assume that lower “inflammation markers” always mean low disease activity.
- Here’s how the study described the methotrexate-treated patients with Remaining Pain: They tended to be older, more disabled, rate their disease as worse (PGA), had a higher 28-tender joint count, higher CRP, and higher DAS28 (disease activity score). Does that sound like they are sicker, or just amplifying their pain?
- The authors define low disease activity as a low CRP level (“As a measurement of objective absence of systemic inflammation at three months follow-up, we used the parameter ‘low inflammatory activity’, defined as CRP level < 10 g/L”) despite the fact that CRP is not always high in the presence of inflammation, whether visible or detected with MSUS.
- Pain and inflammation are not necessarily linked, as new studies document.(8) Specific physical processes can cause pain by acting directly on sensory neurons, possibly the same processes that can cause RD damage or disability without significant external swelling or high CRP. More on this soon.
WHAT IS YOUR EXPERIENCE WITH REMAINING PAIN?
DO PAIN, SWELLING, & DAMAGE ALWAYS OCCUR TOGETHER?
DOES TREATMENT REMOVE ALL PAIN FROM RD?
Stay tuned for PART 3 where you’ll learn why “Remaining Pain” is a useless term. We’ll see how science may unravel this misleading concept. And we’ll consider what is best for people living with rheumatoid disease.
Important to read
- Chronic Pain vs. Recurrent Acute Pain in Rheumatoid Disease
- Some Rheumatologists Don’t Understand How Much It Hurts
- Patient’s Rebuttal to RA Pain Catastrophizing Claims
- What is Rheumatoid Arthritis (RA) / Rheumatoid Disease (RD)? 10 Facts Every Doctor Needs
- What’s the Big Deal about Rheumatoid Disease?
(1) A Reem, S Saedis, Wedrén S, Alfredsson L, Klareskog L, Lampa J. Remaining pain is common in early rheumatoid arthritis patients treated with methotrexate. Arthritis Care Res. Jul 22 2016 (68):8;1061-1068. DOI: 10.1002/acr.22790. Online version available: http://onlinelibrary.wiley.com/doi/10.1002/acr.22790/full
(2) Brown AK, P. G. Conaghan, Karim Z, Quinn MA, K. Ikeda K, Peterfy CG, Hensor E, Wakefield RJ, O’Connor PJ, Emery P. An explanation for the apparent dissociation between clinical remission and continued structural deterioration in rheumatoid arthritis. Arthritis Rheum 2008 Sep 29 (58)10:2958-2967. DOI: 10.1002/art.23945
(3) Brown AK, M. A. Quinn MA, Karim Z, Conaghan PG, Peterfy CG, Hensor E, Wakefield RJ, O’Connor PJ, Emery P. Presence of significant synovitis in rheumatoid arthritis patients with disease-modifying antirheumatic drug–induced clinical remission. Arthritis Rheum. 2006 Dec (54)12:3761–3773. DOI 10.1002/art.22190.
(4) Access Physiotherapy. Concise Pathology, Chapter 3: The Acute Inflammatory Response. Available from http://acccessphysiotherapy.mhmedical.com/content.aspx?bookid=333§ionid=40013175&jumpsectionid=40013682
(5) Villeneuve E, Haraoui B. Uncoupling of disease activity and structural damage. Does it matter clinically? Ann Rheum Dis 2013;72:12. DOI:10.1136/annrheumdis2012202650
(6) Chemin K, Klareskog L, Malmstrom V. Is rheumatoid arthritis an autoimmune disease? Curr Opin Rheumatol 2016, 28:181-188. DOI:1 0.1 097/BOR.0000000000000253
(7) W. Maksymowych , V. Bykerk , K. Siminovitch, M. Boers, R. Landewé, D. van der Heijde, P. P. Tak, M. Genovese, M. Weinblatt, E. Keystone, K. Young, A. Marotta. 14-3-3eta Sero-positivity marks more severe disease and titres inform response to therapy, also in patients with lower CRP. EULAR poster abstract. Available from: http://www.rawarrior.com/14-3-3eta-marker-in-rheumatoid-arthritis-patients-with-low-crp/
(8) Wigerblad G, et al. Autoantibodies to citrullinated proteins induce joint pain independent of inflammation via a chemokine-dependent mechanism. Ann Rheum Dis. 27 Nov 2016;75:730–738. DOI: 10.1136/annrheumdis-2015-208094