Erythrocyte Sedimentation Rate and C-Reactive Protein: Old But Useful Biomarkers for Pain Treatment
The erythrocyte sedimentation rate (ESR or sed rate) and C-reactive protein (CRP) are among the oldest laboratory tests still in use.1-3 Both bloods tests are used to detect inflammation in the body.4-6 Inflammation can present as either acute (ie, from injury or infection) or chronic. Multiple cells are involved in the release of inflammatory mediators, which combine to generate pain in joints, muscle, discs, ligaments, tendons, fascia, etc. Since pain and inflammation are often intertwined, it is my opinion that these two tests can be indicators that pain and inflammation are present, as well as be markers of treatment effectiveness.7 I have found a high prevalence of elevated ESR and CRP levels in my intractable pain patients, which generally return to normal when appropriate pain treatment is initiated or enhanced.8 In my experience, the ESR and CRP tests are very inexpensive and are essentially always covered by insurance plans. Both tests can be part of a complete blood count or ordered separately. Some in-office test kits are available. This article has been inspired due to the fact that inflammatory biomarkers are not routine, but should be in pain practice as inflammation and pain are so intertwined. This article will review the basics of ESR and CRP tests and how they may be helpful to the busy pain practitioner.
Erythrocyte Sedimentation Rate
The ESR rate increases as a result of any cause or focus of inflammation. When an inflammatory process is present, fibrinogen enters the blood in high amounts and causes red cells to stick to each other, which raises the ESR.1 Moderate elevations are common in active inflammatory diseases.1,6 But because the test is often normal in patients with neoplasm, connective tissue disease, and infection, a normal ESR cannot be used to exclude these diagnostic possibilities. The ESR has been profoundly useful in diagnosing and monitoring polymyalgia rheumatica and temporal arteritis, for example, where the elevation is typically 3 to 4 times above normal.1
In my opinion, ESRs also can be very helpful in diagnosing and monitoring chronic pain patients. I have found that about 20% of chronic pain patients referred for medical management have elevated ESRs. After 3 months of opioid stabilization, however, only about 5% to 6% of patients continue to have an elevated ESR.8 It must be emphasized that an elevated ESR in a pain patient poses a diagnostic challenge because the practitioner likely will not know the focus of inflammation—is it in a peripheral pain site or within the central nervous system (CNS, central sensitization)? Even though the mechanism may be unclear, a patient with an elevated ESR should be assumed to have a chronic, inflammatory focus. An attempt should be made to diagnose the focus of the inflammation, which then should be eliminated as part of a pain treatment regimen.
CRP is a protein that was first isolated from the plasma of patients with pneumococcal pneumonia in 1930.2 The protein was so named because it binds to the C-polysaccharide of the pneumococcus. It was later found that the protein appeared in plasma during many infectious or inflammatory conditions.3-6 CRP is synthesized in the liver. Its physiologic role is to bind to phosphocholine expressed on the surface of dead or dying (apoptosis) cells in order to activate the complement/immune system, which enhances phagocytosis by macrophages. Levels of CRP begin to rise within 2 hours of an insult, and has a half-life of about 18 hours. The rapid action of CRP makes it a participant in the acute or first phase of the inflammatory process, which is why it is often called an "acute-phase protein."3,4
Rapid, marked increases in CRP occur with a wide variety of disorders including infection, trauma, tissue necrosis, malignancies, and autoimmune disorders.9-13 Since a large number of disparate conditions can increase CRP production, it cannot be used to diagnose a specific disease such as rheumatoid arthritis. CRP is merely an indicator or biomarker of a disease process that is causing cell death due to inflammation.
Today, a high-sensitivity CRP test, usually designated as hs-CRP, measures low levels of CRP using laser nephelometry.3,4 Several studies suggest that an elevated hs-CRP is predictive of coronary heart disease.14,15 Arterial damage results from white blood cell invasion and inflammation within the walls of coronary arteries. 14 A high hs-CRP, therefore, is a rough proxy for cardiovascular risk. The widespread use and publicity surrounding the association of hs-CRP with heart disease may have obscured its diagnostic role in pain and other non-cardiac conditions.6,9-13 If a pain patient has an elevated hs-CRP, it simply means that there is an active focus of inflammation—be it in the heart, CNS, or elsewhere in the body—and efforts must be made to eliminate it.
Basic Differences Between ESR and CRP
While both are biomarkers for inflammation, ESR and CRP should be interpreted differently. Due to this basic physiologic difference, CRP is a more sensitive and accurate reflection of the acute phase of inflammation than is the ESR. The half-life of CRP is constant, so an elevated level is mainly determined by the rate of production and, hence, the severity of the precipitating cause. In the first 24 hours of a disease process, the ESR may be normal and CRP elevated. The CRP will return to normal, within a day or so, if the focus of inflammation is eliminated. The ESR will remain elevated for several days until excess fibrinogen is removed from the serum (Table 1).
It is unclear whether chronic pain can exist without some inflammation. I make this statement because the ESR and CRP may not be sensitive enough to detect small amounts of inflammation that may occur with neuropathic pain. In fact, ESR and CRP levels are normal in the majority of chronic back pain cases.5,6 In contrast, acute sciatica is associated with high CRP levels.12 In patients with osteoarthritis, ESR is usually normal but CRP may be elevated.6 In fact, the CRP level in osteoarthritis may be a predictive biomarker for severity and duration of the disease.9-11 Remember that the presence of elevated ESR and CRP levels also can indicate the presence of an infection, so neither test can be used as a definitive diagnostic tool for pain or inflammation.
When to Order Blood Tests
It is recommended that all patients who have severe enough chronic pain to require daily pain control medication— antidepressants, neuropathic agents, anti-inflammatory agents, or opioids—be screened for ESR and CRP. The reason is that a high percentage of chronic pain patients will show elevations, and this finding can, over-time, be a good indicator of treatment success. Once high levels of ESR or CRP are detected, these tests should be repeated every 1 to 3 months to help determine whether the pain regimen is eliminating inflammation.