Since pain and inflammation are often intertwined, these two commonly ordered blood tests can be helpful indicators that pain and inflammation are present.

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.

C-Reactive Protein

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.

Clinical Study of ESR

Many clinical reports detail high ESR levels in a variety of clinical conditions. 1 After a literature review, I could not find any prior attempts to show whether pain treatment, per se, will lower an elevated ESR. To this end, I conducted a study of ESR levels in 50 consecutive pain patients referred to my pain clinic by their primary care providers.8 All patients had chronic pain conditions that were not adequately controlled by a daily morphine equivalent dosage of 20 to 40 mg. The causes of pain in these patients were spine ailments (60% [n=30]); neuropathy (24% [n=12]); headaches (4% [n=2]); and miscellaneous (12% [n=6]). None had rheumatoid arthritis, temporal arteritis, or acute infection, which are well known to elevate the ESR. Opioids administered at the time of referral included low dosages of hydrocodone, codeine, or oxycodone. Ten of the 50 patients (20%) had ESRs >20 mm/h (normal: men, 3 mm/h; women, 7 mm/h). Treatment in the first 90 days was simply to increase opioid dosages to a level that controlled the patient's pain and enabled them to function and not be bed- or house-bound. With essentially no other treatment other than increased pain relief with opioids, 7 of the 10 patients (70%) with elevated ESRs returned to normal levels. The mean ESR was reduced from 33.9 mm/h (SD 10.3) to 10.5 mm/h (SD 7.4) (P<0.01). There was no obvious reason why the remaining 3 patients continued to have an elevated ESR. No attempt was made to determine whether one or more chronic, nonrheumatologic pain disorders had more frequent or higher ESRs.

Although the specific focus of inflammation in these patients was unknown, it was probably in the CNS—at least in some patients. Other sites of inflammation could have been in dental structures and the liver, among others.

Clinical Study of CRP

In preparation for this article, I reviewed the CRP results for the last 115 patients referred to my clinic. All these patients had severe, intractable pain; all were already taking opioid medications, but their pain was poorly controlled. A total of 32 patients (27.8%) had elevated CRP levels. Twenty-five of these 32 patients (78%) had their CRP levels return to normal with enhanced opioid therapy, while 7 patients (22%) continued to show an elevated CRP test. While a minority of patients had an elevated CRP, 27.8% is a significant percentage. Patients who were tested were already receiving pain treatment with opioids and other pharmaceutical agents, so the treatment at the time of testing undoubtedly had a positive effect on lowering the CRP. It is also possible and likely that some patients had a high CRP due to severe neuroinflammation. Two case reports illustrate how I interpreted the results.

Case Example #1

A 50-year-old woman with severe spinal degeneration was referred to my pain clinic. Two back surgeries had failed to relieve her pain. The patient had been in severe pain for more than 10 years and it had intensely worsened in the 2 years prior to testing. She was tested for genetic abnormalities and was found to have 2 cytochrome P450 defects, which explained why she had responded poorly to oxycodone and hydrocodone. On referral, the patient's blood test revealed a high hs-CRP level of 6.4 mg/L (normal <1.0 mg/L). She was prescribed hydromorphone to bypass the cytochrome system and her pain markedly reduced. When her blood test was repeated, her hs-CRP level had returned to normal within 90 days.

Case Example #2

A 49-year-old woman with severe fibromyalgia for more than 20 years was seen in my pain clinic. Her pain was reasonably well controlled with a daily oral morphine equivalent of about 400 mg per day. Over 2 years, she has routinely shown, on 6 different blood tests, elevated ESR and CRP levels that were 3 to 5 times above normal levels. No specific focus of inflammation has been identified. This patient described her pain as typical fibromyalgia in that it was "all over." She had received a variety of non-opioid pharmaceuticals including duloxetine, pregabalin, milnacipran, and gabapentin. Numerous physicians including rheumatologists had evaluated her. Although it has been possible to reasonably control her pain with opioids, no therapy has reduced her CRP and ESR. Just why she continues to have an elevated ESR or CRP is unknown, and it may not be related to her pain. Practitioners who test for inflammatory markers need to be prepared that neither a cause nor successful anti-inflammatory treatment can be found.

Elevated CRP Levels Despite efforts to control pain, ESR and/or CRP levels may remain elevated. This is a perplexing and challenging occurrence, which may indicate that active inflammation is somewhere in the body. Unfortunately, the focus of the inflammation may be in the CNS, which can indicate that nerve tissue in the brain is being progressively destroyed. Left unchecked, this could lead to the development of comorbid depression, insomnia, and anxiety.16,17 Even worse, enough tissue destruction may result in deterioration of cognitive abilities and even dementia.

There may be another cause for elevated blood levels of ESR and CRP. During ongoing pain treatment, I have found that elevated ESR and CRP levels can help identify a newly developed clinical problem. This case is illustrative:

Case Example #3

A 60-year-old woman has had bilateral hip replacement for congenital dysplasia. Her pain was well controlled and routinely she had normal ESR and CRP levels. Rather acutely, she developed severe pain in one hip. Her ESR and CRP levels rose to 1.5 to 2.0 times normal and remained so until one of the original hip replacements was removed and a second one placed.

This case illustrates the point that a new pain flare or setback during ongoing treatment can be evaluated and diagnosed by ordering ESR and CRP blood tests.

Summary

ESR and CRP are very old biomarkers of inflammation. Elevated levels only indicate that there is a focus of inflammation somewhere in the body, but the tests can not pinpoint the exact location of inflammation. Elevated ESR and CRP levels in a pain patient usually revert to normal with adequate pain treatment. Until biomarkers specific for neuroinflammation are developed and available, I suggest that the ESR and CRP can be used as routine aides to detect inflammation and monitor treatment effectiveness. Before testing, check with your patient's insurance carrier to make sure such testing is covered. In my experience, these are almost always covered, as they are inexpensive. Once high levels are detected, the patient should have repeat tests every 1 to 3 months to help determine whether treatment is successful in reducing inflammation. Further studies will be needed to confirm the value of ESR and CPR as biomarkers of pain and treatment effectiveness.