Laboratory investigations

Laboratory studies are conducted to identify disorders that could be primary or contributory causes of a chronic pain disorder. Relatively few laboratory studies contribute substantially to the diagnosis of painful conditions. Inflammatory markers may be among the most important.

Erythrocyte sedimentation rate (ESR) and C‐reactive protein (CRP) are acute phase reactants that function as relatively non‐specific indicators of a systemic inflammatory response. ESR is usually, but not universally, elevated in polymyalgia rheumatica, and CRP is often elevated in this condition as well [2]. Both ESR and CRP are commonly used as markers of active rheumatoid arthritis [3]. Active inflammatory processes that consume complement can be identified by a reduction in circulating complement (C3, C4) levels. Hepatitis C antibody testing is warranted in individuals with unexplained polyarticular pain and idiopathic neuropathy, particularly if clinical or laboratory evidence of hepatic disease is present [4]

Sjögren’s syndrome is an inflammatory disorder that is probably under‐recognized and is commonly associated with widespread pain as well as pain from associated sensory neuropathy [5]. Dry eyes and dry mouth (sicca symptoms) are the fundamental clinical feature. Diagnostic criteria include a combination of clinical, paraclinical and laboratory parameters including autoantibodies against Ro (SS‐A) and/or La (SS‐B) antigens [6]. Many patients who fulfill criteria are seronegative. Nonetheless, Sjögren’s antibody testing should be obtained in patients with unexplained myofascial or neuropathic pain and sicca symptoms

Vasculitides can present with unexplained pain, from diffuse aches and pains that are difficult to pinpoint to more specific pain from nerve infarction or gastrointestinal ischemia. Protoplasmic or classic staining antineutrophil cytoplasmic antibodies (p‐ANCA and c‐ANCA) are more specific markers of systemic vasculitides. c‐ANCA is a highly sensitive marker for Wegener’s granulomatosis, polyarteritis nodosa and Churg–Strauss vasculitis, whereas p‐ANCA is a sensitive marker for vasculitis due to systemic lupus erythematosus, rheumatoid arthritis and Sjögren’s syndrome. Vasculitis is a tissue diagnosis and must be confirmed pathologically; however, these serologic markers can be helpful in providing justification for tissue biopsy and, on occasion, therapeutic intervention pending a tissue diagnosis in the appropriate clinical setting.

There is a strong correlation between spondyloarthritis (a spectrum of conditions including ankylosing spondylitis and reactive arthritis) and HLA B27 positivity. HLA B27 testing can be very helpful in patients with an appropriate clinical syndrome, particularly if imaging studies are non‐diagnostic (see below).

Many rheumatological conditions, such as rheumatoid arthritis, cause chronic multifocal or widespread pain on the basis of inflammatory joint and connective tissue disease. These are diagnosed principally on the basis of clinical criteria with laboratory support.

The following laboratory abnormalities are occasionally obtained, with little evidence of value, in chronic pain states:

1. There is, to our knowledge, no compelling evidence that evaluating thyroid function, serum cortisol or growth hormone levels is of value in the investigation of fibromyalgia [7].
   
2. It has been proposed that reduced levels of 1,25OH vitamin D can be responsible for a reversible widespread pain syndrome, although the evidence supporting this assertion is modest [8].
   
3. Creatine phosphokinase (CPK) is commonly elevated in inflammatory muscle disease, but these conditions are usually painless. CPK is normal in myofascial pain syndromes.

To date neither biomarkers for pain, such as substance P or other inflammatory cytokines, nor known genetic information (such as the role of the pain protecting haplotype for guanosine triphosphate [GTP] cyclohydrolase 1) [9], can be used as independent indicators of pain or the transition from acute to chronic pain [10].

X‐rays

X‐rays are inexpensive, readily available in any medical facility and can provide information about the skeletal system but provide little information about soft tissues. They remain useful investigations for musculoskeletal medicine which are used as starting point to demonstrate degenerative changes in joints, pathologic fractures, diffuse idiopathic skeletal hyperostosis (DISH), scoliosis, tumors with osseous involvement or calcified tendons or cystic and sclerotic changes where tendons insert into bone.

Computed tomography scan

Computed tomography (CT) scan is a two‐dimensional gray‐scale representation of the relative densities of tissues usually acquired axially. CT can provide information regarding both bony structures and soft tissues. Three‐dimensional reconstructions are possible as are multiplanar images that reconstruct axial slices into three‐dimensional images. The main limitation of CT scanning is that it may provide a significant dose of radiation and does not visualize soft tissues as well as magnetic resonance imaging (MRI). CT scanning, often with contrast, may be the investigation of choice when MRI scanning is contraindicated.

Magnetic resonance imaging

Magnetic resonance imaging (MRI) evaluates soft tissues such as discs, tendons, ligaments, cartilage and nerve roots and is sensitive for imaging tumors. A non‐contrast MRI is sufficient in the majority of cases. The addition of intravenous gadolinium allows better imaging of infection, tumor or fibrosis. MRI scans are not good for showing bony cortex architecture because bone cortex has little water content and hence appears as black on MRI scans. MRI scans can show change in marrow signal and can demonstrate bone marrow edema, a non‐specific finding associated with a variety of painful conditions including insufficiency or fatigue fractures, inflammatory or ischemic disorders, degenerative conditions such as osteoarthritis, cartilage defects, tendon abnormalities and complex regional pain syndrome but this is only a surrogate marker of bony cortex architecture. MRI cannot diagnose osteoporosis but quantitative CT (QCT) scanning can be used to evaluate bone density. MRI is more sensitive than bone scan for detection of vertebral compression fractures but CT scans are the investigations of choice for demonstrating abnormalities within bone, a radiodense material.

MRI has a few important limitations. First, the strong magnetic field precludes investigation of patients with metallic fragments in the eye, pacemakers, cochlear implants or some intracranial vascular clips. Most metal placed as part of orthopedic procedures, including spine procedures, is considered permissible. Administration of gadolinium‐containing MRI contrast agents should be avoided in patients with moderately or severely impaired renal function (e.g. estimated glomerular filtration rate <15–30 mL/min).

Magnetic resonance neurography and peripheral nerve evaluation

Magnetic resonance neurography (MRN) and peripheral nerve ultrasonography are emerging techniques for imaging individual peripheral nerves for identification of localized structural abnormalities, such as edema, focal entrapment or hypertrophy due to infiltration or demyelination [27,28] and can be used as a diagnostic adjunct in conditions affecting proximal nerve segments, where the value of EMG/NCS is limited.

A recent study evaluated 239 patients with sciatica who had failed to recover with standard diagnosis and treatment. Using MR neurography and an MR guided piriformis injection of local anesthetic and steroid confirmed piriformis syndrome in 67.8%. Rediagnosis was achieved in all but 4.2% [29]

Myelography and post‐myelogram CT

Myelography and post‐myelogram CT scanning allows visualization of bony structures and neural elements and are indicated when both are needed and MRI is contraindicated. Myelography and upright MRI scanning enable imaging of the thecal sac and emerging nerve roots while weight‐bearing and/or while performing flexion–extension movements. If an infiltrative, malignant or infectious process is being considered, cerebrospinal fluid should be withdrawn for analysis during the procedure. Myelograms are done very infrequently because MRI imaging has evolved to provide the same information previously provided by myelograms.

Nuclear imaging

Nuclear imaging involves detection of gamma radiation produced either as the direct result of radioactive decay (e.g. ^99mTc) or positron‐electron annihilation (e.g. ¹⁵O).

Bone scanning

Bone scanning uses technetium agents that affix to the bone surface by attaching to the hydroxyapatite crystals in bone and calcium crystals in mitochondria. Tracer is increased locally where there is new bone formation because these regions are hyperemic, and increased blood flow exposes the bone to more tracer over a given period of time. Bone scanning can be very sensitive but not very specific, as fractures, degenerative disease and other benign findings may also produce a positive scan and up to 40% of positive findings occur at sites that are asymptomatic. Painful lesions identified by bone scanning include malignancies, prosthetic loosening in a cemented prosthesis (a normal bone scan essentially rules out prosthetic complications), pars defects and complex regional pain syndrome (CRPS), although the yield in early CRPS is limited.

Single photon emission computed tomography

Single photon emission computed tomography (SPECT) scanning allows three‐dimensional views and may improve the localization and characterization of an image. SPECT of known facet joint disease may help to predict which patients are most likely to respond to facet joint injections [11].

Positron emission tomography

Positron emission tomography (PET) scanning is based on the principle that specific radio‐labeled tracers can bind to specific receptors on various tissues, and depending on which tissue and its metabolic step is being studied highly specific tracers are produced. Synthesis of tracers is technologically very involved and available only at imaging centers that specialize in nuclear imaging. PET scanning is most useful in differentiation of malignant and non‐malignant lesions but otherwise has limited use in pain management. False positive results are generally due to metabolically active infectious or inflammatory lesions such as granulomas (fungal or tuberculous) or rheumatoid nodules and are more common than false negative results [12]. PET scanning will have a lower specificity in areas where these types of infection are endemic.

Combined Magnetic Resonance Imaging (MRI) and Positron emission tomography (PET) in the evaluation of neuropathy and musculoskeletal pain

Combined PET/MRI scanning is a promising tool to provide whole body quantitative multiparametric evaluation to assist in determining possible pain generators including inflammation. One technique used to identify the cause of sciatica symptoms used fluorodeoxyglucose (18F‐FDG) as a tracer as it’s uptake is increased in injured nerves and denervated calf muscles in rats. To overcome the poor spatial resolution of PET, patients in this study were simultaneously scanned after tracer in a PET/3TMRI scanner. In 5 of 9 patients, spinal nerve impingement due to a herniated disk was identified as a relevant lesion on the basis of both MRI morphology and high ¹⁸F‐FDG uptake [30].

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