Chronic pain is a common complaint in the population.  It is an unpleasant, complex, and perceived experience that places a significant burden on patients and clinicians. Its severity may be mediated by emotion, attitude, and environmental influences, and expressed differently in children and adult of either gender.  This blog considers common and uncommon causes of chronic pain. 

Small-fiber neuropathy (SFN), a disorder of thinly myelinated A-delta and unmyelinated C fibers, is characterized by chronic and severe complaints, such as neuropathic pain and autonomic symptoms. SFN is associated with metabolic, infectious, inflammatory and genetic diseases, but the cause is often idiopathic. The incidence and prevalence of SFN is unknown, but it is probably not rare. In patients with diabetes mellitus, a disease with increasing incidence and prevalence, an estimated 20% have painful neuropathy. This has been largely attributed to small-fiber involvement. Other associated causes include sarcoidosis, systemic lupus, Sjögren disease, plasma cell dyscrasia, B6 intoxication, B12 deficiency, Lyme disease, alcoholism, medication induced, thyroid disease, Celiac disease, chronic leukemia, and a mutation in the novel voltage-gated sodium channel gene, SCN9A. 

Joint hypermobility syndrome is a connective tissue disease characterized by joint instability, chronic pain, and minor skin changes. With about 3% of the general population believed to have joint hypermobility syndrome, it has been largely overlooked as a cause of pain. The disorder lies in the spectrum of Ehlers Danlos Syndrome (EDS), a genetic disorder of joint laxity. Joint hypermobility syndrome also commonly overlaps with neuropathic pain due to small fiber neuropathy resulting from aberrant or deficient innervation of the skin and joints that become traumatized over time. 

Traumatic brain injury (TBI) and concussive injury may be associated with chronic body pain.  The perception of pain can be significantly associated with certain socio-demographic, injury-related, behavioral, and clinical variables. Factors associated with prognosis in post-traumatic headache relate to the severity of TBI, stress, emergence of post-traumatic stress disorder, psychiatric comorbidities, sociocultural and psychosocial factors.  

Trigeminal neuralgia one of the most severe facial pain syndromes with an annual incidence of 4 to 13%. It is recognized by sudden, usually unilateral, severe, brief, stabbing recurrent episodes of pain within the distribution of one or more branches of the trigeminal nerve. Pharmacologic therapy with antiepileptic agents such as carbamazepine or gabapentin, are widely used for the treatment of TN. The neuromodulator serotonin (5-HT) transport system, which inhibits 5-HT into the synaptic cleft, terminating serotonergic neurotransmission, has been implicated in the pain associated with trigeminal neuralgia, as well as, migraine and temporomandibular joint (TMJ) pain. 

Migraine is the most common pain condition in children and adolescents visiting a pediatrician.  Its prevalence increases throughout childhood, affecting up to one-quarter of teenagers. This neurovascular disorder generally presents on a genetic background of migraines in first degree relatives.  Children and adults with recurrent migraine headache can suffer from depression, anxiety, sleep disorders, dizziness, poor school and work performance.  Women with migraine experience heightened attacks during the perimenstrual period. Although there are many prophylactic medications to choose from including alpha antagonists, anti-convulsants, beta-blockers, botulinum-A, calcium channel blockers, serotonin agonists, serotonin reuptake inhibitors (SSRIs), and tricyclic antidepressants (TCAs), one recent analysis found a benefit in tailoring prophylactic medication according to patient characteristics and expected side effects. For example, a beta blocker with concomitant hypertension; SSRI or TCA with known depression; and an anticonvulsant when indicated such as topiramate or valproate.
  
Stroke is associated with chronic pain, particularly when structures along the spinothalamic tract, lateral thalamus, and thalamic–parietal projections are affected. Despite the fact that the classic description of thalamic stroke producing pain was published >100 years ago, the mechanisms underlying the severe, spontaneous, burning pain that occurs with thalamic stroke remain unclear.  Two related disorders of the brain and spinal cord, syringobulbia and syringomyelia, associated with Arnold–Chiari malformation, incur pain due differential alterations in CSF flow and pressure, and syrinx pressure on crossing spinothalamic tracts. 

Neurofibromatosis (NF1) and NF2, lead to formation of benign tumors, the neurofibroma, can arise anywhere in the nervous system including the skin and produce unmanageable pain. Common sites for neurofibromatosis-related tumors include intraspinal, paraspinal, brachial plexus, femoral nerve and sciatic nerve. These tumors illustrate two processes involved in pain: (i) compressive neuropathy where there is nerve sheath involvement; and (ii) the contribution of inflammatory mediators (through mast cells) to pain. In neurofibromatosis-1, these inflammatory mediators induce vascular changes that may lead to vasculo-occlusive disease producing microinfarcts in the vasa vasorum that contribute to painful symptoms. 

Temporal mandibular joint (TMJ) pain affects up to 25% of the population, yet their etiology and progression are poorly understood. This degenerative musculoskeletal condition is associated with morphological and functional deformity in up to 70% of cases, resulting in malpositioning of the TMJ disc, termed “internal derangement.” Although onset is not well characterized, there are correlations between internal derangement and osteoarthritic change. Due to the complex and unique nature of each case, diagnosis requires patient-specific analysis accompanied by various diagnostic modalities. Treatment, likewise, requires customized plans to address the specific characteristics of each patient’s disease.

Fibromyalgia is a chronic, multi-symptom complex that affects an estimated 2% of the population.  In addition to unrefreshing sleep, cognitive difficulties and affective symptoms, there is chronic widespread pain and fatigue. Despite its disabling effects, fatigue has not received the same research attention in fibromyalgia as has pain, for a variety of reasons. First, there is no established nomenclature with which to describe the multiple types and manifestations of fatigue. Second, clinical experience indicates that patients usually do not feel comfortable making an appointment for 'just’ fatigue. And third, the lack of understanding of the mechanisms of fatigue contributes to poor assessment and treatment strategies, and may make providers wary of broaching the topic in a clinical encounter. Traditional teaching requires assessment of “tender points” with a diagnosis of fibromyalgia being made when the patient reported 11 or more of the 18 discrete points during physical examination. While most patients with fibromyalgia satisfy the tender point criteria, it is common for patients to describe other areas of pain and tenderness, along with other comorbid symptoms and diagnoses. Consequently, the American College of Rheumatology created new diagnostic criteria for fibromyalgia that replace the tender point evaluation with a self-report measure of widespread body pain and comorbid symptomatology (fatigue, trouble thinking, waking up tired, depression, abdominal pain/cramps, and headache. 

Complex Regional Pain Syndrome (CRPS) is a chronic pain syndrome that follows nerve injury (either defined or subclinical) and may evolve into a number of other manifestations over time. CRPS type 1 occurs without detectable nerve trauma, and minor injuries or a limb fracture often precede the onset. CRPS type 2 CRPS develops following injury of a major peripheral nerve.  Patients may present with complaints and findings implicating a more widespread disturbance beyond the peripheral nervous system (PNS) to the central nervous system (CNS) and autonomic nervous system (ANS). Such findings include: spontaneous and evoked spreading pain that involves undamaged regions in the affected limb to the opposite limb and other parts of the body with hemi-inattention, tremor, focal dystonia, emotional and cognitive changes; and swelling and skin discoloration. CRPS patients are profoundly affected by their ability to participate in normal activities of daily living.  There is an expanding literature from animal and human research that suggests focal and disseminated effects of cytokine alterations in the PNS and CNS that affect brain circuits through changes in brain glia, astrocytes and neurons.

Shingles is a painful blistering skin rash due to the virus that causes chicken pox. Although the symptoms of acute herpes zoster (AHZ) typically resolves within 2–4 weeks, approximately 10 % of patients develop postherpetic neuralgia (PHN), often defined as pain persisting more than 3 months after the onset of the rash in the same affected area. The risk of PHN increases with age. In the Olmsted County Study, 73 % of PHN cases were in individuals aged ≥ 60 years. PHN pain results from sensory nerve damage and may be intermittent, chronic or spontaneous in nature. PHN symptoms frequently include allodynia, wherein pain is evoked by normally non-painful mechanical stimuli, such as light brushing of the skin. Even with appropriate treatment, PHN pain can interfere with sleep and routine daily activities. Despite the potentially debilitating nature of this disorder, PHN tends to be underdiagnosed and inadequately managed, especially in primary care.  It should be considered in the differential diagnosis of dermatomal pain even in the absence of a preceding rash. 

Mast cells are important cellular regulators of physiological and pathological pain pathways. They induce nociceptor activation through the release of chemical mediators during degranulation and can be activated by mediators released from nociceptors upon injury. Several associations have been reported between mast cell activation and abundance and clinical pain disorders. Migraine attacks are reported to occur with higher frequency in asthma and allergy patients likely suggesting a role for mast cell activation in migraine onset. Bladder mast cell activation was confirmed by electron microscopy in interstitial cystitis patients, while mast cell-derived tryptase levels were increased in expressed prostatic secretions in men with chronic pelvic pain syndrome, and tryptase levels were also increased in the skin of the affected extremities of patients with CRPS.

Inflammatory spine disease as a cause of body pain that is commonplace among those with spondyloarthritis (SpA). Back pain occurs in childhood, late adolescence, and early adulthood. Ankylosing spondylitis and non-radiographic SpA are two ends of the spectrum of axial SpA. The diagnosis can be challenging because patients may not show radiographic changes in the sacroiliac (SI) joints. A key to prompt and accurate diagnosis is finding the HLA-B27 genetic marker in blood tests.  

Pelvic inflammatory disease (PID) can lead to chronic unremitting pelvic pain. PID is characterized by inflammation of the endometrium, fallopian tubes, or peritoneum, and occurs when microorganisms ascend from the vagina or cervix to the fallopian tubes and other upper genital tract structures. Untreated chlamydia and gonorrhea can lead to infertility, ectopic pregnancy, and chronic pelvic pain. There is no single diagnostic test for PID, so most clinicians rely on nonspecific signs and symptoms for diagnosis.
Vulvodynia is a chronic vulvar pain condition. Chronic vulvar pain is reported in 4.0 % of women, including a quarter of women lack vaginal dryness. Women with current chronic vulvar pain symptoms are more likely to have used hormones during the preceding year than women without vulvar pain symptoms. 

Mast cells are important cellular regulators of physiological and pathological pain pathways. They induce nociceptor activation through the release of chemical mediators during degranulation and can be activated by mediators released from nociceptors upon injury. Mast cells release a variety of mediators such as histamine, serotonin, IL-1β, TNF-α, and IL-6, all of which have the ability to independently induce [or mediate chemical-, infection-, or allergen-evoked hyperalgesia via direct effects on nociceptors or by stimulating the production of final mediators such as leukotrienes and prostanoids. Furthermore, mast cells residing in close proximity to unmyelinated nerve fibers, such as the nociceptive C-fibers, can undergo ultrastructural alterations that allow differential or selective “piecemeal degranulation.  Several associations have been reported between mast cell activation and abundance and clinical pain disorders including migraine, pelvic and bladder pain, atopic dermatitis, inflammatory bowel pain, fibromyalgia, vulvodynia, CRPS, self-injurious behavior associated pain. 

Polymyalgia rheumatica (PMR) should be considered when there is diffuse body pain in patients > age 50 years, with morning stiffness duration, non-rheumatoid arthritic hip and shoulder pain and limited range of motion, particularly in association with an elevated blood erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP).  Temporal (TA) or giant cell arteritis (GCA) are due to frank inflammation of cranial arteries. Low-grade fever, malaise, fatigue, anorexia, and weight loss accompanies headache and tenderness over one or both temporal areas.  There is pain in the jaw during mastication, facial pain, and scalp tenderness, and the ESR and CRP are always elevated to > 100 mm/hr. Strokes occur in < 10% of patients due to involvement of the vertebral basilar arterial system. Visual loss which is a medical emergency and due to unilateral anterior ischemic optic neuropathy, warrants prompt treatment with glucocorticoids and low-dose aspirin to prevent irreversible blindness.  

Chronic pancreatitis is an uncommon causes of chronic abdominal pain, but one that should not be missed because of the progressive change in pancreatic morphology and function that accompanies inflammation and fibrosis that can lead to diabetes, pancreatic insufficiency, metabolic bone disease, and even pancreatic cancer.