CHAPTER 11

Other Pain Syndromes

EPIDEMIOLOGY

EPIDEMIOLOGY OF WIDESPREAD PAIN

Definition

•  ≥4 anatomic sites (with bilateral counting one) for 3 months or longer although not universally accepted

Prevalence

•  Up to ~10% by survey in adult population

•  Fibromyalgia (FM): most common (MC) cause of widespread pain (up to 3%), varies by geography (1)

•  Female > male, bell-shaped curve in age prevalence (highest between 60 and 69 years)

Risk factors

•  Depressive symptoms, psychiatric disorder, and sociocultural factors (more important than regional pain syndrome) in addition to mechanical factors (2)

EPIDEMIOLOGY OF CANCER PAIN

Prevalence

•  Varies widely due to lack of standardization in definition and heterogeneity of classification

•  High prevalence of pain in several cancers (up to 90%): head and neck, prostate, uterine, genitourinary, breast, and pancreatic (International Association for the Study of Pain)

EPIDEMIOLOGY OF COMMON NEUROPATHIC PAIN CONDITIONS (3)

Prevalence

•  In general population: ≥1.5%

•  Chronic pain with neuropathic pain character: ~7%

•  Peak in age 50 to 64 years old (YO)

DIFFERENTIAL DIAGNOSIS

FLOWCHART 11.1

Classification of diffuse pain syndrome.

GENERALIZED MUSCULOSKELETAL PAIN (FLOWCHART 11.1)

Differential diagnosis of polyarthralgia

•  Acute polyarthralgia

      Acute migratory polyarthritis: Neisserial (gonorrhea) infection, reactive or postinfectious arthritis (acute rheumatic fever, Reiter’s syndrome, poststreptococcal arthritis), early stage of Lyme disease, viral infection (rubella, mumps, Epstein–Barr virus [EBV]), serum sickness (occasionally), and acute leukemia

      Acute nonmigratory polyarthritis: rheumatoid arthritis (RA), polyarticular juvenile RA, serum sickness, systemic lupus erythematosus (SLE), acute phase of seronegative spondyloarthropathies (psoriatic arthritis, Reiter’s syndrome, ankylosing spondylitis (AS), enteropathic arthritis), crystal-induced disease, sarcoidosis, vasculitis, hematologic disorders (leukemia, sickle cell, lymphoma), serum sickness, viral arthritis (HIV, EBV)

•  Chronic polyarthralgia

      RA, polyarticular juvenile RA, SLE, sarcoid arthritis, connective tissue disease or overlap syndrome, and the like

Differential diagnosis of generalized myalgia (4)

•  Without muscle weakness (or mild weakness with pain)

      Polymyalgia rheumatica (PMR)

      FM

      Myalgia in collagen-vascular disease and myalgia in infection or fever

      Muscle pain-fasciculation syndrome

      Steroid withdrawal, hypothyroidism

      Parkinsonism

      Fabry’s disease

•  With muscle weakness

      Inflammatory muscle disease (polymyositis, dermatomyositis, etc.)

      Infection

  Trichinosis, toxoplasmosis, poliomyelitis, West Nile virus infection, viral syndrome

  Secondary to bacterial toxin, for example, toxic shock syndrome

      Toxic and metabolic disorders

  Hypophosphatemia, potassium deficiency, total parenteral nutrition (essential fatty acid deficiency)

  Acute alcoholic myopathy

  Necrotic myopathy secondary to malignancy

  Hypothyroid myopathy

  Carnitine palmitoyltransferase 2 deficiency (autosomal recessive, most common inherited disorder of lipid metabolism affecting skeletal muscles)

      Medications (lipid-lowering agent, ± weakness)

      Amyloidosis

      Osteomalacia, hyperparathyroidism

DIFFERENTIAL DIAGNOSIS OF DIFFUSE NEUROPATHIC PAIN (FLOWCHART 11.2)

FLOWCHART 11.2

Classification of diffuse neuropathic pain.

Source: Adapted from Ref. (5). Baron R, Binder A, Wasner G. Neuropathic pain: diagnosis, pathophysiological mechanisms, and treatment. Lancet Neurol. 2010;9(8):807–819.

CMT2B, Charcot–Marie–Tooth disease type 2B; HAART, highly active antiretroviral therapy; MC, most common; PN, peripheral neuropathy.

PHYSICAL EXAMINATION

EXAMINATION FOR NEUROPATHIC PAIN (3)

DIAGNOSTIC STUDIES

SEROLOGIC TESTS (8)

•  Basic serologic workup: complete blood count (CBC), basic metabolic panel, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), thyroid function test

•  Rheumatologic workup (see Chapter 1, Other Workup section)

•  Serologic test for peripheral neuropathy: glucose, serum B12, serum protein electrophoresis (SPEP; immunofixation)

      Genetic test: Charcot–Marie–Tooth disease type 1A (CMT 1A; PMP 22 duplication)/hereditary neuropathy with liability to pressure palsies (PMP 22 deletion), Cx 32, GJB 1 mutation (CMT X linked), GQ1b (Miller Fisher variant of Guillain–Barré syndrome [GBS]), and GM1Ab (multifocal motor neuropathy)

ELECTRODIAGNOSIS (9)

•  Evaluation of large diameter nerve fiber

      Large fiber-mediated symptoms: numbness, proprioceptive loss (ataxia), or tingling

      Limited in small fiber neuropathy (without large fiber involvement)

  Small fiber mediated symptoms: pins and needles, burning sensation consider small fiber study such as epidermal nerve fibers density in skin biopsy or autonomic nervous system study

      Radiculopathy involving motor (subclinical and clinical) segment and axonal involvement

  Pure sensory radiculopathy (preganglionic lesion) or focal demyelination lesion: negative in electromyography (EMG) test somatosensory evoked potential study may show abnormality

•  Nerve conduction studies (NCS) and needle EMG

      Sensory NCS: sural, superficial peroneal ± medial plantar (may be more sensitive for distal peripheral neuropathy), ulnar, radial, and median nerve

      Motor NCS: posterior tibial, deep peroneal, ulnar, and median, with F waves (can be more sensitive)

      H reflex to evaluate S1 root, sciatic, tibial nerve, or multifocal lesion (eg, demyelinating neuropathy)

      Needle EMG study: motor nerve involvement (axonal involvement, limited in focal demyelinating lesion) and muscle pathology

•  Interpretation

      Findings suggestive of demyelinating lesion: conduction block, delayed distal latency, and F wave latency (>125% of upper limits of normal), decreased conduction velocity <70% of lower limits of normal)

      Findings suggestive of axonal lesion

  Reduced amplitude or unobtainable action potentials in nerve conduction study

           –  Sensory nerve action potential effected more than compound motor action potential (CMAP); CMAP amplitude is less affected due to compensation mechanism with terminal sprouting

           –  Cautious of conduction block (can be misinterpreted as axonal lesion if stimulation is at proximal to the lesion)

  Abnormal spontaneous activity and neuropathic motor units (decreased recruitment and increased duration of motor unit action potential) in needle EMG

      Mixed pattern

OTHER DIAGNOSTIC TESTS

•  Workup for autonomic (or small fiber) neuropathy; only available in selective centers

      Three main tests for sudomotor response (sympathetic cholinergic efferent); the quantitative sudomotor axon reflex test (QSART), the thermoregulatory sweat test (TST), and sympathetic skin response

•  Nerve biopsy: rule out vasculitis, sarcoidosis, chronic inflammatory demyelinating polyneuropathy (CIDP), infectious disease (eg, leprosy), tumor, and amyloidosis

IMAGING TESTS

•  Anatomic diagnosis and possible underlying structural evaluation

•  Evaluation of central nervous system (spinal cord and brain): MRI of cervical, lumbar, and thoracic spine and brain

GENERALIZED MUSCULOSKELETAL PAIN

FIBROMYALGIA

Introduction (10)

•  Epidemiology: most common cause of generalized musculoskeletal pain in women between the ages of 20 and 55 years

      Prevalence: 2% (up to 8% in some studies), increases with age, female > male by 2 times or more

•  Etiology and risk factors

      Unknown etiology; not associated with tissue inflammation

  Muscle pathology is secondary to pain and inactivity rather than primary cause

      Many physical and/or emotional stressors may trigger or aggravate symptoms

      A disorder of pain regulation (central sensitization); altered pain processing

      Oxidative stress and mitochondrial dysfunction or neurohormonal perturbation

      Others: sleep abnormalities, autonomic system dysfunction, and altered immune system

•  Prognosis

      Little change in the patient’s symptoms (pain and fatigue) after an average follow-up of 14 years

      Two-thirds of patients work full-time

History and physical examination

•  History

      Chronic, generalized pain involving both sides of the body and above and below the waist

  Pain may initially be localized, often in the neck and shoulders

  ± Swelling (without history of synovitis) and paresthesia

      Fatigue

      Sleep disturbances

  Waking frequently during the early morning and having difficulty getting back to sleep

      Cognitive disturbances

  Difficulty with attention and doing tasks that require rapid thought changes

      Mood disturbances: depression and/or anxiety in 30% to 50%

      Headache: >50%, migraine and muscular (tension) types

      Irritable bowel syndrome, pelvic pain, and bladder symptoms of frequency and urgency

      Others: ocular dryness, multiple chemical sensitivity, palpitations, dyspnea, vulvodynia, dysmenorrhea, sexual dysfunction, weight fluctuations, night sweats, dysphagia, dysgeusia, and orthostatic intolerance

•  Physical examination

      Multiple tender areas of muscles and tendons (not required for the diagnosis)

  ≥11/18 tender points, both above and below the waist, and affecting both the right and left sides of the body (sensitivity >85%, specificity >85%; Figure 11.1)

  The amount of pressure: ≥4 kg/cm² (enough to whiten the nail bed of the examiner’s finger tip)

  Control locations: over the thumb, the mid forearm, or the forehead (less tender generally)

      Joint examination: for signs of synovitis and tenderness over the joint line

      Normal neurological examination (can have concomitant problem or minor abnormalities)

FIGURE 11.1

Tender points in fibromyalgia.

Diagnosis

•  Clinical diagnosis (diagnosis of exclusion) using diagnostic criteria (11)

      Widespread pain index (WPI) ≥7 and symptom severity (SS) scale score ≥5 or WPI 3–6 and SS scale score ≥9. Duration of symptoms ≥3 months

      WPI: involvement of pain or tenderness during past 7 days, 0–19

  Neck, jaw left/right (L/R), shoulder girdle L/R, upper arm L/R, lower arm L/R, chest, abdomen, upper back, lower back, hip (buttock, trochanter) L/R, upper leg L/R, lower leg L/R

      SS scale

  The SS scale score: the sum of the severity of the three symptoms (fatigue, waking un-refreshed, cognitive symptoms, 0–3 each) plus the extent (severity) of somatic symptoms in general (0–3)

           –  No symptoms (0); few, intermittent, mild symptoms (1); a moderate number of symptoms (2); continuous, severe, and life disturbing (3)

  For each of the three symptoms just noted, indicate the level of severity over the past week using the following scale (total score: 0–12)

•  Laboratory tests; unremarkable

      CBC, ESR, CRP, BMP, TSH (antinuclear antibody [ANA], RF only if significant clinical suspicion of inflammatory, systemic rheumatic disease, otherwise very poor predictive value; CPK if any suspicion of inflammatory muscle disease)

  10% to 15% of FM patients have + ANA; also + in 5% to 10% of healthy women

•  Differential diagnosis (often concomitant)

Abx, antibiotic; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; HTLV, human T-cell lymphotropic virus; RA, rheumatoid arthritis.

Treatment

•  Education of chronic but generally nonprogressive nature of FM

•  Identify and treat other coexisting disorders (especially treatable) (eg, depression, restless legs syndrome, sleep apnea, regional musculoskeletal disorders, etc)

•  Oral medication

      Initial: low dose of a tricyclic antidepressants (TCA) (amitriptyline 25 mg or nortriptyline 10–25 mg) qhs or cyclobenzaprine 5 mg tid

      If (+) more problems with sleep: amitriptyline 25 mg initially (to 199 mg qhs [1st])

  Pregabalin 75 mg qhs (2nd) upto 150 mg bid, gabapentin 200 to 3,600 mg/d (alternative, cheaper)

      If (+) more exhaustion: duloxetine 30 mg qd or milnacipran q 12.5 mg a.m. initially

      Combination: serotonin–norepinephrine reuptake inhibitors (SNRI) q a.m. + anticonvulsant q p.m.

      Nonsteroidal anti-inflammatory drugs: not effective, not recommended as first-line. May have synergistic effect in combination with central nervous system active drugs

      Problems: high noncompliance, ~50%

•  Low-impact aerobic activities

      Walking, biking, swimming, or water aerobic exercises

•  Cognitive behavioral therapy: most effective if combined with an ongoing exercise program

•  For nonresponders

      To confirm the diagnosis and provide additional advice on management

      Multidisciplinary therapy may be most useful in such patients

POLYMYALGIA RHEUMATICA (PMR)

Introduction (13)

•  Incidence: <2 (Japan) to 113 (Norway)/100,000

      Female > male by 2 to 3 times

      Age: >50 YO, prevalence: 700/10⁵, >50 years, average age at diagnosis: >70 years

•  Associated with giant cell (temporal) arteritis (GCA)

      Prevalence of PMR > GCA by 2 to 3 times

      PMR occurs in ~50% of patients with GCA and 15% to 30% of patients with PMR eventually develop GCA

•  Etiology: unknown

      Both environmental and genetic factors

  HLA-DR4, similar sequence polymorphism within the hypervariable region of the HLA-DRB1 increased (similarity between PMR and GCA)

  A cyclical pattern in incidence and seasonal variation

•  Prognosis

      Self-limited course over months to years

      No evidence of increased mortality associated with PMR

History and physical examination

•  Subacute or chronic aching pain and morning stiffness in the shoulders, hip girdles, neck, and torso, usually symmetric

      Shoulder pain (70%–95%), hip/neck pain (50%–70%); worse with movement; may interfere with sleep

      Morning stiffness ≥30 (to 45) minutes

  Bilateral aching and morning stiffness (≥2/3: neck or torso, shoulders or proximal regions of the arms, and hips or proximal aspects of the thighs; ≥30 minutes) for ≥1 month

•  Joint swelling, pitting edema of hands/wrists and ankles/feet (dorsum), and tenderness

      Synovitis and bursitis: ~50%, palpable synovitis in more peripheral joints (knees, wrists, and metacarpophalangeal [MCP] joints); mild, nonerosive, and asymmetric

    º  Tenosynovitis: can be the presenting symptom (± paresthesia: carpal tunnel syndrome: 10%–15% of PMR patients)

•  Mild muscle tenderness (likely from synovial or bursal rather than direct muscle involvement) and subjective weakness (↓ effort because of pain or disuse atrophy; rather than true weakness)

•  Decreased range of motion (ROM) of proximal (and peripheral) joints

•  Systemic signs and symptoms: ~40%; malaise, fatigue, depression, anorexia, weight loss, and fever (high spiking fever sometimes in GCA, rare in only PMR)

Diagnosis

•  Clinical diagnosis with serologic test

      Mandatory criteria

  Age ≥50 years at disease onset, aching in both shoulders, abnormal CRP, ESR, or both

      Additional criteria (points)

  Morning stiffness >45 minutes (2), hip pain or reduced ROM (1), negative RA or CCP Ab (2), absence of peripheral synovitis (1) and US findings of bursitis and synovitis in one shoulder (1), both (2); in imaging findings

      Diagnosis mandatory criteria + ≥4 points for additional criteria without US findings (sensitivity: 68% and specificity: 78%) and ≥5 points with ultrasonographic findings (diagnostic sensitivity and specificity, 66% and 81%, respectively)

•  Serologic test

      Increased ESR ≥40 mm/hour (78%–93%) and 100 mm/hour (~20%) and CRP

  ESR: <40 mm/hour in limited disease with fewer systemic symptoms, treatment with glucocorticoids

  CRP: >5 mg/L in 99%, >22 mg/L in 90%; more sensitive than ESR

      CBC: normocytic anemia, thrombocytosis (as part of a general inflammatory response), usually (–) ANA/RF/anti-CCP Ab, elevated alkaline phosphatase (more common in GCA than PMR alone)

      For differential diagnosis: blood glucose, urinalysis, blood urea nitrogen, creatinine, aminotransferases, ALP, and calcium

•  Imaging studies

      Musculoskeletal ultrasound (additional criteria)

  ≥1 shoulder with subdeltoid bursitis, biceps tenosynovitis, or glenohumeral synovitis, or ≥hip with synovitis or trochanteric bursitis

  Subdeltoid bursitis, biceps tenosynovitis, or glenohumeral synovitis in both shoulders

  Effusions within both shoulder bursae (>90%) (14)

      MRI of shoulder: subacromial and subdeltoid bursitis (typically bilateral) in almost all patients with active PMR

      Baseline bone density measurement for steroid induced osteoporosis

•  Differential diagnosis

      Giant cell arteritis (concomitant in 15%–30% of those with PMR)

  New headache, jaw claudication, scalp tenderness, visual change/loss, fever, or cough in addition to symptoms suggestive of PMR, signs of inflammation of temporal arteries

  Referral for temporal artery biopsy

           –  Routine biopsy strongly discouraged (because they seldom develop ischemic complications)

      Other differential diagnosis

ANCA, anti-neutrophil cytoplasmic antibody; CPPD, calcium pyrophosphate dihydrate crystal; CRP, C-reactive protein; DTR, deep tendon reflex; EMG, electromyography; ESR, erythrocyte sedimentation rate; PMR, polymyalgia rheumatica; RA, rheumatoid arthritis; SPEP, serum protein electrophoresis; TSH, thyroid-stimulating hormone; UPEP, urine protein electrophoresis; URI, upper respiratory infection.

Treatment (15)

•  Initial therapy: prednisone 15 to 20 mg/d for 1 to 2 months

      Dramatic improvement: often after 1st dose; 50% to 70%, ↓ in pain and stiffness within 3 days

      If symptoms not well controlled within 1 week, increase by 5 mg/d each week up to a maximum of 30 mg/d

      If (+) evening or night-time pain or stiffness: use of a divided (twice daily) dose

•  Maintain the effective dose for 1 to 2 months, and then taper 20%/month as tolerated (↓ in 2.5 mg decrements every 2–4 weeks) taper slowly if the dose reaches 10 mg/d) (↓ 1 mg per month)

    º  Duration for 1 to 2 (3) years typically

  Some patients require long-term therapy with stable doses less than 5 mg/d

      Relapses are common with tapering

  Earlier relapse: associated with higher ESR, larger initial doses of prednisone, and rapid tapering

  ~10% of patients will relapse within 10 years

•  Monitor the clinical response closely

      Clinical response: presence and/or recurrence of symptoms of PMR or GCA

      Continued and/or recurrent high levels of ESR/CRP: alternative or additional diagnoses (malignancy or GCA)

      Order: CBC, ESR, CRP-initially, after 2 months of treatment, then every 3 months during glucocorticoid therapy (interleukin-6 [IL-6]: correlates well with disease activity [16])

•  Therapy has not been shown to clearly improve prognosis or prevent progression to GCA

•  Glucocorticoid sparing therapies; Not proven to be effective

      Methotrexate (MTX), tumor necrosis factor (TNF) inhibitors, infliximab, etanercept, and the like

      NSAIDs

  Associated with drug-related morbidity

  If with glucocorticoids: gastrointestinal protection should be used

•  Physical therapy (PT)

      ROM in affected joints and gradual strengthening exercise to prevent deconditioning

CHRONIC FATIGUE SYNDROME

Introduction

•  Prevalence: 75–267/100,000, peak in 20 to 55 years, female (up to 80%–90%) > male

      Well under 10% of patients with chronic fatigue have chronic fatigue syndrome (CFS)

      70% of patients with FM meet the criteria for CFS

•  Etiology and risk factors; unclear

      Infection: EBV, xenotropic murine leukemia virus-related virus (XMRV), HIV, human herpes virus-6 (HHV-6), enteroviruses, coxsackie B virus, Ross river virus, Borna disease virus, human T-cell lymphotropic virus (HTLV)

  Often associated with infection (upper respiratory infection [URI], infectious mononucleosis, etc) although none has been proven to cause CFS

      Immune dysfunction, endocrine-metabolic dysfunction

      Neurally mediated hypotension

      Depression and sleep disruption

      Genetic predisposition

•  Course and prognosis

      Symptomatic improvement in 64% at 1.5 years but complete resolution in only 2% (17)

History and physical examination

•  Relatively sudden onset, overwhelming fatigue

      Typically highly functioning individuals previously

      Myalgia and fatigue in >90%

      Neurocognitive and mood disturbances, headaches, and sleep disturbances

      History predicting persistent symptoms

  >8 medically unexplained physical symptoms

  A lifetime history of dysthymic disorder

  >1.5 years of chronic fatigue

  <16 years of formal education and age >38 years at presentation

•  Normal physical examination unless overlap with other disorders such as FM

Diagnosis

•  Clinical diagnosis: diagnosis of exclusion (18)

      Unexplained, persistent, or relapsing fatigue with new or definite onset

      Not the result of ongoing exertion and not alleviated by rest

      Substantial reduction in previous levels of occupational, educational, social, or personal activities

      ≥4 of the following symptoms for ≥6 consecutive months

  Self-reported impairment in short-term memory or concentration

  Sore throat, tender cervical or axillary nodes

  Muscle pain (throbbing, shooting often burning), multijoint pain (often migratory) without redness or swelling

  Headaches of a new pattern or severity

  Unrefreshing sleep and postexertional malaise lasting ≥24 hours

      Other symptoms: unexplained muscle weakness, abdominal pain with altered bowel habit, mild fever (37.5–38.6°C) or chills

•  Normal laboratory finding: CBC, ESR, chemistry, and thyroid-stimulating hormone (TSH)

      Do not routinely order EBV, CMV, Lyme disease, or ANA (in the setting of low pretest probability, any positive test is likely to be a false positive)

•  Normal radiologic test

•  Differential diagnosis

      FM and temporomandibular dysfunction (19)

Treatment (20)

•  No highly effective therapy available; cognitive behavioral and graded exercise therapy are beneficial

•  Referral to comprehensive center (sleep center, psychology for depression/panic): less fatigue and better physical function (21)

      Sleep apnea or nocturnal myoclonus are common

•  Cognitive behavioral therapy: to alter beliefs and behaviors that might delay recovery

•  Graded exercise therapy: may worsen temporarily

      PT for cardiovascular fitness training, myofascial release and modality (massage) for a few sessions

•  Supportive approach with reassurance

      Patient and family education and validate the diagnosis

•  Medications and diet: none has proved successful

      Low dose of TCA, if not responsive, add selective serotonin reuptake inhibitors (SSRI)

      Benzodiazepine low dose if repetitive limb movement

      Analgesic and NSAIDs as needed

      Trigger point or tender point injection

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