Muscle pain

MUSCLE PAIN & DISCOMFORT

GENERALIZED MUSCLE PAIN: Differential Diagnosis

Myopathic pain: Usually with High CK & Abnormal EMG; Weakness common

Inflammatory
- Inflammatory myopathies
- Muscle infections
  - Viral myositis
  - Pyomyositis
  - Toxoplasmosis
  - Trichinosis
Rhabdomyolysis ± Metabolic disorder
Other myopathies with pain
- Myoadenylate Deaminase
- Myopathy with focal depletion of mitochondria
- Myopathy with tubular aggregates ± cylindrical spirals
- Neuromyopathy with internalized capillaries
- Myotonias: PROMM; Dominant myotonia congenita (Occasional)
- Selenium deficiency
- Toxic myopathy: Eosinophilia myalgia; Rhabdomyolysis
- Hypothyroid myopathy
- Mitochondrial disorders
- Camurati-Engelmann syndrome
Pain of muscle origin without chronic myopathy
- Muscle ischemia: Atherosclerosis; Calciphylaxis
- Cramps
- Muscle overuse syndromes
  - Drugs & toxins
  - Delayed onset muscle soreness (DOMS)
- Muscle injury (strain): External link-Iowa
Drugs & Toxins

Polymyalgia syndromes

Features
- Muscle pain without weakness: Pain may interfere with effort
- Pain present at rest & ± ↑ with movement
- Serum CK: Normal
- No pathologic change in muscle
Disorders
- Polymyalgia rheumatica
- Fibromyalgia
- Chronic fatigue syndrome
- Infections
  - Viral & post-viral syndromes
  - Brucellosis; Leptospirosis; Falciparum malaria
- Systemic connective tissue disorders: Sjögren's
- Drugs & Toxins
- Familial Mediterranean fever : Febrile myalgia syndrome
- Non-muscle pain with defined origin

Muscle Cramps

Clinical features
- Acute onset
- Short duration
- Muscle contraction: Strong & palpable
- Relief by stretching muscle
Etiologies
- Ordinary: Common in normal people
  - Distribution
    - Gastrocnemius
    - Frequent cramps in other muscles suggests neuromuscular disease
  - Onset: During or after exercise; Sleep
  - Provoked
    - Especially by contraction of shortened muscle
    - 10 Hz electrical stimulation
  - Neurogenic: ? Terminal region of peripheral nerve
  - Stretching muscle terminates cramp
- Familial
  - Becker Dystrophy
  - Phosphorylase deficiency (McArdle's)
    - Always provoked by ischemic exercise
    - Electrically (EMG) silent
  - Other familial cramp syndromes
- Hypothyroid
- Electrolyte & metabolic disorders
  - Dehydration: Hidrosis; Diuretics; Hemodialysis
  - Metabolic: Low Sodium, Magnesium, Calcium, Glucose
- Neurogenic
  - ALS
  - Neural Overactivity Syndromes
  - Spinal Stenosis
- Drugs & Toxins
- Note: Myotonic cramps are not usually painful

MUSCLE DISCOMFORT ± MYOPATHY: DRUGS & TOXINS
Inflammatory Myopathy	Rhabdomyolysis ± Chronic myopathy	Painful myopathy ± Rhabdomyolysis	Myalgia ± Myopathy	Cramps
Definite Hydralazine Penicillamine Procainamide L-tryptophan (impurity) Possible Cimetidine Ipecac Lansoprazole Leuprolide Levodopa Penicillin Phenytoin Propylthiouracil Sulfonamide	Alcohol e-Amino Caproic Acid Amphetamines Cocaine Cyclosporine Hypokalemia Isoniazid Lipid lowering agents Bezafibrate Clofibrate Gemfibrozil Lovastatin Simvastatin Lithium Mibefradil Propofol Zidovudine	AMPD1 deficiency Colchicine Emetine Germanium Hypervitaminosis E Taxenes Zidovudine	All-Trans-Retinoic Acid Azathioprine Bryostatin 1 Captopril Corticosteroids Withdrawal Cytotoxics Danazol Enlapril Gold Interferon α-2a Interferon α-2b Ketorolac Labetalol Metolazone Paclitaxel Retinoids Rifampin Spanish toxic oil Suxamethonium (Succinylcholine) Vinca alkaloids Zimeldine	Albuterol Anti-Cholinesterase Caffeine Clofibrate Cyclosporine Diuretics Labetalol Lithium Nifedipine Terbutaline Tetanus Theophylline Vitamin A

Non-muscle disorders: Usually with Normal CK & EMG

Connective tissue disorders: Fasciitis; Systemic
Bone: Osteomalacia; Fracture (Hip); Myeloproliferative; Fluorosis
Endocrine: Thyroid ↑ or ↓; Parathyroid ↑ or ↓
Vascular: Ischemia; Thrombophlebitis
Polymyalgia syndromes
Joint disease: Immune; Hypermobility syndromes; Gout; Degenerative
Polyneuropathy
CNS: Restless legs; Dystonias (Focal)

Localized Muscle Pain

Trauma
Mass: Hematoma; Neoplasm; Infection
Vascular: Thrombophlebitis; Ischemia
Nerve: Neuropathy; Radiculopathy
Movement disorder: Restless legs; Moving toes
Adenosine, intraarteriolar: Ischemic-like pain
Cramps

PAIN: Principles³

Pain Categories

Nociceptive pain: Elicited by noxious stimulation of normal tissue

Arises after stimulus producing tissue damage
Clinical relevance: Short term pain control may be needed

Nociceptive pain: Elicited when tissue is in pathological state

Associated with inflamed or damaged tissue
Stimulus: Not necessary
Nociceptive system may become more sensitive to stimuli
- Hyperalgesia: Stimulus produces exaggerated pain
- Allodynia: Pain induced by stimuli not usually causing pain
- Referred pain: Pain in regions apart from damaged tissue
Pain may become chronic

Neuropathic pain: Elicited when sensory axons or cell bodies are damaged

Sensation: Often burning
May occur spontaneously: Continuous or Episodic
Abnormal: Not related to damage in innervated tissue
Often chronic and difficult to treat

Nociceptive system

Stimulation of nociceptive sensory terminals
- Types of stimulation
  - Activation
  - Sensitization: Underlies spontaneous pain, hyperalgesia & allodynia
- Stimuli
  - Mechanical
  - Chemical
Primary afferent neurons
- Cell body: Small; Located in dorsal root or trigeminal ganglion
- Axons
  - Aδ: Thin myelin sheath
  - C: No myelin
  - Aβ fibers may be associated with allodynia
- Transmitters: Glutamate; Substance P; Calcitonin gene-related peptide (CGRP)
- Transmitter release
Secondary afferent neurons
- Cross sides in spinal cord
- Ascend: Especially in spinothalamic tract
- Terminate: Thalamus (nucleus submedius); Brain stem
Pain perception: ? Located in Cortex
- Psychophysical features
  - Components: Location; Intensity; Character; Duration
  - Location: 1° & 2° somatosensory cortex
- Affective features
  - Components: Unpleasantness & Rejection
  - Location: Limbic cortex (Cingulate & Insula)
- Central mechanisms of nociception
  - Acute; Increased flow of action potentials
  - Chronic stimulation: May produce central sensitization
    - Central neurons have increased response to peripheral stimuli
    - Related to increased efficacy to synaptic transmission
    - Presynaptic mechanisms: Entry of Ca⁺⁺ ions through N-type & P-type Ca⁺⁺ channels
    - Transmitter system: Glutamate, N-methyl-D-aspartate (NMDA) receptors
Descending pathway
- Origins: Brain stem
  - Nucleus raphe magnus & Surrounding rostral ventromedial medulla
  - Perisylvian aqueduct grey matter
- Terminations: Trigeminal & Spinal relay areas (Lamina I)
- Function: Inhibitory (Endogenous analgesia system)

Possible mechanisms of chronic pain

Persistent stimulation of nociceptors: Activation; Sensitization; Ectopic discharges along axons
Persistent central sensitization
Loss of inhibition: Segmental; Descending
Structural changes in neurons & synapses: Sprouting of nociceptors or sympathetic axons

MUSCLE PAIN: Principles

Anatomy
- Sensory afferent pathways
  - Mechanical: Thinly myelinated (Group III or A δ) axons
  - Noxious: Unmyelinated (Group IV or C) axons
- Nerve Terminals
  - Type: Freely branching, Unencapsulated
  - Location: Tendons; Fascia
Muscle pain: Subtypes
- Pain onset: During exercise
  - Exhaustion of fuel supply in muscle
    - Features
      - Normal exercise may not be painful
      - Serum CK: High
    - Types
      - Vascular ischemia
      - Metabolic defect
      - Sustained muscle contraction
  - Other
    - Features
      - Normal exercise often painful
      - Serum CK: Normal
    - Types
      - Structural damage: Muscle; Tendon; Joint; Bone
      - Polymyalgia syndromes
- Pain onset: Hours after exercise
  - Muscle
    - Onset: Hours after exercise
    - Serum CK: High
    - Time course: Persists up to 5 days
    - Predisposing factors
      - Unaccustomed exercise
      - Eccentric contraction: Contraction while muscle is being stretched
    - Disorders: Myopathy, especially disorders associated with rhabdomyolysis
  - Non-muscle: Structural damage; Polymyalgia syndromes
- Pain unaffected by exercise: Polymyalgia; Small fiber or painful polyneuropathy
- Cramps
- Pain with prolonged immobility
- CNS related: Restless legs; Upper motor neuron disorders; Dystonias
- Fatigue syndromes: Chronic fatigue; Depression
Typical evaluation for generalized muscle pain or discomfort
- History: Precipitating factors; Nature & Location of pain
- Examination: Strength; Sensory loss; Trigger & tender regions; Endurance
- Laboratory
  - Blood: CBC; Sedimentation rate; CK; K⁺; Ca⁺⁺; Phosphate; TSH & T₄;
    Connective tissue antibody screen (ANA)
  - Exercise testing: Ischemic lactate & Ammonia; Lactate after mild exercise
  - EMG & Nerve conduction studies
  - Muscle biopsy: If abnormal CK or myopathic EMG

Other myopathies with pain

Myoadenylate Deaminase (AMPD1) Deficiency
● Chromosome 1p21-p13; Recessive
- Genetics
  - C-to-T mutation at nucleotide 34 (Glu12Ter)
    - Produces stop codon
    - Caucasians & African-Americans: 20% heterozygous; 2% homozygous
    - No clear correlation with severity of clinical phenotype
    - Alternative splicing of exon 2: May provide phenotypic rescue & explain clinical variability
    - Heterozygotes with heart failure may have better prognosis
  - Other mutations with consistent severe reductions in AMPD1 function: Produce symptomatic phenotype
- AMPD1 protein
  - Component of multi-gene family: Several tissue & development stage specific isoforms
  - High levels of expression of AMPD1 in skeletal muscle: 100x higher than other tissues
  - Catalyzes deamination of AMP to IMP
  - Component of purine nucleotide cycle: Purine nucleotide interconversion
  - AMPD activity can be determinant of adenylate energy charge & energy metabolism in cells
  - Severe reductions in protein function (< 1%) produce symptomatic phenotype
- Clinical features
  - Often asymptomatic: Especially with 34C>T mutation
  - Rhabdomyolysis
  - Exertional myalgias
    - Worsen steadily during intensive exercise
    - No second wind
    - Location: Legs & hands
  - Symptomatic when < 2% residual enzyme activity
  - Serum CK: Normal or slightly increased
  - EMG: Normal
  - Ischemic exercise
    - Ammonia: Reduced rise
    - Lactate: Normal rise
Myopathy with focal depletion of mitochondria
● ? Dominant with incomplete penetrance
- Weakness: Mild; Proximal
- Myalgias
- Serum CK: High; Increases after exercise
Delayed onset muscle soreness (DOMS)
- Clinical
  - Produced by
    - Eccentric contraction: Downhill running
    - Unaccustomed exercise
  - Time course
    - Onset: 1/2 to 2 days after exercise
    - Peak: 1 to 3 days
    - Duration: Hours to 1 week
    - No long term damage
  - Symptoms
    - Discomfort & Pain in skeletal muscles
    - Temporary weakness: ? Related to pain
- Laboratory
  - Serum CK: High
  - Muscle pathology: Structural abnormalities in Z band
  - MRI
    - Increased signal intensity on T2-weighted image: Often uniform through muscle
    - External link: MRI image

POLYMYALGIA RHEUMATICA

Diagnostic Criteria*	Bilateral shoulder pain or stiffness Bilateral tenderness in upper arms Abrupt onset of illness (< 2 weeks) Erythrocyte sedimentation rate > 40 mm/hr Morning stiffness (> 1 hour in duration) Age: > 65 years (72% sensitivity); > 50 years (100% sensitivity) Systemic signs: Depression; weight loss
* Presence of any 3 criteria, or at least 1 criterion coexisting with a clinical or pathological abnormality of the temporal artery suggests probable polymyalgia rheumatica.

General features
- Epidemiology
  - Female > Male: 2:1
  - White > African-American
  - Northern hemisphere
  - Frequency
    - 12 to 65 per 100,000 in patients > 50 years
    - England: Up to 400 per 100,000 in patients > 65 years
  - Onset age: > 50 years old; Average 70 years
- General: Fever; Malaise; Fatigue; Night sweats
- Pain
  - Symmetrical
  - Involves shoulder, neck, and hip girdle
  - Greatest after inactivity & sleeping
  - May be unilateral at onset
- Associated arteritis: Visual loss; Cerebral ischemia; Aortic arch syndrome
- Lab
  - ESR: > 40; Often > 100
  - Acute phase response: ↑ Serum C-reactive protein & Interleukin-6 (IL-6)
  - Anemia of chronic disease
  - Thrombocytosis
  - Negative: ANA & Rheumatoid factor
  - Temporal artery: ↑ cytokines IL-1, IL-2, IL-6 & TGF-β1
- Muscle
  - Type II fiber atrophy
  - ↑ # capillaries per muscle fiber
Associated disorders: Giant cell (Temporal) arteritis in 20% to 50%
Treatment
- Rapid response to Prednisone @ doses < 20 mg in 75%
- Better response with
  - Short disease course
  - Lower ESR (pre-treatment < 50 mm/h)
  - ↓ IL-6 (post-treatment < 10 pg/ml)
Course: Often self-limited @ 18 to 24 months

CHRONIC FATIGUE SYNDROME

CDC DEFINITION
Both major criteria, and either 8 minor symptom criteria, or 6 minor symptom criteria and 2 examination criteria

Major criteria

Fatigue: Relapsing or easily evoked
- No resolution with bed rest
- Severe: Reduced daily activity by 50% for > 6 months
Exclusion of other illnesses: Especially psychiatric

Minor symptom criteria

Fever or chills: Mild
Sore throat
Lymph node pain
- Cervical or axillary
Muscle discomfort or myalgia
Muscle weakness
- Unexplained; Generalized
Fatigue: Generalized
- After previously tolerated levels of exercise
- Prolonged: > 24 hours

Headaches: New; Generalized
Arthralgias: Migratory; Non-inflammatory
Neuropsychiatric
- Visual: Photophobia; Transient scotoma
- Behavior: Forgetfulness; Irritablilty; Depression; Confusion
Sleep disturbance: Hyper- or Insomnia
Onset: Acute or subacute

Physical examination criteria

Low grade fever
Pharyngitis: Non-exudative
Lymph nodes: < 2 cm in diameter
- Palpable or tender
- Cervical or axillary

COMMON SYMPTOMS & SIGNS

Systemic
- Fever & Night sweats
- Weight loss or gain
- Lymph nodes: Swollen in neck
Respiratory
- Onset: Sudden with flu-like illness
- Sore throat; Cough
Musculoskeletal
- Myalgias
- Malaise: Postexertional
- Arthralgias
- Generalized subjective weakness
- Morning stiffness

Neuropsychological
- Awakening unrested
- Concentration: Poor
- Headaches
- Forgetful
- Depression or anxiety
- Alcohol: Exacerbates symptoms
- Tingling/Numbness in extremities
- Photophobia
Functional status: Intermittently bedridden

ASSOCIATED DISORDERS

Fibromyalgia
- Widespread pain
  - Bilateral; Truncal; Above & below waist
  - > 3 months
- Pain on palpation of tender point sites
Sleep disorders
↑ Lactate response to exercise: In patients with fewer type I fibers

DIFFERENTIAL DIAGNOSIS

Connective tissue diseases
Drug or alcohol abuse
Endocrine diseases
Fibromyalgia
Infections
Malignancy
Medications
Neuromuscular disorders
Sleep disorders
Psychiatric disorders

All-Trans-Retinoic Acid (ATRA)¹

Uses: Induction therapy for acute promyelocytic leukemia
Muscle syndrome
- Myalgias: Legs > Arms; Reduced by corticosteroid treatment or ↓ ATRA dose
- Serum CK: Normal or mildly elevated
- MRI: ↑ T2 signal in fascia & muscle
CNS: Intracranial hypertension; Headache
Systemic side effects
- Fever
- Dyspnea
- Weight gain
- Effusions: Pleural; Pericardial
- Hypotension
- Sweet's syndrome: Acute neutrophilic dermatosis

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References
1. Am Jour Hematol 2000;63:94-98
2. Balliere's Clinical Rheumatology 2000;14:797-811
3. Nature Neuroscience 2001;4:9-10,72-77

01/07/2001