A. Characteristics

1. Severe unrelenting neuropathic pain, usually burning in nature
2. Distal Extremity; usually whole hand or foot
3. Accompanying Symptoms
   1. Tenderness
   2. Swelling
   3. Dystrophic skin changes
   4. Atrophy
   5. Vasomotor ± "submotor" changes - temperature, hair, sweat, others
4. Neurologic Changes
   1. Hyperesthesias - burning sensation
   2. Marked sensitivity to touch (allodynia) and gentle pressure (hyperpathia)
5. Men = Women; may have predisposition for older patients
6. Also called "post-traumatic algodystrophy" and causalgia
7. This is a classic neuropathic pain syndrome
8. Role of Cutaneous Vasoconstrictor Neurons (CVN) [11]
   1. CVN projecting to painful arm or leg enhances spontaneous pain and hyperalgesia
   2. Elevated sympathetic activity increases pain and hyperalgesia
   3. Sympathetic stimulation activates CVN
   4. Sympathetic blockade reduces pain and hyperalgesia
9. Classified as Complex Regional Pain Syndrome 1

B. Precipitating Events [1]

1. Trauma is most common
   1. Severity of trauma is not a major contributor to risk
   2. Fractures - wrist fractures associated with ~20% of wrist fractures [8]
2. Hemiplegia
3. Peripheral nerve injury, cervical spondylosis, etc.
4. Drug Exposure: isoniazid, barbiturates, other anti-tuberculous agents
5. Possible role for internal trauma (myocardial infarction, stroke, others)
6. Arterial or venous thrombosis
7. Surgery, particularly with inadequate pre- and/or post-operative anesthesia
8. Emotional component, stimulating sympathetic autonomics, may be present
9. Overall, there are peripheral, spinal, and supraspinal components to RSDS

C. Stages [2]

1. Acute (3-6 months)
   1. Burning pain, tenderness, swelling
   2. Vasomotor symptoms
   3. Due to sympathetic microcirculatory disturbances
2. Dystrophic
   1. Persistant aching or burning pain
   2. Dystrophic nail or skin changes
   3. Toxic oxygen radicals may be involved
3. Atrophic: gradual development, skin and subcutatneous atrophy with contractures
4. Radiographic Changes
   1. ~85% of patients with changes
   2. diffuse, patchy osteopenia (may be marked)
5. Bone Scan
   1. Three phase usually helpful
   2. Asymmetric blood flow and pooling (increase in ~50%, decrease in ~20%)
   3. Overall limb blood flow usually decreased
   4. Longstanding or resolving RSD may show atypical bone scan pattern
6. Abnormal diastolic blood flow pattern may be due to abnormal sympathetic tone

D. Pathogenesis

1. Unclear etiology
2. Sympathetic nervous system dysfunction likely plays a role
   1. May be caused by primary lesion in central or peripheral nerves
   2. Stress response (hypothalmic-pituitary-adrenal) axis plays some role in pain sensation
   3. However, it appears that spinal neurons play a critical role in persistance of pain
3. Spinal neuron hyperexcitatio
   1. May be involved in post-traumatic and surgical pain
   2. Spontaneous activity in C fibers thought to be responsible for burning pain
   3. In addition, C fiber activity may be responsible for spinal neuron hyperexcitation
4. Stimulus independent activity in large myelinated type A fibers can cause paresthesias
   1. Tetrodotoxin insensitive sodium channels are likely involved in spontaneous activities
   2. Reduction in GABA inhibitory neurotransmitters in dorsal horn has also been found
   3. Mechanism of hyperalgesia in stimulus evoked pain is related to glutamate neurons
   4. NMDA type glutamate receptors in the CNS also play a key role

E. Criteria [9]

1. Absolute Criteria
   1. Pain
   2. Impaired function
   3. Symptoms beyond area of trauma
   4. Cold, warm, or intermittent cold and warm feeling in affected area
2. Relative Criteria
   1. Edema
   2. Increased nail growth
   3. increased hair growth
   4. Hyperhidrosis
   5. Abnormal skin color
   6. Hypoesthesia
   7. Hyperalgesia
   8. Mechanical or thermal allodynia or both
   9. Patchy demineralization of bone

F. Treatment

1. Initial Therapy
   1. Non-steroidals - may provide some relief
   2. Glucocorticoids - no controlled trials. 15mg qid [3]
   3. Local iv glucocorticoids with Bier Block
   4. Physical therapy, exercise, is probably most important modality [4]
   5. Whirlpool probably more effective than ultrasound
   6. Pain control is therefore very important
2. Sympathetic Blockade
   1. Most patients obtain considerable pain relief
   2. Most effective if used early; may help with diagnosis
   3. Less effective if neural tissue is injured (<30% response)
   4. Local anesthetic in area of stellate ganglion (UE) or lumbar ganglia (LE)
3. Spinal Cord Stimulation [9]
   1. Electrode is positioned in epidural space on dorsal aspect of spinal cord
   2. Placed at level of nerve roots innervating painful area
   3. Electrical current from electrode induces paresthesias, which suppresses pain
   4. Current supplied by a pulse generator position subcutaneously in anterior abdominal wall
   5. Patients can alter the current with a remote control device
   6. Combined with physical therapy, can reduce pain of RSD and improve quality of life
4. Intrathecal Baclofen [10]
   1. Specific gamma-aminobutyric acid (GABA) type B receptor agonist
   2. Inhibits sensory input to neurons of the spinal cord
   3. Bolus injections in women with RSD greatly improved hand function
   4. Continuous infusion improved leg symptoms and allowed 50% of patients to walk
   5. Intrathecal baclofen should be considered in severe RSD
5. Causalgia
   1. Much more difficult to treat due to nerve injury
   2. Spinal blocks may be used and are only proven therapy
6. Calcitonin [5,6]
   1. May improve calcification of bone (decreased bone loss) in RSD
   2. Clear analgesic properties as well
   3. SC may be more effective than nasal calcitonin (which is now FDA approved)
   4. Begin 25U qd sc x 4-7 days, increase to 100U qd sc (or
   5. Effect should begin within 2-4 weeks; stop if no improvement in pain within 8 weeks
   6. Monitor calcium and phosphate at start of therapy, and q1-3 weeks
7. Other Agents
   1. Tricyclic antidepressants - improve sleep, good for chronic pain, alpha blocker activity
   2. Peripheral Alpha-Blockers - may have sympatholytic activity
   3. Clonidine - centrally acting alpha2 agonist; decreases sympathetic activity
   4. Opiates - generally avoided due to very high addictive potential
   5. However, opiates are often the only effective pain therapy
   6. Tramadol (Ultram®) - 50-100mg po bid-qid may be helpful
   7. Capsaicin (Zostrix®) may provide some relief
8. Vitamin C [8]
   1. Evaluated prophylactically in wrist fracture patients not requiring surgery
   2. 52 wrist fracture patients received vitamin C (500mg/d) versus 63 patients on placebo
   3. RSD occurred in 4 (7%) of vitamin C group and 14 (22%) of the placebo group
   4. Anti-oxidants may have some efficacy in RSD

H. Transient Migratory Osteoporosis (TMO)

1. Rapidly developing painful osteoporosis
2. Properties
   1. often with swelling, severe tenderness,
   2. usually lower extremity
   3. may have migratory pattern
   4. not associated with trauma
   5. usually spontaneous resolution within 6-12 months
3. Precipitating Events
   1. ? viral or (auto)immune irritation
   2. ? metabolic factors
   3. ? genetic predisposition
   4. Pregnancy - usually 3RD trimester, ? obturator nn injury
4. Relationship to RSD
   1. similar properties but begins spontaneously
   2. no history of trauma in TMO
   3. more migratory than RSD
   4. SRD may precede TMO
5. Laboratory Tests
   1. Bone scan shows increased periarticular uptake
   2. ESR normal
   3. May have increased Alkaline Phosphatase ± other markers of bone turnover
6. Other names of syndrome
   1. Transient painful osteoporosis
   2. Migratory osteolysis
   3. Regional migratory osteoporosis
   4. Idiopathic regional osteoporosis
7. Treatment [2]
   1. NSAIDs for pain; no proven benefit with steroids or ACTH
   2. Infrequent reports of benefit from sympathetic block
   3. No reports of calcium / vitamin D trials
   4. Neuropathic pain modulators such as carbamazepine should be considered
   5. Calcitonin is investigational (see above); clear scientific rationale for use here

References

1. Hardy MA, Hardy SG. 1997. J Hand Ther. 10(2):137
2. Mailis A, Inman R, Pham D. 1992. J. Rheumatol. 19(5):758
3. Kozin F, Ryan LM, Carerra GF, et al. 1981. Am J Med. 70(1):23
4. Lopez RF. 1997. Postgrad Med. 101(4):185
5. Gobelet C, Waldburger M, Meier JL. 1992. Pain. 48(2):171
6. Bickerstaff DR, Kanis JA. 1991. British J Rheumatol. 30(4):291
7. Viel E, Ripart J, Pelissier J, Eledjam JJ. 1999. Ann Med Interne (Paris). 150(3):205
8. Zollinger PE, Tuinebreijer WE, Kreis RW, Breederveld RS. 1999. Lancet. 354(9195):2025
9. Kemler MA, Barendse GAM, van Kleef M, et al. 2000. NEJM. 343(9):618
10. van Hilten BJ, van de Beek WJT, Hoff JI, et al. 2000. NEJM. 343(9):625
11. Baron R, Schattschneider J, Binder A, et al. 2002. Lancet. 359(9318):1655