Complex Regional Pain Syndrome (CRPS)

Complex regional pain syndrome (CRPS) is a chronic regional neuropathic pain condition characterized by excruciating pain (out of proportion to apparent tissue damage or inciting trauma), paresthesia, allodynia, temperature abnormalities, skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin discoloration, edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema, reduced range of motion, and bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones demineralization. This syndrome is most often associated with an inciting traumatic event (e.g., fracture Fracture A fracture is a disruption of the cortex of any bone and periosteum and is commonly due to mechanical stress after an injury or accident. Open fractures due to trauma can be a medical emergency. Fractures are frequently associated with automobile accidents, workplace injuries, and trauma. Overview of Bone Fractures, surgery, burn) and predominantly affects the limb(s). Diagnosis is clinical, but it is supported by imaging and electrodiagnostic testing. Treatment centers around multidisciplinary pain management Pain Management Pain is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage. Pain is a subjective experience. Acute pain lasts < 3 months and typically has a specific, identifiable cause. Pain Management and maintenance of function.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Definitions

  • A chronic painful condition characterized by: 
    • Regional pain
    • Sensory changes (e.g., allodynia, paresthesia, dysesthesia)
    • Temperature abnormalities
    • Abnormal sweating
    • Edema
    • Skin discoloration 
    • Loss of range of motion of local joint
  • Pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain and disability greater than that expected from the original injury or apparent tissue damage

Epidemiology

  • Incidence: 5–25 per 100,000 per year
    • Female-to-male ratio: 2–4 to 1
    • Highest in postmenopausal women
  • Most common in ages 36–46 years 

Classification

  • CRPS-1 (also known as reflex sympathetic dystrophy (RDS)): no definitive nerve involvement 
  • CRPS-2 (also known as causalgia): A specific nerve injury correlates with the area of regional pain.

Etiology

Complex regional pain syndrome occurs after an initiating noxious event, such as trauma:

  • Fracture (20%–40%)
  • Strain or sprain (10%–20%)
  • Postoperative (10%–20%)
  • Contusion or crush injury (10%–20%)
  • Idiopathic (no identifiable preceding injury) (approximately 10%)

Pathophysiology

The pathophysiology of CRPS is not completely understood, but there are multiple likely mechanisms.

Inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation (cytokine-mediated):

  • Local increase in proinflammatory cytokines:
    • IL-1, 2, 6
    • Tumor necrosis factor Tumor necrosis factor Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF) alpha ( TNF TNF Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF)-α)
  • Abnormal local up-regulation of the immune system 

Neurogenic inflammation (neuropeptide-mediated):

  • Local release of pain producing peptides by peripheral nerves:
    • Calcitonin-gene–related peptide (CGRP)
    • Neuropeptide Y
    • Substance P
  • Abnormal proximal–distal propagation of depolarization in afferent nerves
  • Abnormal signaling between afferent and efferent nerves

Central sensitization:

  • Occurs in the setting of persistent nociceptive input to the dorsal horn of a given spinal segment or segments
  • Results in pathologic rearrangement of sensory input territories in the dorsal horn of the spinal cord Spinal cord The spinal cord is the major conduction pathway connecting the brain to the body; it is part of the CNS. In cross section, the spinal cord is divided into an H-shaped area of gray matter (consisting of synapsing neuronal cell bodies) and a surrounding area of white matter (consisting of ascending and descending tracts of myelinated axons). Spinal Cord (also known as Rexed lamina)
  • Results in abnormal cross talk at the level of the spinal interneurons

Sympathetic dysregulation:

  • Local hyperactivity of the sympathetic nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. General Structure of the Nervous System and/or abnormal local sensitivity to catecholamines
  • Afferent neurons carry nociceptive inputs to the CNS, triggering an abnormal reflex of vasoconstriction in the corresponding area(s).
  • Up-regulation of adrenergic receptors

Cortical reorganization:

  • Occurs in the setting of persistent nociceptive input to the cerebral cortex Cerebral cortex The cerebral cortex is the largest and most developed part of the human brain and CNS. Occupying the upper part of the cranial cavity, the cerebral cortex has 4 lobes and is divided into 2 hemispheres that are joined centrally by the corpus callosum. Cerebral Cortex of a given spinal segment or segments
  • Results in pathologic rearrangement of sensory inputs in the cerebral cortex Cerebral cortex The cerebral cortex is the largest and most developed part of the human brain and CNS. Occupying the upper part of the cranial cavity, the cerebral cortex has 4 lobes and is divided into 2 hemispheres that are joined centrally by the corpus callosum. Cerebral Cortex areas corresponding to the affected area(s)

Genetic predisposition:

  • CRPS-1 has been observed at a greater frequency in individuals with HLA-DQ1.
  • CRPS is more likely to become multifocal in individuals with HLA-DR3.

Clinical Presentation

History

  • History of trauma or other noxious event from which the individual has recovered:
    • An adequate amount of time for expected healing for a given injury(ies) has passed.
    • No residual wound or tissue damage that might otherwise produce pain is readily identifiable.
  • The pain is neuropathic in nature. Affected individuals describe the pain as:
    • Burning
    • Aching
    • Pricking
    • Shooting
  • Affected individuals may report pain with innocent activities:
    • Wearing socks or shoes (if foot/feet affected)
    • Brushing hair (if scalp affected)
  • Individuals may report motor symptoms in the affected area(s):
    • Muscle cramps
    • Restless legs
  • Individuals may report concomitant psychological symptoms: 
    • Depression
    • Anxiety
  • History of prior failed therapies such as physical therapy, pharmacotherapy, nerve blocks 

Physical examination

  • Excruciating pain is the cardinal feature.
  • Hyperalgesia: 
    • Level of pain is disproportionate to the initial injury or apparent tissue damage.
    • Pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain may persist longer than expected after noxious or nonnoxious stimulus is removed.
    • Pinprick test evokes excruciating pain.
  • Allodynia: Application of a normally nonnoxious mechanical stimulus is perceived as painful.
    • Light touch → mechanical allodynia 
    • Cooling stimulus (e.g., drop of alcohol or water) → thermal allodynia 
  • Greater receptive field:
    • Hyperalgesia and allodynia beyond the area of initial injury
    • Not limited to a dermatome or expected peripheral nerve distribution 
  • Edema:
    • Mild to severe subcutaneous edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema is common in affected area(s).
    • Can mimic mild cellulitis Cellulitis Cellulitis is a common infection caused by bacteria that affects the dermis and subcutaneous tissue of the skin. It is frequently caused by Staphylococcus aureus and Streptococcus pyogenes. The skin infection presents as an erythematous and edematous area with warmth and tenderness. Cellulitis owing to accompanying erythema and trophic changes of the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin
  • Autonomic dysfunction:
    • Temperature asymmetry: up to 1°C difference between affected and unaffected areas
    • Discoloration of affected area(s):
      • Erythema, pallor, and/or cyanosis may manifest at any time in the same body area(s).
      • Skin color can fluctuate in a matter of minutes to hours (e.g., reddish to pale or blue).
      • Livedo reticularis is common.
  • Dystrophic manifestations:
    • Increased/decreased nail and hair growth in affected area(s)
    • Hyperkeratosis/thin, glossy skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin
    • Osteoporosis Osteoporosis Osteoporosis refers to a decrease in bone mass and density leading to an increased number of fractures. There are 2 forms of osteoporosis: primary, which is commonly postmenopausal or senile; and secondary, which is a manifestation of immobilization, underlying medical disorders, or long-term use of certain medications. Osteoporosis of underlying bones
  • Motor dysfunction:
    • Mild weakness
    • Decreased range of motion 
    • Dystonia Dystonia Dystonia is a hyperkinetic movement disorder characterized by the involuntary contraction of muscles, resulting in abnormal postures or twisting and repetitive movements. Dystonia can present in various ways as may affect many different skeletal muscle groups. Dystonia
    • Tremor/myoclonus
Complex regional pain syndrome type 1 (crps-1)

Complex regional pain syndrome type 1 (CRPS-1)
The individual presented dystonic equinus of the right ankle and a swollen foot and calf with tightened, pale, gleaming, cold skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin.

Image: “CRPS-1 (Complex regional pain syndrome)” by Voet C, le Polain de Waroux B, Forget P, Deumens R, Masquelier E. License: CC BY 4.0

Stages of complex regional pain syndrome progression

There are 3 stages of CRPS:

  • Stage 1:
    • Pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain/hypersensitivity/allodynia in primary affected area
    • Mild edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema
    • Skin temperature increased to the touch
    • Minimal localized bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones demineralization on x-ray
  • Stage 2:
    • Worsening of pain
    • Expansion of affected area(s) 
    • Worsening soft tissue edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema
    • Muscle atrophy
    • Onset of atrophic skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin and soft tissue changes
  • Stage 3:
    • Severe pain 
    • Spread of pain to contralateral (unaffected) limb, distant body region(s) or even entire body
    • Cold and cyanotic extremities
    • Significant atrophic skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin changes
    • Joint contractures
    • Muscular and bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones atrophy
    • Severe bony demineralization in affected area(s)

Diagnosis

History and physical exam

Suspect CRPS when the following historical features are present:

  • Inciting trauma
  • Persistent symptoms after 4–6 weeks or expected course of healing:
    • Pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain/sensory changes
    • Swelling
    • Temperature changes
    • Trophic changes
    • Autonomic dysfunction
    • Motor symptoms
  • Especially if the following features are present:
    • Distal limb is affected.
    • Symptoms span beyond injured area.
    • Symptoms span beyond expected peripheral nerve receptive field.

Official diagnostic criteria (Budapest Criteria)

  • Continuing pain (disproportionate to any triggers or inciting event)
  • Symptom in ≥ 3 of the following categories:
    • Sensory: hyperesthesia and/or allodynia
    • Vasomotor: temperature asymmetry and/or skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin discoloration
    • Sudomotor/ edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema: asymmetrical edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema and/or sweating
    • Motor/trophic: decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or dystrophic changes in the hair, nails, and/or skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin
  • ≥ 1 sign in 2 of the 4 following categories (at the time of evaluation):
    • Sensory: hyperalgesia (to pinprick) and/or allodynia (to light touch and/or temperature sensation and/or deep somatic pressure and/or joint movement)
    • Vasomotor: temperature asymmetry (> 1°C) and/or skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin color changes and/or asymmetry
    • Sudomotor/ edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema: asymmetrical edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema and/or sweating
    • Motor/trophic: decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or dystrophic changes in the hair, nails, and/or skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin
  • There is no other diagnosis that better explains the signs and symptoms.

Imaging

  • Plain films (x-ray): 
    • May show evidence of fracture Fracture A fracture is a disruption of the cortex of any bone and periosteum and is commonly due to mechanical stress after an injury or accident. Open fractures due to trauma can be a medical emergency. Fractures are frequently associated with automobile accidents, workplace injuries, and trauma. Overview of Bone Fractures or bony abnormality related to inciting trauma
    • May show patchy osteoporosis as compared with the contralateral (unaffected) limb or affected area
  • MRI: 
    • Not useful for the diagnosis of CRPS, but may be useful in excluding other diagnoses 
    • May show patchy areas of osteoporosis, but not recommended for screening of bony lesions
  • Bone scan (also known as bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones scintigraphy):
    • Used to detect a large variety of bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones and joint disorders:
      • Fracture
      • Infection
      • Tumor
      • Arthritis
      • Metabolic bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones disease
    • Useful for detecting and monitoring bony demineralization in CRPS
    • Presence of bony demineralization is not diagnostic of CRPS, but it supports the diagnosis.

Autonomic testing

  • Resting sweat output (RSO)
  • Resting skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin temperature (RST)
  • Quantitative sudomotor axon reflex test (QSART)

Diagnostic regional anesthesia Anesthesia Anesthesiology is the field of medicine that focuses on interventions that bring a state of anesthesia upon an individual. General anesthesia is characterized by a reversible loss of consciousness along with analgesia, amnesia, and muscle relaxation. Anesthesiology: History and Basic Concepts procedures

  • Bier block:
    • IV regional anesthesia Anesthesia Anesthesiology is the field of medicine that focuses on interventions that bring a state of anesthesia upon an individual. General anesthesia is characterized by a reversible loss of consciousness along with analgesia, amnesia, and muscle relaxation. Anesthesiology: History and Basic Concepts technique wherein a tourniquet is used to simultaneously exsanguinate blood from the affected limb and infuse IV local anesthetic.
    • Accomplishes sympathetic and somatic peripheral nerve block regionally
    • A positive response leads to pain relief and improvement in autonomic manifestations.
    • A positive response is not diagnostic, but it is supportive of CRPS diagnosis.
  • Regional sympathetic nerve block:
    • Interventional injection technique performed under image guidance wherein a needle is advanced to the sympathetic chain ganglia corresponding to a given affected limb or body region (i.e., stellate ganglion for upper extremity, lumbar sympathetic ganglia for lower extremity).
    • A positive response leads to pain relief and improvement in autonomic manifestations.
    • A positive response is not diagnostic, but it is supportive of CRPS diagnosis.

CRPS diagnostic aids

Table: CRPS diagnostic aids
Method Rationale Confounding factors
X-ray Look for gross bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones pathology (fractures, osteomyelitis Osteomyelitis Osteomyelitis is an infection of the bone that results from the spread of microorganisms from the blood (hematogenous), nearby infected tissue, or open wounds (non-hematogenous). Infections are most commonly caused by Staphylococcus aureus. Osteomyelitis) or other causes of soft tissue swelling. Sensitivity for CRPS is low, as even trivial injuries can be the trigger.
3-phase bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones scan Demineralization may be seen even in early stages of CRPS. Not a sensitive/specific finding, as result may be related to disuse of the extremity rather than a direct result of CRPS
Sympathetic block Provides diagnostic and therapeutic value with individual response Not diagnostic if pain is unchanged or somatic nerves are blocked at the same time
Electromyography (EMG) Can help determine presence of nerve injury to confirm diagnosis of CRPS-2
  • Test itself is painful.
  • EMG is not able to differentiate painful nerve damage from nonpainful nerve damage.
Qualitative sensory testing (QST) The lack of sensitivity to temperature changes suggests dysfunction, which includes the sympathetic nerves. Little positive and negative predictive value

Management

The management of CRPS is difficult. Management requires a multidisciplinary approach to pain in order to be successful.

Therapeutic goals

  • Prompt initiation of treatment
  • Pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain relief
  • Functional recovery
  • Psychological improvement

Bone preservation

  • Bisphosphonate therapy is indicated in individuals with CRPS with evidence of bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones demineralization.
  • Adjunctive vitamin D and/or calcium supplementation may be considered as a prophylactic or therapeutic measure.

Pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain management

Control of pain is critical for full compliance with rehabilitation.

Pharmacologic therapy:

  • Tricyclic antidepressants Tricyclic antidepressants Tricyclic antidepressants (TCAs) are a class of medications used in the management of mood disorders, primarily depression. These agents, named after their 3-ring chemical structure, act via reuptake inhibition of neurotransmitters (particularly norepinephrine and serotonin) in the brain. Tricyclic Antidepressants (TCAs) or serotonin–norepinephrine reuptake inhibitors (SNRIs) may help with neuropathic pain, depression and/or sleep Sleep Sleep is a reversible phase of diminished responsiveness, motor activity, and metabolism. This process is a complex and dynamic phenomenon, occurring in 4-5 cycles a night, and generally divided into non-rapid eye movement (NREM) sleep and REM sleep stages. Physiology of Sleep disturbance:
    • Amitriptyline
    • Nortriptyline 
  • Anticonvulsants may help with neuropathic pain: 
    • Gabapentinoids (gabapentin, pregabalin)
    • Carbamazepine
  • NSAIDs to suppress underlying inflammation that contributes to CRPS pathogenesis and pain:
    • Naproxen
    • Ibuprofen
  • Opioids Opioids Opiates are drugs that are derived from the sap of the opium poppy. Opiates have been used since antiquity for the relief of acute severe pain. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Opioid Analgesics are reserved for difficult-to-manage, moderate to severe pain:
    • Morphine
    • Fentanyl patch
    • Tramadol, tapentadol, and levorphanol are oral opioids with a dual mechanism of action involving classic mu opioid receptor agonization and inhibition of norepinephrine reuptake that have anecdotal evidence of superior control of neuropathic pain. 

Procedural therapy:

  • Peripheral nerve blocks targeting nerves known or suspected to be involved in the receptive field of the affected area(s):
    • Injection performed proximal to the affected area(s)
    • Diagnostic blocks are performed by injecting a local anesthetic only to the target nerve(s) and noting response to somatic blockade.
    • Successful peripheral nerve blockade may be followed by repeat injection with added steroid for a longer duration of action.
    • Successful peripheral nerve blockade may be followed by chemical or thermal neurolysis for an even longer duration of action (an option only for pure sensory peripheral nerves).
  • Sympathetic nerve blocks targeting the sympathetic chain ganglia (preaortic and/or periaortic) at the spinal level corresponding with involved area(s):
    • Diagnostic blocks are performed by injecting a local anesthetic only to the target area and noting response to sympathetic blockade.
    • Successful sympathetic blockade may be followed by repeat injection with added steroid for a longer duration of action.
    • Successful sympathetic blockade may be followed by chemical or thermal neurolysis for an even longer duration of action (higher risk of complications).
  • Spinal cord stimulation (SCS) or dorsal root ganglion (DRG) stimulation:
    • Involves the placement of conductive leads over the posterior columns (SCS) or DRG corresponding to the affected area(s)
    • Electrical stimulation delivered by an implantable pulse generator (IPG) “overrides” incoming nociceptive input from the affected area(s)
    • This is an example of the “gate theory” of afferent nerve conduction.
  • Intrathecal drug delivery:
    • Implantable reservoir of liquid drug agents delivered continuously to the intrathecal space via a tunneled catheter
    • Morphine is the only drug approved by the FDA for intrathecal delivery for pain control.
    • Ketamine, baclofen, bupivacaine, ziconotide, and hydromorphone are often added “off-label” as adjuvants or may be used as monotherapy.

Physical therapy

  • Affected individuals must use the affected area regardless of pain level. 
  • Irreversible atrophy and joint ankylosis may arise if an extremity is not used.
  • Using the extremity is important for desensitization and reeducating centrally mediated pain. 

Psychotherapy Psychotherapy Psychotherapy is interpersonal treatment based on the understanding of psychological principles and mechanisms of mental disease. The treatment approach is often individualized, depending on the psychiatric condition(s) or circumstance. Psychotherapy

  • For individuals at > 2 months after diagnosis
  • Identifying and treating anxiety, depression, or personality disorders
  • Psychological support is often very important to encourage participation, motivate, and maintain compliance with these difficult treatment regimens.
  • Follow-up must be frequent owing to unpredictable prognosis and potential for sudden deterioration of condition. 

Recurrence

  • Can be triggered by new trauma, cold exposure, psychological stress, or new surgical procedures
  • Surgery/interventional procedures are avoided during exacerbations of symptoms.
  • Risk-reduction measures for individuals who require surgery:
    • Intensive rehabilitation
    • Sympathetic block before surgery
    • Regional anesthesia Anesthesia Anesthesiology is the field of medicine that focuses on interventions that bring a state of anesthesia upon an individual. General anesthesia is characterized by a reversible loss of consciousness along with analgesia, amnesia, and muscle relaxation. Anesthesiology: History and Basic Concepts/analgesia
    • Bier block of the affected limb(s)
    • Perioperative calcitonin prophylaxis
    • Neuromodulation after surgery

Prognosis

  • Variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables 
  • Majority of individuals have at least moderate persistent chronic pain and some level of disability.
  • Prompt treatment improves prognosis.
  • Multidisciplinary pain management Pain Management Pain is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage. Pain is a subjective experience. Acute pain lasts < 3 months and typically has a specific, identifiable cause. Pain Management (pharmacologic, procedural, physical therapy, psychiatric) improves prognosis 
  • Recurrence: 10%–30% of cases (greater risk in younger individuals)

Differential Diagnosis

  • Somatic symptom disorder Somatic symptom disorder Somatic symptom disorder (SSD) is a condition characterized by the presence of 1 or more physical symptoms associated with excessive thoughts and feelings about symptom severity. Symptoms are usually not dangerous, but the patient devotes excessive time and energy to figuring out their underlying cause and how to treat them. Somatic Symptom Disorder (SSD): condition characterized by the presence of ≥ 1 physical symptom associated with excessive thoughts and feelings about their severity. Symptoms are usually not dangerous, but the individual devotes excessive time and energy to figuring out their underlying cause and how to treat them. Management relies on a strong therapeutic alliance between the individual and the provider. 
  • Fibromyalgia Fibromyalgia Fibromyalgia is a chronic pain syndrome characterized by widespread body pain, chronic fatigue, mood disturbance, and cognitive disturbance. It also presents with other comorbid symptoms such as migraine headaches, depression, sleep disturbance, and irritable bowel syndrome. Fibromyalgia: chronic pain syndrome characterized by widespread body pain, chronic fatigue, mood disturbance, and cognitive disturbance. Diagnosis is clinical, with laboratory exams and imaging reserved to rule out other causes for the spectrum of symptoms. Management is centered around education and lifestyle modification, with both pharmacologic (e.g., antidepressants, anticonvulsants) and nonpharmacologic (low-impact exercise, CBT) therapy showing efficacy. 
  • Deep vein thrombosis Deep vein thrombosis Deep vein thrombosis (DVT) usually occurs in the deep veins of the lower extremities. The affected veins include the femoral, popliteal, iliofemoral, and pelvic veins. Proximal DVT is more likely to cause a pulmonary embolism (PE) and is generally considered more serious. Deep Vein Thrombosis ( DVT DVT Deep vein thrombosis (DVT) usually occurs in the deep veins of the lower extremities. The affected veins include the femoral, popliteal, iliofemoral, and pelvic veins. Proximal DVT is more likely to cause a pulmonary embolism (PE) and is generally considered more serious. Deep Vein Thrombosis): most common form of thrombosis in the deep veins Veins Veins are tubular collections of cells, which transport deoxygenated blood and waste from the capillary beds back to the heart. Veins are classified into 3 types: small veins/venules, medium veins, and large veins. Each type contains 3 primary layers: tunica intima, tunica media, and tunica adventitia. Veins of the calf. Deep vein thrombosis Deep vein thrombosis Deep vein thrombosis (DVT) usually occurs in the deep veins of the lower extremities. The affected veins include the femoral, popliteal, iliofemoral, and pelvic veins. Proximal DVT is more likely to cause a pulmonary embolism (PE) and is generally considered more serious. Deep Vein Thrombosis describes the occlusion of the lumen of the deep venous plexus of the lower limb, due to endothelial injury, hypercoagulability, or venous stasis. The disorder can be distal or proximal, and the latter is more likely to cause pulmonary embolism Pulmonary Embolism Pulmonary embolism (PE) is a potentially fatal condition that occurs as a result of intraluminal obstruction of the main pulmonary artery or its branches. The causative factors include thrombi, air, amniotic fluid, and fat. In PE, gas exchange is impaired due to the decreased return of deoxygenated blood to the lungs. Pulmonary Embolism (PE). One of the cardinal manifestations of DVT DVT Deep vein thrombosis (DVT) usually occurs in the deep veins of the lower extremities. The affected veins include the femoral, popliteal, iliofemoral, and pelvic veins. Proximal DVT is more likely to cause a pulmonary embolism (PE) and is generally considered more serious. Deep Vein Thrombosis is unilateral edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema. Edema in CRPS can be so severe that Doppler ultrasonography is required to rule out DVT DVT Deep vein thrombosis (DVT) usually occurs in the deep veins of the lower extremities. The affected veins include the femoral, popliteal, iliofemoral, and pelvic veins. Proximal DVT is more likely to cause a pulmonary embolism (PE) and is generally considered more serious. Deep Vein Thrombosis.
  • Local infection: Osteomyelitis, cellulitis Cellulitis Cellulitis is a common infection caused by bacteria that affects the dermis and subcutaneous tissue of the skin. It is frequently caused by Staphylococcus aureus and Streptococcus pyogenes. The skin infection presents as an erythematous and edematous area with warmth and tenderness. Cellulitis, or an infected wound may present with pain, redness, and swelling of the affected limb or body area. Diagnosis is clinical but supported by imaging and cultures of the infected tissue. The mainstay of treatment is antimicrobial therapy. 
  • Compartment syndrome Compartment Syndrome Compartment syndrome is a surgical emergency usually occurring secondary to trauma. The condition is marked by increased pressure within a compartment that compromises the circulation and function of the tissues within that space. Compartment Syndrome: typically preceded by trauma (e.g., fracture Fracture A fracture is a disruption of the cortex of any bone and periosteum and is commonly due to mechanical stress after an injury or accident. Open fractures due to trauma can be a medical emergency. Fractures are frequently associated with automobile accidents, workplace injuries, and trauma. Overview of Bone Fractures, crush injury). The associated edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema is confined to fascial compartments and increases pressure. The increased pressure may lead to vascular ischemia and nerve and muscular tissue damage. The diagnosis is clinical and characterized by pain, pallor, and pulselessness. Compartment syndrome Compartment Syndrome Compartment syndrome is a surgical emergency usually occurring secondary to trauma. The condition is marked by increased pressure within a compartment that compromises the circulation and function of the tissues within that space. Compartment Syndrome is a surgical emergency that requires prompt intervention to prevent imminent limb loss. 

References

  1. Bruehl, S. (2015). Complex regional pain syndrome. BMJ 351:h2730. https://doi.org/10.1136/bmj.h2730 
  2. Harden, R. N., Bruehl, S., Stanton-Hicks, M., Wilson, P. R. (2007). Proposed new diagnostic criteria for complex regional pain syndrome. Pain Medicine 8:326–331. https://doi.org/10.1111/j.1526-4637.2006.00169.x 
  3. Marinus, J., et al. (2011). Clinical features and pathophysiology of complex regional pain syndrome. Lancet Neurology 10:637–648. https://doi.org/10.1016/S1474-4422(11)70106-5
  4. Ross, E. (2018). Pain syndromes other than headache. DeckerMed Medicine. Retrieved October 5, 2021, from https://doi.org/10.2310/PSYCH.6177 
  5. Dinakar, P. (2021). Pain management. In Jankovic, J., et al. (Eds.), Bradley and Daroff’s Neurology in Clinical Practice, 8th ed. pp. 753–775. Elsevier.
  6. Abdi, S. (2021). Complex regional pain syndrome in adults: pathogenesis, clinical manifestations, and diagnosis. Retrieved October 14, 2021, from https://www.uptodate.com/contents/complex-regional-pain-syndrome-in-adults-pathogenesis-clinical-manifestations-and-diagnosis 
  7. Abdi, S. (2021). Complex regional pain syndrome in adults: treatment, prognosis, and prevention. Retrieved October 14, 2021, from https://www.uptodate.com/contents/complex-regional-pain-syndrome-in-adults-treatment-prognosis-and-prevention

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