Complex Region Pain Syndrome
The following is based on the work: Complex regional pain syndrome: a recent update (2017). En Lin Goh, Swathikan Chidambaram, and Daqing Ma.
Classification
CRPS types I and II that are characterised by the absence or presence of identifiable nerve injury.
CRPS type I: usually develops after an initiating noxious event. Is not limited to the distribution of a single peripheral nerve, and is disproportionate to the inciting event. Associated with oedema, changes in skin blood flow, abnormal sudomotor activity in the region of the pain, allodynia and hyperalgesia and commonly involves the distal aspect of the affected extremity or with a distal to proximal gradient.
CRPS type II: defined as a burning pain, allodynia and hyperpathia occurring in a region of the limb after partial injury of a nerve or one of its major branches innervating that region
Epidemiology
CRPS occurs most frequently in:
61 to 70 yoa.
< female (3x more females than males).
Increased preponderance for the upper limbs with a ratio of 3:2 compared to the lower limbs.
Risk factors: menopause, history of migraine, osteoporosis, asthma and angiotensin-converting enzyme (ACE) inhibitor therapy and elevated intracast pressure due to a tight case or extreme positions.
Prognosis poorer in smokers.
Pathophysiology
Inflammation
Acute phase of CRPS supports the hypothesis that the development of this condition is due to an exaggerated inflammatory response to trauma.
Clinical findings reveal the five cardinal signs of inflammation: pain, oedema, erythema, increased temperature and impaired function.
Tissue trauma triggers the release of pro-inflammatory cytokines such as interleukin(IL)-1β, IL-2, IL-6 and tumour necrosis factor-α (TNF-α) along with neuropeptides including calcitonin gene-related peptide, bradykinin and substance P. These substances increase plasma extravasation and vasodilation, producing the characteristic features of acute CRPS
Altered cutaneous innervation
Initial neuronal injury, however imperceptible has been implicated as an important trigger in the development of both CRPS types I and II.
This has been supported by studies demonstrating a reduction in C-type and Aδ-type cutaneous afferent neuron fibre density in the CRPS-affected limb compared to the unaffected limb, with these changes primarily affecting nociceptive fibres.
The decrease in C-type and Aδ-type fibres was associated with an increase in aberrant fibres of unknown origin, and it has been postulated that the exaggerated pain sensation may be due to altered function of these fibres
Central and peripheral sensitisation
Following tissue damage and/or neuronal injury, alterations in the central and peripheral nervous systems lead to increased inflammation, and an enhanced responsiveness to pain. These adaptations act as protective mechanisms to promote avoidance of activities that cause further injury.
Within the central nervous system (CNS), persistent and intense noxious stimulation of peripheral nociceptive neurons results in central sensitisation.
Accordingly, there is alteration in nociceptive processing in the CNS and increased excitability of secondary central nociceptive neurons in the spinal cord.
This is mediated by the release of neuropeptides such as substance P, bradykinin and glutamate by peripheral nerves, which sensitise and increase the activity of local peripheral and secondary central nociceptive neurons resulting in increased pain from noxious stimuli (hyperalgesia) and pain in response to non-noxious stimuli (allodynia).
Research has shown that CRPS patients have a significantly greater windup to repeated stimulation of the affected limb compared to the contralateral limb or other limbs.
Altered sympathetic nervous system function
In the chronic (cold) phase of the clinical course of CRPS, the CRPS-affected limb is cyanosed and clammy as a result of vasoconstriction and sweating. This suggests that excessive sympathetic nervous system outflow is a driving factor in progression of the condition and maintenance of the pain.
Expression of adrenergic receptors on nociceptive fibres following injury may contribute to sympatho-afferent coupling increasing the pain intensity
Circulating catecholamines
Variation in the clinical features of CRPS as the condition progresses from the acute (warm) phase to the chronic phase may be attributed to alterations in catecholaminergic mechanisms.
During the acute phase, the CRPS-affected limb demonstrates a reduction in the levels of circulating plasma norepinephrine compared to the unaffected limb.
As a result, there is compensatory upregulation of peripheral adrenergic receptors causing supersensitivity to circulating catecholamines. Consequently, excessive vasoconstriction and sweating occurs following exposure to catecholamines, giving rise to the characteristic cold and blue extremity seen during the chronic phase.
Autoimmunity
The presence of immunoglobulin G (IgG) autoantibodies against surface antigens on autonomic neurons in the serum of patients with CRPS suggests that autoimmunity may play a role in the development of this condition.
This is supported by the results of a small pilot trial where patients with CRPS who were given intravenous immunoglobulin treatment demonstrated a significant reduction in pain symptoms when compared with those given a placebo.
Brain plasticity
Neuroimaging studies of patients with CRPS have demonstrated a decrease in area representing the CRPS-affected limb in the somatosensory cortex compared to the unaffected limb.
The sensory representation of the affected limb, as part of the Penfield homunculus is distorted, with shrinkage and shifting of the area.
The extent of reorganisation bears significant correlation with the pain intensity and degree of hyperalgesia experienced by the patient, and these alterations return to normal following successful CRPS treatment.
Genetic factors
Although there is a lack of consensus regarding the influence of genetic factors in CRPS, family studies have suggested a genetic preponderance towards developing this condition.
Psychological factors
Due to the prevalence of anxiety and depression in patients with CRPS and the unusual nature of symptoms, psychological factors have been hypothesised to play a role in the development or propagation of CRPS.
Management
Physical and occupational therapy
Physical and occupational therapy is a key component of the rehabilitation process in patients with CRPS and is recommended as the first-line treatment. Patients can develop kinesophobia and the aim of therapy is to overcome this fear of pain and enable the patient to gain the best functional use of the limb.
Psychological therapy
Chronic pain affects the health-related quality of life and places a huge emotional and psychological burden on patients. Thus, it is essential for newly diagnosed patients with CRPS to have a discussion with a psychological care provider regarding their condition and its progression as well as the need for active self-management and participation in a care plan
Medical management
Corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs) reduce inflammation and have been used in the treatment of CRPS.
Anti-oxidants in the treatment of CRPS has been based on the perception that oxygen free radicals generated by the inflammatory process may be a key component of the propagation of the disease process.
Anti-convulsant drugs such as gabapentin
NMDA (ketamine): the central sensitisation and alteration of brain plasticity that occurs could potentially be reversed with the use of the NMDA receptor antagonist ketamine.
Placebo-controlled studies have shown both topical and intravenous administration of ketamine to be effective at alleviating pain and inducing complete remission in treatment resistant patients, thereby highlighting the potential of this approach
Phenoxybenzamin: sympathetically mediated pain in CRPS has led to the studies investigating the role adrenergic receptor antagonists or alpha-2 adrenergic agonists in treating this condition.
Nifedipine: calcium-channel blockade with nifedipine has been reported to be effective in managing the vasoconstriction occurring in this phase of CRPS
Calcitonin preserves bone mass, has effects on microvasculature and has anti-nociceptive effects, which have been found to be effective in treating acute and chronic pain. Bisphosphonates inhibit osteoclasts, slowing down bone resorption and increasing bone mineral density and are well-established to be effective at providing pain relief.
Opiods: there are contrasting views regarding the use of opioid therapy in the treatment of CRPS.
Intravenous immunoglobulin (IVIG): The discovery of autoantibodies against adrenergic receptors suggesting that CRPS has an autoimmune component provides the basis for the use of intravenous immunoglobulin (IVIG), which is a potent anti-inflammatory and immune-modulator
Anaesthesia therapy
An alternative approach studied involves the use of sympathetic blockade, which has diagnostic and therapeutic benefits.
Surgical management
Neuromodulation (spinal cord stimulation): may play a role in treating CRPS, especially in patients in unresponsive to sympathetic blockade.
Sympathectomy (including radiofrequency sympathectomy).
Emerging treatments
Immunomodulation (anticancer drugs)
Chronic regional and neurogenic inflammation are thought to play a key role in the initiation and propagation of CRPS.
Patients suffering from this condition display systemic elevation of pro-inflammatory cytokines and a corresponding reduction in the anti-inflammatory cytokine IL-10.
Anti-cancer drugs such as lenalidomide and thalidomide possess anti-inflammatory and immunomodulatory effects and have shown promise in alleviating this condition.
Hyperbaric oxygen therapy
The anti-nociceptive effect of hyperbaric oxygen therapy (HBOT) has been well-documented in animal models.
Botulinum toxin-A (BTX-A)
BTX-A has been shown to confer pain relief in neuropathic pain, which complicates disorders of the central and peripheral nervous system and may therefore demonstrate efficacy in managing CRPS.
Plasma exchange
Recent developments in the understanding of the autoimmune aetiology of CRPS have highlighted the potential use of plasma exchange therapy, which has demonstrated benefit in other autoimmune disorders.
