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Issue 1, Volume 2
Neuropathic Pain Review
Overview, Assessment, and Treatment
6 Articles in this Series
Neuropathic pain: a maladaptive response of the nervous system to damage
Clinical features and pathophysiology of complex regional pain syndrome
Diabetic neuropathy: clinical manifestations and current treatments
NeuPSIG guidelines on neuropathic pain assessment
Treatment of neuropathic pain: an overview of recent guidelines
Recommendations for the pharmacological management of neuropathic pain: an overview and literature update

Clinical features and pathophysiology of complex regional pain syndrome

Lancet Neurol. 2011;10(7):637-48

The pathophysiology of complex regional pain syndrome (CRPS) is multifactorial.  In this review, the authors suggest that the following factors account for most or all of the clinical features in CRPS:

Inflammation (Neurogenic Inflammation)
In-vivo experiments in humans have shown that cytokine signaling is amplified even after minor tissue trauma.  This excites nociceptors and can induce long-term peripheral sensitization; it can also increase the release of inflammatory neuropeptides in primary afferent neurons.  Substance P and calcitonin-gene-related peptide (CGRP) can be released, causing vasodilation and protein extravasation; the signs this causes are termed neurogenic inflammation.

The authors suggest that post-junction signaling, which is caused by either hampered inactivation of neuropeptides or increased receptor availability, is the most likely mechanism leading to this neurogenic inflammation in CRPS.

Vasomotor Dysfunction
Patients with CRPS often experience vasomotor dysfunction.  Typically, the pattern is:  the affected limb is warmer than the unaffected limb early on, but later, it becomes colder than the unaffected limb.  This pattern of temperature change in CRPS has been studied, and the data suggest that in CRPS, there is a unilateral inhibition of cutaneous sympathetic vasoconstrictor neurons.  The authors suggest that the initial trauma triggers functional changes in the spinal cord, brainstem, or brain, and these changes lead to thermoregulatory impairment.

It should be noted that not all CRPS patients demonstrate this pattern of temperature change in the affected limb.

Nociceptive Sensitization
The inhibition of cutaneous sympathetic vasoconstrictor neurons may lead to the sensitization of the nociceptors.  There may be sympathetic-afferent coupling, which is the theoretical basis for sympathetically maintained pain.

Maladaptive Neuroplasticity
Hyperalgesic priming may explain why some patients develop chronic pain.  This theory suggests that transient insult causes long-term changes in the primary afferent nociceptors, particularly the epsilon isoform of protein kinase C.  They are then “primed” to be hyperresponsive to further insults, even mild ones.  This aberrant afferent activity can lead to plastic changes in the CNS.


Complex regional pain syndrome (CRPS) has been described in the literature as early as 1864 during the Civil War, when Silas Weir Mitchell published his book titled Gunshot Wounds and Other Injuries of Nerves.  In it, he describes "long after the trace of the effects of a wound has gone….neuralgic symptoms are apt to linger, and too many carry with them throughout long years this final reminder of the battlefield."

Until about a decade ago, CRPS was called reflex sympathetic dystrophy (RSD) or causalgia (if a known nerve was injured).  As our limited understanding of this disease has grown, it was clear that we had to change the name to a more inclusive term, hence CRPS.

As mentioned in the introduction, there have been recent changes to meeting the clinical definition of CRPS. This article discusses what we currently think are some of the multifactorial components of the pathophysiology which include inflammation, vasomotor dysfunction, nociceptive sensitization, and maladaptive neuroplasticity.   All these components are still unable to fully provide us with a clear understanding of why this phenomenon occurs after an injury, which leaves us to continue the daunting task of piecing together these aspects and finding the missing links.  While CRPS is essentially a diagnosis of exclusion, it is important to keep this in our differential since early recognition and subsequent intervention has shown better outcomes.

Next Article:
Diabetic neuropathy: clinical manifestations and current treatments
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