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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

Neuropathic pain: a maladaptive response of the nervous system to damage

Annu Rev Neurosci. 2009;32:1-32

This article provides a useful overview of neuropathic pain.  The authors begin by distinguishing it from other types of pain (nociceptive, inflammatory, and dysfunctional).  They then go on to describe neurobiological mechanisms involved in neuropathic pain.

Key points from this article are summarized below.

Causes of Neuropathic Pain
The overarching cause of neuropathic pain is lesions to the peripheral nervous system (PNS).  Those can be caused by:

  1. mechanical trauma
  2. metabolic diseases
  3. neurotoxic chemicals
  4. infection
  5. tumor invasion

Most important to note is that in neuropathic pain, there are many pathophysiological changes in the PNS and the central nervous system (CNS).  It is, in fact, a manifestation of maladaptive plasticity of the nervous system, and while the primary disease (and the neural changes secondary to it) is important to understand, it is the cascade of PNS and CNS changes that cause chronic neuropathic pain.

The authors also point out that “the pain associated with acute neural damage usually transitions to chronic neuropathic pain in a minority of patients.”

Multiple Neurobiological Mechanisms Involved in Neuropathic Pain
Changes in the PNS and the CNS are widespread and multiple in neuropathic pain.  These changes include:

  1. ectopic generation of action potentials
  2. central sensitization
  3. low-threshold Aβ fibers
  4. gene regulation
  5. disinhibition at multiple levels of the neuraxis
  6. loss of synaptic connectivity
  7. creation of new synaptic circuits
  8. neuroimmune interactions

Genetics Play a Role
There are several risk-conferring genes for the development of neuropathic pain, and while no whole-genome association study has been done for neuropathic pain, candidate gene-association studies have noted (preliminarily) polymorphisms in catechol-O-methyltransferase (COMT) that modulate nociceptive and dysfunctional pain.  This and other genetic polymorphisms may provide clues to the genetics of neuropathic pain.

Effect on Treatment
Currently, treatment of neuropathic pain is done based on the underlying disease.  This article suggests that “given the complexity of numerous intertwined genetic, cellular, and molecular components that cause neuropathic pain, clinical classifications need to incorporate multiple aspects of the pain phenotype to guide the identification of underlying mechanisms and helps assess the likelihood of response to treatment.”


As recently as five years ago, the definition of neuropathic pain was pain thought to be resulting from "dysfunction" of the central or peripheral nervous system.  More recently, that definition has changed to a "disease" of the somatosensory nervous system.

This article provides a wonderful review of exactly why this definition has changed: that pain is actually an expression of maladaptive plasticity within the nociceptive system and that several changes must occur to create this disease state.  The authors have been able to nicely describe a very complex disease state that is continuing to be further elucidated into the causes and mechanisms associated with it.

It is important to note at the end of the article that the authors discuss how our current treatment regimens need to change.  Right now, we merely suppress symptoms, but we need to move toward a more disease-modifying strategy that can prevent the neuronal plasticity as well as reduce the potential risk for developing this disease.

Next Article:
Clinical features and pathophysiology of complex regional pain syndrome
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