Neuropathic Pain: A Literature Review
Chronic pain is a common problem in the community and major source of healthcare utilization in the United States. In one study, the reported prevalence of chronic pain in the general population was as high as 46.5%.1 Discussion of chronic pain can be quite complex, but one simplified approach is to classify it into 3 categories: pain from tissue damage (nociceptive pain), pain from somatosensory damage (neuropathic pain), or a mix of the two. The term “neuropathic pain” has come into common use only in the last 25 years and is frequently cited as a common cause of chronic pain.
In this article, I have reviewed 6 papers published recently that provide important information in answering questions that general practitioners may be faced with when seeing patients with neuropathic pain.
Classifying Neuropathic Pain
Clifford Woolf, MD, PhD, is a pioneer in advancing our knowledge of neuropathic pain and its associated conditions. As recently as 5 years ago, the definition of neuropathic pain was pain thought to be resulting from “dysfunction” of the central or peripheral nervous system (PNS). More recently, that definition has changed to a “disease” of the somatosensory nervous system. Dr. Woolf and his colleagues present a good introduction to the causes of neuropathic pain, the mechanisms involved (including genetics), and the effect of treatment.2 Table 1 summarizes key points from the article.
Dr. Woolf and colleagues review exactly why the definition of neuropathic pain has changed: that neuropathic pain is actually an expression of maladaptive plasticity within the nociceptive system and that several changes must occur to create this disease state. 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 (Table 2). As the authors note: “the pain associated with acute neural damage usually transitions to chronic neuropathic pain in a minority of patients.”2
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 based on the underlying disease. It is important to note 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. Woolf et al suggest 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.”2
Specific Neuropathic Conditions
While the number of neuropathic conditions are long and numerous, I chose to review 2 specific conditions: complex regional pain syndrome3 and diabetic peripheral neuropathy.4
Complex regional pain syndrome (CRPS) has been described in the literature as early as 1864 during the Civil War, when Silas Weir Mitchell and colleagues published their book titled Gunshot Wounds and Other Injuries of the Nerves.5 In it, they describe “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.”
CRPS was previously called reflex sympathetic dystrophy (RSD) or causalgia (from the greek, kausis meaning “burning,” and algos meaning “pain”). However, not every presentation of the disease presents with a sympathetic component. For this reason, the Special Consensus Group of the International Association for the Study of Pain (IASP) created the term complex regional pain syndrome in 1994 to allow for a more broad inclusion of patients that showed varying levels of the disease process. In 2007, the diagnostic criteria were further revised and are commonly referred to as the “Budapest criteria.”6
While the exact mechanisms are still not fully understood, Marinus et al presents the current understanding of the mechanisms involved.3 The pathophysiology of 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.
Patients with CRPS often experience vasomotor dysfunction. Typically, this is the pattern: 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.
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. Figure 1 illustrates a patient with lower extremity CRPS.