Neuropathic pain occurs when something has gone terribly wrong with the normal protective mechanisms of nociception and pain signaling. The International Association for the Study of Pain defines neuropathic pain as "pain caused by a lesion or disease of the somatosensory nervous system."1
The much more difficult part of this definition has to do with "disease," because central and peripheral hypersensitization characteristics of neuropathic pain involve biochemical and microanatomical changes below the sensitivity of any conventional imaging to detect.
Sustained or intense nociception and damage to peripheral nerves considerably alters the dynamic of the usual pain machinery, moving it from a physiologic, protective nature to a maladaptive one. The constant or exaggerated presence of inflammatory and bioactive mediators at a peripheral site forms a "sensitizing soup" that creates relentless excitation of afferent nociceptors. This construct of direct nerve damage can cause a tsunami of excitatory neuropeptides in the dorsal horn of the spinal cord.
Normally, stubborn N-methyl-D-aspartate calcium channels are thrown wide open. The resulting calcium influx into postsynaptic interneurons elicits a cascade of signaling mechanisms involving protein kinase C, nitrous oxide, substance P and neurokinin (NK-1) receptors (expression of the NK-1 receptor appears to also contribute to opioid-induced hyperalgesia and tolerance2 ), calcitonin gene-related peptide and more. Not only does the interneuron stay depolarized, but a phenotypic change may be induced where it may not reset. Expressions of the c-fos, c-jun and Krox-24 genes transcribe new (probably aberrant) proteins that produce permanent microstructural changes of the neuron.
Furthermore, the afferent nociceptor can conduct a signal efferently, in an antidromic fashion. There, at the peripheral site of original stimulus, further release of inflammatory mediators is elicited, recruiting and activating other previously innocent bystanding nociceptors, further bombarding the dorsal horn with impulses.2 As the feedback loop persists, more and more cells express c-fos and other genes, nerve growth factor is stimulated into production (suspected to be from glial cells) and more interconnections are made between types and locations of neurons in the spinal cord.3 And mere touch now can be perceived as pain.
These interconnections are not isolated to somatosensory neurons, for they've been shown to newly express adrenoceptors that are activated by catecholamines. Sympathetic stimulation may then result in nociception4,5 and may in fact be central to the pathophysiology of some of the more intense refractory forms of neuropathic pain known as complex regional pain syndrome. Moreover, neuropathic pain is associated with alterations in receptor location (more places on more axons) and sensitivity to excitatory amino acids (greater) throughout the nervous system.6
Glial cells (astrocytes, microglia, oligodendrocytes) in the spinal cord, whose purpose was once thought to be merely structural and macrophage-like in nature (i.e., providing synaptic architecture, host defense, and myelin, respectively), are now known to also be highly integrated into the pain process, particularly regarding chronic and neuropathic pain.7 Recently, this was described as the tetrapartite synapse, which includes an astrocyte, microglial cell and the pre- and post-synaptic neuronal terminal.8
Glia are the predominate source of nerve growth factor, and a recently isolated chemokine, fractalkine, appears to be a neuron-glial cell signal, activating glially dependent pain.9 Indeed, glia appear to play a primary role regarding synaptic strength, plasticity and sensitization in the spinal cord, which exhibits substantial change under the influence of chronic or intense pain.10
The result of all this is reduced firing thresholds, upregulation of central neuronal activity, downregulation of inhibitory activity, expansion of the receptive field, peripheral hypersensitivity and intensified pain responses to further stimulation.11 In short, it is a neurologic natural disaster.
Eventually, as the process of pain becomes located centrally (i.e., in the spinal cord) rather than at the site of the original stimulus, the pain is said to be "neuropathic" in origin. Once neural pathways are thus sensitized, the physiologic (and physical) responses to pain may persist, even when the peripheral nerves themselves are blocked (or even transected).12 Clearly, at this point, pain has become a disease itself: Pain is created either without the presence of a noxious stimulation or far out of proportion to it.
Understand that the progression to neuropathic pain does not necessarily result from chronic pain conditions. In some cases, a patient can find itself moving toward a neuropathic state within a matter of minutes to hours of experiencing tissue damage.
Identifying neuropathic pain
How do we know if a patient has neuropathic pain? It isn't easy to discern. Two main clinical features are:
Human patients are considered to have neuropathic pain if they fulfill five of the eight following criteria13,14 :
1. History consistent with nerve injury
2. Pain in the absence of ongoing tissue damage
3. Pain plus sensory deficit
4. Character of pain is burning, pulsing, shooting or stabbing
5. Paroxysmal or spontaneous pain
6. Associated dysesthesia (e.g., tingling)
7. Allodynia, hyperpathia or hyperalgesia
8. Associated autonomic features (e.g., edema, vasodilation/constriction).
In people, these criteria are divined through history, physical examination and semiquantitative dynamic testing (e.g., feather brushing, use of von Frey devices, touching with hot or cold objects), necessarily involving patient self-reporting as well as observer evaluation. Two scoring systems in common use are the Neuropathic Pain Scale (NPS) and Leeds Assessment of Neuropathic Systems and Signs (LANSS).
In veterinary medicine—in the obvious absence of self-reporting—we can rely only on observer evaluation. Adapting from the human scheme, Karol Mathews proposed the following qualitative criteria in animals15 :
Hyperalgesia involves stimuli that would be uncomfortable for normal patients but observably painful in a neuropathic state. It is suggested that a "normal" area be tested in the affected patient, against which testing the suspected neuropathic region can be compared (clipping hair may be required):
Allodynia involves stimuli that a normal animal would sense but not consider painful at all, yet in a neuropathic state is observably painful:
Two studies looked at the prevalence of pain and neuropathic pain in veterinary patients—one in an outpatient population and one in an emergency and critical-care setting.16,17 For outpatient dogs and cats, pain was present in 20 percent and 14 percent of patients, respectively, and neuropathic pain in 7 percent to 8 percent of both species.16 In the emergency setting, pain was present in more than 50 percent of both patient populations, and neuropathic pain was present in 9 percent of dogs and 3 percent of cats.17
In part two of this series, we'll examine neuropathic pain syndromes and neuropathic components.
Dr. Epstein is president of the International Veterinary Academy of Pain Management and medical director at the Total Bond Animal Hospital in Gastonia, N.C.
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