Neuropathic pain in veterinary patients, Part 1

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 easy part of this definition is "lesion," because it's something that can be identified via a history of trauma, surgery (e.g., severing nerve trunks during amputation) or imaging (e.g., tumor or intervertebral disk herniation).

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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.

"Sensitizing soup"

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

Downstream effects

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:

• Hyperalgesia: A noxious stimulus is more painful that it should be.

• Allodynia: A normally nonnoxious stimulus (e.g., touch) is painful.

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):

• Manual pinprick

• Thermal cold (acetone, cold metal 32 F [0 C])

• Thermal heat (object at 115 F [46 C])

• Pressure (algometer).

Allodynia involves stimuli that a normal animal would sense but not consider painful at all, yet in a neuropathic state is observably painful:

• Manual light pressure

• Light manual prick (e.g., with a sharpened wooden stick, stiff von Frey hair)

• Stroking (e.g., brush, gauze, cotton applicator)

• Thermal cold (object at 68 F [20 C])

• Thermal warm (object at 104 F [40 C]).

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.

References

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3. Doubell TP, Mannion RJ, Woolf CJ. The dorsal horn: state-dependent sensory processing, plasticity, and the generation of pain. In: Wall PD, Melzak R, eds. Textbook of pain. 4th ed. New York: Churchill-Livingston, 1999;165-182.

4. Baron R. Peripheral neuropathic pain: from mechanisms to symptoms. Clin J Pain 2000;16(2 Suppl):S12-S20.

5. Ramer MS, Thompson SW, McMahon SB. Causes and consequences of sympathetic basket formation in dorsal root ganglia. Pain 1999;6:S111-S120.

6. Devor M, Govrin-Lippmann R, Angelides K. Na+ channel immunolocalization in peripheral mammalian axons and changes following nerve injury and neuroma formation. J Neurosci 1993;13(5):1976-1992.

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9. Sun S, Cao H, Han M, et al. New evidence for the involvement of spinal fractalkine receptor in pain facilitation and spinal glial activation in rat model of monoarthritis. Pain 2007;129(1-2):64-75.

10. Honoré P, Menning PM, Rogers SD, et al. Neurochemical plasticity in persistent inflammatory pain. Prog Brain Res 2000;129:357-363.

11. Giordano J. The neuroscience of pain and analgesia. In: Boswell MV, Cole BE, eds. Weiner's pain management. 7th ed. Boca Raton, Fla: Taylor & Francis, 2006.

12. Lascelles BD, Cripps PJ, Jones A, et al. Efficacy and kinetics of carprofen, administered preoperatively or postoperatively for the prevention of pain in dogs undergoing ovariohysterectomy. Vet Surg 1998;27(6):568-582.

13. Geber C, Baumgartner U, Schwab R, et al. Revised definition of neuropathic pain and its grading system: an open case series illustrating its use in clinical practice. Am J Med 2009;122(10 Suppl):S3-S12.

14. Treede RD, Jensen TS, Campbell JN, et al. Neuropathic pain: redefinition and grading system for clinical and research purposes. Neurology 2008;70(18):1630-1635.

15. Mathews KA. Neuropathic pain in dogs and cats: if only they could tell us if they hurt. Vet Clin North Am Small Anim Pract 2008;38(6):1365-1414.

16. Muir WW 3rd, Wiese AJ, Wittum TE. Prevalence and characteristics of pain in dogs and cats examined as outpatients at a veterinary teaching hospital. J Am Vet Med Assoc 2004;224(9):1459-1463.

17. Wiese AJ, Muir WW 3rd, Wittum TE. Characteristics of pain and response to analgesic treatment in dogs and cats examined at a veterinary teaching hospital emergency service. J Am Vet Med Assoc 2005;226(12):2004-2009.