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10 Articles in Volume 9, Issue #5
Dextrose Prolotherapy for Recurring Headache and Migraine Pain
Diagnosis of Low Back Pain
Ethics, Education, and Policy: Relationship and Mutual Reliance
Human Chorionic Gonadotropin in Pain Treatment
Musculoskeletal Ultrasound
Painful Herpetic Reactivation and Degenerative Musculoskeletal Injury
Post-stroke Pain
Preventive Medications for Chronic Daily Headache
The Pathophysiology of Neuropathic Pain
Use of Pulsed Radiofrequency in Clinical Practice

The Pathophysiology of Neuropathic Pain

A discussion of the pathophysiology of neuropathic pain and an overview of the modalities used to alleviate it.
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Neuropathic Pain is a complex, chronic pain state that usually is accompanied by tissue injury. Neuropathic pain is common in clinical practice and presents a challenge to patients and clinicians alike. With neuropathic pain, the nerve fibers themselves may be damaged, dysfunctional or injured. Neuropathic pain is the result of disease or injury to the peripheral or central nervous system and the lesion may occur at any point. These damaged nerve fibers send incorrect signals to other pain centers. The impact of a nerve fiber injury includes a change in nerve function—both at the site of the injury and areas around the injury.1 Clinical manifestations of neuropathic pain typically include positive sensory phenomena such as spontaneous pain, paresthesias and hyperalgesia.2

Neuropathic pain as defined by the International Association of the Study of Pain (IASP) is “pain initiated or caused by a primary lesion or dysfunction of the nervous system.”3 It can result from damage anywhere along the neuraxis: peripheral nervous system, spinal or supraspinal nervous system. Traits that differentiate neuropathic pain from other types of pain include pain and sensory symptoms lasting beyond the healing period. It is characterized in humans by spontaneous pain, allodynia (the experience of non-noxious stimuli as painful), and causalgia (constant burning pain). Spontaneous pain includes sensations of ‘pins and needles,’ shooting, burning, stabbing and paroxysmal pain (electric-shock like) often associated with dysesthesias and paresthesias.4 These sensations not only affect the patient’s sensory system, but also the patient’s well-being, mood, focus and thinking. Neuropathic pain consists of both “negative” symptoms (sensory loss and numbness) and “positive” symptoms (paresthesias, spontaneous pain, increased sensation of pain).

Conditions frequently associated with neuropathic pain can be categorized into two major groups: pain due to damage in the central nervous system and pain due to damage to the peripheral nervous system. Cortical and sub-cortical strokes, traumatic spinal cord injuries, syringo-myelia and syringobulbia, trigeminal and glossopharyngeal neuralgias, neoplastic and other space-occupying lesions are clinical conditions that belong to the former group. Nerve compression/ entrapment neuropathies, ischemic neuropathy, peripheral polyneuropathies, plexopathies, nerve root compression, post-amputation stump and phantom limb pain, postherpetic neuralgia and cancer-related neuropathies are clinical conditions that belong to the latter group.5


The pathophysiologic processes and theories underlying neuropathic pain are multiple. Before going into these processes, a review of normal pain circuitry is imperative. Normal pain circuitries involve activation of a nociceptor (pain receptor) in response to a painful stimulus. A wave of depolarization is sent to the first-order neurons, with sodium rushing in via sodium channels and potassium rushing out. First order neurons end in the brain stem in the trigeminal nucleus or in the dorsal horn of the spinal cord. It is here that the electrochemical signal opens voltage-gated calcium channels in the pre-synaptic terminal, allowing calcium to come in. Calcium allows glutamate, an excitatory neurotransmitter, to be released into the synaptic space. Glutamate binds to NMDA receptors on the second-order neurons, causing depolarization. These neurons then cross over in the spinal cord and go up to the thalamus, where they synapse with third-order neurons. These, in turn, connect to the limbic system and cerebral cortex. There is also an inhibitory pathway that prevents pain signal transmission in the dorsal horn. Anti-nociceptive neurons originate in the brain stem and travel down the spinal cord where they synapse with short interneurons in the dorsal horn by releasing serotonin and norepinephrine. The interneurons modulate the synapse between the first-order neuron and the second-order neuron by releasing gamma amino butyric acid (GABA), an inhibitory neurotransmitter. Hence, pain cessation is the result of inhibition of synapses between first and second order neurons, while pain enhancement may be the result of suppression of inhibitory synaptic connections.

The mechanism underlying neuropathic pain, however, is not as clear. Several animal studies have shown that many mechanisms may be involved. However, one must keep in mind that what applies to animals may not necessarily apply to humans. First order neurons may increase their firing if they are partially damaged and increase the number of sodium channels. Ectopic discharges are a result of enhanced depolarization at certain sites in the fiber, leading to spontaneous pain and movement-related pain. Inhibitory circuits may be impaired at the level of the dorsal horn or brain stem (or both) allowing pain impulses to travel unopposed. In addition, there may be alterations in the central processing of pain when—due to chronic pain and use of some drugs—second- and third-order neurons may develop a “memory” of pain and become sensitized. There is then heightened sensitivity of spinal neurons and reduced activation thresholds. Another theory entertains the idea of sympathetically-maintained neuropathic pain. This idea has been demonstrated by analgesia following sympathectomy in animals6 and humans.7 However, a combination of mechanisms can be involved in many chronic neuropathic or mixed somatic and neuropathic pain states.

One of the challenges in the pain field, and even more so in regards to neuropathic pain, is the ability to assess it. There is a dual component to this: (1) assessing quality, intensity and improvement; and (2) accurately diagnosing neuropathic pain.

There are, however, some diagnostic tools that may assist clinicians in evaluating neuropathic pain. For starters, nerve conduction studies and sensory-evoked potentials can identify and quantify the extent of damage to sensory, but not nociceptive, pathways by monitoring neurophysiological responses to electrical stimuli.8,9 In addition, quantitative sensory testing measures perception in response to external stimuli of varying intensities by applying stimuli to the skin. Mechanical sensitivity to tactile stimuli is measured with von Frey hairs, pinprick with weighted needles, vibration sensitivity with vibrameters and thermal pain with thermodes.10 It is also very important to perform a thorough neurological evaluation to identify motor, sensory and autonomic dysfunctions. Finally, there are numerous questionnaires used to distinguish neuropathic pain from nociceptive pain. Some of them include only interview questions (e.g., the Neuropathic Questionnaire11 and ID Pain12), while others include both interview questions and physical tests (e.g., the Leeds Assessment of Neuropathic Symptoms and Signs scale13) and the very novel tool, the Standardized Evaluation of Pain that combines six interview questions and ten physical tests.10

Last updated on: December 29, 2011
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