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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.

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

Treatment Modalities

Pharmacological regimens aim at the mechanisms of neuropathic pain. However both pharmacologic and non-pharmacologic therapies provide complete or partial relief in only about half of patients.14 Many evidence-based reviews suggest using combinations of drugs to target as many mechanisms as possible.15-19 The majority of studies have investigated mostly post-herpetic neuralgia and painful diabetic neuropathies but the results may not necessarily apply to all neuropathic pain conditions.


Antidepressants increase synaptic serotonin and norepinephrine levels thus enhancing the effect of the descending analgesic system.15,18,20 They have been the mainstay of neuropathic pain therapy. Analgesic actions may be attributable to nor-adrenaline and serotonin reuptake blockade (presumably enhancing de-scending inhibition), NMDA-receptor antagonism and sodium-channel blockade.21 Tricyclic antidepressants (TCAs; e.g., amitriptyline, imipramine, nortrip-tyline and doxepine) are effective against steady burning or aching pain and spontaneous pain. Tricyclic antidepressants have been proven significantly more effective for neuropathic pain than the selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, paroxetine, sertraline and citalopram. The reason may be that they inhibit reuptake of both serotonin and nor-epinephrine, while SSRIs only inhibit serotonin reuptake.22-26

Tricyclic antidepressants can have unpleasant side effects, including sedation, constipation, confusion, cardiac conduction blocks, tachycardia and ventricular arrhythmias. They can also cause weight gain, a lowered seizure threshold and orthostatic hypotension. Tricyclics must be used with caution in the elderly, who are especially prone to their serious side effects. The drug concentration in the blood should be monitored to avoid toxicity in patients who are slow drug metabolizers.19

Serotonin-norepinephrine reuptake inhibitors (SNRIs) are a new class of antidepressants. Like TCAs, they seem to be more effective than SSRIs for treating neuropathic pain because they also inhibit reuptake of both nor-epinephrine and serotonin.27 Venlafaxine is as effective against painful polyneuropathies (including painful diabetic neuropathy) as imipramine (the reference TCA) and both are significantly better than placebo. Like the TCAs, the SNRIs seem to confer benefits independent of their antidepressant effects. Side effects include sedation, confusion, hypertension and withdrawal syndrome.

Antiepileptic Drugs

Antiepileptic drugs can be used as first-line therapy especially for certain types of neuropathic pain. They act by modulating voltage-gated sodium and calcium channels, by enhancing the inhibitory effects of GABA and by inhibiting excitatory glutaminergic transmission. Anti-epileptic drugs have not been shown to be effective for acute pain.28 In chronic pain cases, antiepileptic drugs seem to be effective only in trigeminal neuralgia. Carbamazepine is routinely used for this condition. Gabapentin, which acts by inhibiting calcium channel function through agonist actions at the alpha-2 delta subunit of the calcium channel, is also recognized as effective for neuropathic pain. However, gabapentin acts centrally so it may cause fatigue, confusion and somnolence.

Non-Opioid Analgesics

There is a lack of solid data supporting the use of non-steroidal anti-inflammatory drugs (NSAIDs) in the relief of neuropathic pain. This may be due to the lack of an inflammatory component in neuropathic pain. However, they have been used synergistically with opioids as adjuvants in treating cancer pain. There have been reported complications, though, especially in severely debilitated patients.29

Opioid Analgesics

Opioid analgesics have been a topic of much debate in relieving neuropathic pain. They act by inhibiting central ascending pain impulses. Traditionally, neuropathic pain has been viewed as opioid-resistant and that opioids are more appropriate modalities for visceral and somatic nociceptive types of pain.30 Many physicians avoid using opioids to treat neuropathic pain, in large part because of concerns about drug abuse, addiction and regulatory issues. However, there are many trials that have found opioid analgesics to be effective.31,32 Oxycodone was superior to placebo for relieving pain, allodynia, improving sleep and disability. Controlled-release opioids, given on a scheduled basis, are recommended for patients with continuous pain to promote constant levels of analgesia, prevent fluctuations in blood levels and avoid adverse events associated with high dosing. Most commonly, oral preparations are used thanks to their greater ease of use and cost-effectiveness. Trans-dermal, parenteral and rectal preparations are commonly used in patients who cannot tolerate oral drugs.29

Local Anesthetics

Local acting anesthetics are appealing because—thanks to their local action—they have minimal side effects. They act by stabilizing sodium channels in the axons of peripheral first-order neurons. They work best when there is only partial nerve injury and excess sodium channels have accumulated.33 Topical lidocaine is the best-studied agent of this class for neuropathic pain. In particular, the use of the 5% lidocaine patch for post-herpetic neuralgia has led to its approval by the FDA.34 The patch appears to work best when there is damaged, but retained, peripheral nervous system nociceptor function in the involved dermatome manifesting as allodynia. It should be placed directly on the symptomatic area for 12 hours and removed for the next 12 hours and can be used for years in this manner. Aside from local skin reactions, it is well tolerated.

Miscellaneous Drugs

Clonidine, an alpha-2-agonist, was shown to be effective in a subset of patients with diabetic peripheral neuropathy.35 Cannabinoids have been found to play a role in experimental pain modulation in animal models and evidence of their efficacy is accumulating.36 CB2-selective agonists suppress hyperalgesia and allodynia and normalize nociceptive thresholds without inducing analgesia.

Interventional Pain Management

Invasive treatments may be considered for patients with intractable neuropathic pain. These treatments include epidural or perineural injections of local anesthetics or corticosteroids, implantation of epidural and intrathecal drug delivery systems and insertion of spinal cord stimulators. These approaches are reserved for patients with intractable chronic neuropathic pain who have failed conservative medical management and have undergone thorough psychological evaluation. In a study by Kim et al, it was shown that a spinal cord stimulator was effective in treating neuropathic pain of nerve root origin.37

Other Interventions

Many patients with neuropathic pain pursue complementary and alternative treatments such as acupuncture. Other regimens include exercise, percutaneous electrical nerve stimulation, transcutaneous electrical nerve stimulation, cognitive behavioral therapy, graded motor imagery and supportive therapy.


Neuropathic pain is a multifaceted entity with no specific guidelines to treat. It is best managed using a multidisciplinary approach. Pain management requires ongoing evaluation, patient education, ensuring patient follow-up and reassurance. Neuropathic pain is such a devastating chronic condition that renders the choice for the best treatment challenging. Individualizing treatment entails consideration of the impact of the pain on the patient’s well-being, disabilities and depression together with ongoing education and evaluation. Neuropathic pain research—both on the molecular level and in animal models—is relatively new but very promising. Many advances are expected in the basic and clinical fields of neuropathic pain thus opening the doors to new or improved treatment modalities for this disabling condition.

Last updated on: December 29, 2011
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