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Neuropathic Pain

By

James C. Watson

, MD, Mayo Clinic College of Medicine and Science

Last full review/revision Mar 2022| Content last modified Mar 2022
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Neuropathic pain results from damage to or dysfunction of the peripheral or central nervous system, rather than stimulation of pain receptors. Diagnosis is suggested by pain out of proportion to tissue injury, dysesthesia (eg, burning, tingling), and signs of nerve injury detected during neurologic examination. Treatment is often with adjuvant drugs rather than analgesics (eg, antidepressants, antiseizure drugs, baclofen, topical drugs) or with nondrug treatments (eg, physical therapy, neuromodulation).

Pain can develop after injury to any level of the nervous system, peripheral or central; the sympathetic nervous system may be involved (causing sympathetically maintained pain). Specific syndromes include

Etiology of Neuropathic Pain

Neuropathic pain may result from efferent activity (sympathetically maintained pain) or from interruption of afferent activity (deafferentation pain).

Peripheral nerve injury or dysfunction can result in neuropathic pain. Examples are

Mechanisms of neuropathic pain are complex and involve changes

  • At the peripheral nociceptor and nerve level

  • At the dorsal root ganglion

  • In central nervous system (CNS) nociceptive pathways and terminal structures

At the peripheral nerve and nociceptor level, injury results in inflammation and in activation and over-representation of cation channels, particularly sodium channels. These changes reduce the threshold for activation and increase the response to noxious stimuli. In chronic states, the peripheral nerve continuously triggers nociceptive ectopic signals to the CNS. This bombardment of continuous peripheral nociceptive input leads to changes in receptive nociceptors (central sensitization); they are primed, interpret pain from minor stimuli (including nonpainful stimuli [allodynia]) as substantial pain, and interpret that pain as coming from a wider area than it is. These changes can be reversed, at least for a time, if the peripheral nociceptive input can be interrupted.

Central neuropathic pain syndromes (pain caused by dysfunction of somatosensory pathways in the CNS) can result from any CNS lesion, but these syndromes most commonly occur after stroke, result from spinal cord injury, or are associated with a multiple sclerosis demyelinating plaque. To be considered central neuropathic pain, the pain must occur in the area clinically affected by the CNS lesion; however, it does not need to involve the entire affected area. Central neuropathic pain develops only if the spinothalamic tract (pinprick, temperature sensation) malfunctions. If pinprick and temperature sensation are normal in the area of pain suspected to be central neuropathic pain, another pain source should be considered. The cause of pain in neurologically impaired patients is more commonly musculoskeletal (eg. shoulder pain related to arm paresis after a stroke or an upper extremity overuse syndrome in wheelchair-bound patients with a spinal cord injury).

Deafferentation pain is due to partial or complete interruption of peripheral or central afferent neural activity. Examples are

Mechanisms are unknown but may involve sensitization of central neurons, with lower activation thresholds and expansion of receptive fields.

Neuropathic pain syndromes are sometimes associated with overactivity of the sympathetic nervous system. The sympathetic overactivity does not cause neuropathic pain, but it can contribute to its clinical features and severity. The pain that results is called sympathetically maintained pain, which depends on efferent sympathetic activity. Complex regional pain syndrome Complex Regional Pain Syndrome (CRPS) Complex regional pain syndrome (CRPS) is chronic neuropathic pain that follows soft-tissue or bone injury (type I) or nerve injury (type II) and lasts longer and is more severe than expected... read more sometimes involves sympathetically maintained pain. Other types of neuropathic pain may have a sympathetically maintained component. What triggers sympathetic overactivity in some neuropathic pain states and not others is unknown. Mechanisms probably involve abnormal sympathetic-somatic nerve connections (ephapses), local inflammatory changes, and changes in the spinal cord.

Symptoms and Signs of Neuropathic Pain

Dysesthesias (spontaneous or evoked burning pain, often with a superimposed lancinating component) are typical, but pain may also be deep and aching. Other sensations—eg, hyperesthesia, hyperalgesia, allodynia (pain due to a nonnoxious stimulus), and hyperpathia (particularly unpleasant, exaggerated pain response)—may also occur.

Patients may be reluctant to move the painful part of their body, resulting in muscle atrophy, joint ankylosis, bone loss, and limited movement.

Symptoms are long-lasting, typically persisting after resolution of the primary cause (if one was present) because the CNS has been sensitized and remodeled.

Diagnosis of Neuropathic Pain

  • Clinical evaluation

Neuropathic pain is suggested by its typical symptoms when nerve injury is known or suspected. The cause (eg, amputation, diabetes, compression) may be readily apparent. If not, the diagnosis is often assumed based on the description of the symptoms; however, those descriptors (eg, burning) are neither sensitive nor specific for neuropathic pain. Thus, additional evaluation, including neurologic examination and electrophysiologic studies, are useful to confirm the diagnosis and to identify the injured nerve. Pain that is ameliorated by sympathetic nerve block is sympathetically maintained pain.

Treatment of Neuropathic Pain

  • Multimodal therapy (eg, physical methods, antidepressants, antiseizure drugs, psychotherapeutic methods, neuromodulation, sometimes surgery)

Successful neuropathic pain management starts with confirming the correct diagnosis and managing treatable causes (eg, herniated disk Herniated Nucleus Pulposus Herniated nucleus pulposus is prolapse of an intervertebral disk through a tear in the surrounding annulus fibrosus. The tear causes pain due to irritation of sensory nerves in the disk, and... read more Herniated Nucleus Pulposus , carpal tunnel syndrome Carpal Tunnel Syndrome Carpal tunnel syndrome is compression of the median nerve as it passes through the carpal tunnel in the wrist. Symptoms include pain and paresthesias in the median nerve distribution. Diagnosis... read more ). In addition to drugs, mobilization and physical therapy are needed to desensitize areas of allodynia and prevent trophic changes, disuse atrophy, and joint ankylosis. Psychologic factors must be considered from the start of treatment. Anxiety and depression must be treated appropriately. If pain persists, neural blockade Neural Blockade Nonopioid and opioid analgesics are the main drugs used to treat pain. Antidepressants, antiseizure drugs, and other central nervous system (CNS)–active drugs may also be used for chronic or... read more may help. When dysfunction does not respond to first-line treatments, patients may benefit from the comprehensive approach provided by a pain clinic.

Several classes of drugs are effective (see table Drugs for Neuropathic Pain Drugs for Neuropathic Pain Drugs for Neuropathic Pain ), but complete relief is unlikely, and setting realistic expectations is important. The goal of pharmacologic management is to lessen neuropathic pain so that it is less debilitating.

Table

Opioid analgesics Opioid Analgesics Nonopioid and opioid analgesics are the main drugs used to treat pain. Antidepressants, antiseizure drugs, and other central nervous system (CNS)–active drugs may also be used for chronic or... read more can provide some relief but are generally less effective than for acute nociceptive pain and are associated with risk of dependence; adverse effects may prevent adequate analgesia.

Adjuvant analgesics, such as antidepressants and antiseizure drugs, are most commonly used to treat neuropathic pain, and their efficacy is supported by randomized trial data ( 1 Treatment reference Neuropathic pain results from damage to or dysfunction of the peripheral or central nervous system, rather than stimulation of pain receptors. Diagnosis is suggested by pain out of proportion... read more ; see table Drugs for Neuropathic Pain Drugs for Neuropathic Pain Drugs for Neuropathic Pain ).

Gabapentin is one of the most widely used drugs for such purposes. For effective analgesia, the dose should usually be > 600 mg orally 3 times a day, and many patients need a higher dose. Maximum dosage is usually considered to be 1200 mg orally 3 times a day.

Pregabalin is similar to gabapentin but has more stable pharmacokinetics; dosing 2 times a day is as efficacious as dosing 3 times a day and results in better compliance. The dosing goal is at least 300 mg/day orally (eg, a starting dose of 75 mg 2 times a day, increased to 150 mg 2 times a day within 1 week). Neuropathic pain syndromes may require up to 600 mg/day. Some patients who do not respond well to or do not tolerate gabapentin do respond to or tolerate pregabalin and vice versa, even though the two drugs have a similar primary mechanism of action (binding to the alpha-2 delta ligand of the presynaptic calcium channel, which modulates nociceptive signaling).

For tricyclic antidepressants (amitriptyline, nortriptyline, desipramine), the primary mechanism of action is blocking the reuptake of serotonin and norepinephrine. Analgesic doses (75 to 150 mg orally once a day) are usually insufficient to treat depression or anxiety. Anticholinergic and adrenergic adverse effects often limit effective dosing. Secondary amine tricyclic antidepressants (nortriptyline and desipramine) have a more favorable adverse effect profile than tertiary amine tricyclic antidepressants (amitriptyline).

Venlafaxine's effects and mechanism of action are similar to those of duloxetine.

Topical drugs and a lidocaine-containing patch may be effective for peripheral syndromes.

Other potentially effective treatments include

Treatment reference

Key Points

  • Neuropathic pain may result from efferent activity (sympathetically maintained pain) or from interruption of afferent activity (deafferentation pain).

  • Consider neuropathic pain if patients have dysesthesia or if pain is out of proportion to tissue injury and nerve injury is suspected.

  • Treat patients using multiple modalities (eg, antidepressants or antiseizure drugs, analgesics, psychotherapeutic methods, physical and occupational therapy, neuromodulation, surgery).

Drugs Mentioned In This Article

Drug Name Select Trade
LIORESAL
NEURONTIN
LYRICA
No US brand name
PAMELOR
NORPRAMIN
CYMBALTA
EFFEXOR XR
XYLOCAINE
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