Neuropathic Pain

Neuropathic Pain
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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. Although neuropathic pain responds to opioids, treatment is often with adjuvant drugs (eg, antidepressants, anticonvulsants, baclofen, topical drugs).

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 postherpetic neuralgia (see Herpesviruses: Symptoms and Signs), root avulsions, painful traumatic mononeuropathy, painful polyneuropathy (particularly due to diabetes), central pain syndromes (potentially caused by virtually any lesion at any level of the nervous system), postsurgical pain syndromes (eg, postmastectomy syndrome, postthoracotomy syndrome, phantom pain), and complex regional pain syndrome (reflex sympathetic dystrophy and causalgia—see Pain: Complex Regional Pain Syndrome).


Peripheral nerve injury or dysfunction can result in neuropathic pain. Examples are mononeuropathies (eg, carpal tunnel syndrome, radiculopathy), plexopathies (typically caused by nerve compression, as by a neuroma, tumor, or herniated disk), and polyneuropathies (typically caused by various metabolic neuropathies—see Table 1: Peripheral Nervous System and Motor Unit Disorders: Causes of Peripheral Nervous System Disorders). Mechanisms presumably vary and may involve an increased number of Na channels on regenerating nerves.

Central neuropathic pain syndromes appear to involve reorganization of central somatosensory processing; the main categories are deafferentation pain and sympathetically maintained pain. Both are complex and, although presumably related, differ substantially.

Deafferentation pain is due to partial or complete interruption of peripheral or central afferent neural activity. Examples are postherpetic neuralgia, central pain (pain after CNS injury), and phantom pain (pain felt in the region of an amputated body part). Mechanisms are unknown but may involve sensitization of central neurons, with lower activation thresholds and expansion of receptive fields.

Sympathetically maintained pain depends on efferent sympathetic activity. Complex regional pain syndrome sometimes involves sympathetically maintained pain. Other types of neuropathic pain may have a sympathetically maintained component. Mechanisms probably involve abnormal sympathetic-somatic nerve connections (ephapses), local inflammatory changes, and changes in the spinal cord.

Symptoms and Signs

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


Clinical evaluation

Neuropathic pain is suggested by its typical symptoms when nerve injury is known or suspected. The cause (eg, amputation, diabetes) may be readily apparent. If not, the diagnosis often can be assumed based on the description. Pain that is ameliorated by sympathetic nerve block is sympathetically maintained pain.


Multimodal therapy (eg, psychologic treatments, physical methods, antidepressants or anticonvulsants, sometimes surgery)

Without concern for diagnosis, rehabilitation, and psychosocial issues, treatment has a limited chance of success. For peripheral nerve lesions, mobilization is needed to prevent trophic changes, disuse atrophy, and joint ankylosis. Surgery may be needed to alleviate compression. Psychologic factors must be constantly considered from the start of treatment. Anxiety and depression must be treated appropriately. When dysfunction is entrenched, patients may benefit from the comprehensive approach provided by a pain clinic.

Several classes of drugs are moderately effective (see Table 4: Pain: Drugs for Neuropathic Pain; see also the practice guideline Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations), but complete or near-complete relief is unlikely. Antidepressants and anticonvulsants are most commonly used. Evidence of efficacy is strong for several antidepressants and anticonvulsants.

Opioid analgesics can provide some relief but are less effective than for nociceptive pain; adverse effects may prevent adequate analgesia. Topical drugs and a lidocaine

patch may be effective for peripheral syndromes. Sympathetic blockade is usually ineffective except for some patients with complex regional pain syndrome.

Complex Regional Pain Syndrome

(Reflex Sympathetic Dystrophy and Causalgia)

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 for the original tissue damage. Other manifestations include autonomic changes (eg, sweating, vasomotor abnormalities), motor changes (eg, weakness, dystonia), and trophic changes (eg, skin or bone atrophy, hair loss, joint contractures). Diagnosis is clinical. Treatment includes drugs, physical therapy, and sympathetic blockade.

CRPS type I was previously known as reflex sympathetic dystrophy (see also the Clinical practice guideline [third edition] for the diagnosis, treatment, and management of reflex sympathetic dystrophy/complex regional pain syndrome [RSD/CRPS] from the Reflex Sympathetic Dystrophy Syndrome Association), and type II as causalgia. Both types occur most often in young adults and are 2 or 3 times more common among women.


CRPS type I typically follows an injury (usually of a hand or foot), most commonly after crush injuries, especially in a lower limb. It may follow amputation, acute MI, stroke, or cancer (eg, lung, breast, ovary, CNS); no precipitant is apparent in about 10% of patients. CRPS type II is similar to type I but involves overt damage to a peripheral nerve.


Pathophysiology is unclear, but peripheral nociceptor and central sensitization and release of neuropeptides (substance P, calcitonin

gene-related peptide) help maintain pain and
inflammation. The sympathetic nervous system is more involved in CRPS than in other neuropathic pain syndromes: Central sympathetic activity is increased, and peripheral nociceptors are sensitized to norepinephrine

(a sympathetic neurotransmitter); these
changes may lead to sweating abnormalities and poor blood flow due to vasoconstriction. Nonetheless, only some patients respond to sympathetic manipulation (ie, central or peripheral sympathetic blockade).

Symptoms and Signs

Symptoms vary greatly and do not follow a pattern; they include sensory, focal autonomic (vasomotor or sudomotor), and motor abnormalities.

Pain—burning or aching—is common. It does not follow the distribution of a single peripheral nerve; it may worsen with changes in environment or emotional stress. Allodynia and hyperalgesia may occur. Pain often causes patients to limit use of an extremity.

Cutaneous vasomotor changes (eg, red, mottled, or ashen color; increased or decreased temperature) and sudomotor abnormalities (dry or hyperhidrotic skin) may be present. Edema may be considerable and locally confined. Other symptoms include trophic abnormalities (eg, shiny, atrophic skin; cracking or excess growth of nails; bone atrophy; hair loss) and motor abnormalities (weakness, tremors, spasm, dystonia with fingers fixed in flexion or equinovarus position of foot). Range of motion is often limited, sometimes leading to joint contractures. Symptoms may interfere with fitting a prosthesis after amputation.

Psychologic distress (eg, depression, anxiety, anger) is common, fostered by the poorly understood cause, lack of effective therapy, and prolonged course.


Clinical evaluation

The following clinical criteria must be present to establish the diagnosis of CRPS:

Occurrence of pain (usually burning)

Allodynia or hyperalgesia

Focal autonomic dysregulation (vasomotor or sudomotor abnormalities)

No evidence of another disorder that could explain the symptoms

If another disorder is present, CRPS should be considered possible or probable.

Other symptoms and findings may support the diagnosis: edema, trophic abnormalities, or a change in temperature of the affected area. Thermography may be used to document the temperature change if clinical evaluation is equivocal and if this finding would help establish the diagnosis. Bone changes (eg, demineralization on x-ray, increased uptake on a triple-phase radionuclide bone scan) may be detected and are usually evaluated only if the diagnosis is equivocal. However, imaging tests may also be abnormal after trauma in patients without CRPS.

Sympathetic nerve block (cervical stellate ganglion or lumbar) can be used for diagnosis and treatment. However, false-positive and false-negative results are common because not all CRPS pain is sympathetically maintained and nerve block may also affect nonsympathetic fibers. In another test of sympathetic involvement, a patient is given IV infusions of saline (placebo) or phentolamine

1 mg/kg over 10 min while pain scores are recorded; a decrease
in pain after phentolamine

but not placebo indicates sympathetically maintained pain.


Prognosis varies and is difficult to predict. CRPS may remit or remain stable for years; in a few patients, it progresses, spreading to other areas of the body.


Multimodal therapy (eg, drugs, physical therapy, sympathetic blockade, psychologic treatments, neuromodulation)

Treatment is complex and often unsatisfactory, particularly if begun late. It includes drugs, physical therapy, sympathetic blockade, psychologic treatments, and neuromodulation. Few controlled trials have been done.

Many of the drugs used for neuropathic pain, including tricyclic antidepressants, anticonvulsants, and corticosteroids (see Table 4: Pain: Drugs for Neuropathic Pain), may be tried; none is known to be superior. Long-term treatment with opioid analgesics may be useful for selected patients.

In some patients with sympathetically maintained pain, regional sympathetic blockade relieves pain, making physical therapy possible. Oral analgesics (NSAIDs, opioids, and various adjuvant analgesics) may also relieve pain sufficiently to allow rehabilitation.

For neuromodulation, implanted spinal cord stimulators are being increasingly used. Transcutaneous electrical nerve stimulation (TENS), applied at multiple locations with different stimulation parameters, should be given a long trial. Other methods of neuromodulation include brisk rubbing of the affected part (counterirritation) and acupuncture. No one form of neuromodulation is known to be more effective than another, and a poor response to one form does not mean a poor response to another.

Neuraxial infusion with opioids, anesthetics, and clonidine

may help, and intrathecal

has reduced dystonia in a few patients.

Physical therapy is essential. Goals include strengthening, increased range of motion, and vocational rehabilitation.

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