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Neuropathic Pain

By

James C. Watson

, MD, Mayo Clinic

Last full review/revision Feb 2020| Content last modified Feb 2020
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Topic Resources

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, antiseizure drugs, baclofen, topical drugs).

(See also Overview of Pain.)

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

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

Mechanisms presumably vary and may involve an increased number of sodium 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

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.

Patients may be reluctant to move the painful part of their body, resulting in muscle atrophy, joint ankylosis, 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

  • 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.

Treatment

  • Multimodal therapy (eg, psychologic treatments, physical methods, antidepressants or antiseizure drugs, neuromodulation, sometimes surgery)

Without concern for diagnosis, rehabilitation, and psychosocial issues, treatment of neuropathic pain 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.

Neuromodulation (spinal cord or peripheral nerve stimulation) is particularly effective for neuropathic pain.

Several classes of drugs are moderately effective (see table Drugs for Neuropathic Pain, but complete or near-complete relief is unlikely. Antidepressants and antiseizure drugs are most commonly used. Evidence of efficacy is strong for several antidepressants and antiseizure drugs (1).

Table
icon

Drugs for Neuropathic Pain

Class/Drug

Dose*

Comments

Antiseizure drugs†

Carbamazepine

200–400 mg 2 times a day

Monitor WBCs and liver function during treatment

May decrease efficacy of oral contraceptives

First-line treatment for trigeminal neuralgia

Gabapentin

300–1200 mg 3 times a day

Starting dose usually 300 mg once a day

Dosing goal: 600–1200 mg 3 times a day

Oxcarbazepine

600–900 mg 2 times a day

Considered as efficacious as carbamazepine for trigeminal neuralgia and useful for other paroxysmal neuropathic pain

May cause hyponatremia or decrease efficacy of oral contraceptives

Unlike carbamazepine, no CBC or liver function monitoring necessary

Phenytoin

300 mg once a day

Limited data; 2nd-line drug

Pregabalin

150–300 mg 2 times a day

Starting dose usually 75 mg 2 times a day, increased by the same dosage weekly as necessary to maximum of 300 mg orally 2 times a day

Mechanism similar to gabapentin but more stable pharmacokinetics

Adjust dose in patients with renal insufficiency

Valproate

250–500 mg 2 times a day

Limited data, but strong support for treatment of headache

Antidepressants

Amitriptyline

10–25 mg at bedtime (starting dose), increased weekly by the same dose to a maximum of 150 mg at bedtime

Dosing goal: ~ 100 mg/day (dosing for pain unlikely to be adequate for relieving depression or anxiety)

Not recommended for older patients or patients with a heart disorder because it has strong anticholinergic effects

May increase dose to 150 mg or sometimes higher

Desipramine or nortriptyline

10–25 mg at bedtime (starting dose), increased weekly by the same dose to maximum of 150 mg at bedtime

Better tolerated than amitriptyline; adverse effect profile better with desipramine than nortriptyline

Dosing goal: ~ 100 mg/day (dosing for pain unlikely to be adequate for relieving depression or anxiety)

Not recommended for older patients or patients with a heart disorder because it has strong anticholinergic effects

May increase dose to 150 mg or sometimes higher

Duloxetine

20–60 mg once/day

Starting at 20–30 mg once a day and increasing by the same dosage weekly to a goal of 60 mg/day; in some cases, increasing to 60 mg 2 times a day (especially in patients with concomitant depression or anxiety)

Better tolerated than tricyclic antidepressants

Dosing goal for pain (60 mg/day) usually sufficient to treat concomitant depression or anxiety

Venlafaxine

Extended-release (easiest to use): 150–225 mg once a day

More norepinephrine reuptake inhibition at higher doses (≥ 150 mg/day); lower dosages ineffective for neuropathic pain

Similar mechanism of action as duloxetine

Effective for pain, depression, and anxiety at this dose

Central alpha-2 adrenergic agonists

Clonidine

0.1 mg once a day

Also can be used transdermally or intrathecally

Tizanidine

2–20 mg 2 times a day

Less likely to cause hypotension than clonidine

Corticosteroids

Dexamethasone

0.5–4 mg 4 times a day

Used only for pain with an inflammatory component

Prednisone

5–60 mg once a day

Used only for pain with an inflammatory component

NMDA-receptor antagonists

Memantine

10–30 mg once a day

Limited evidence of efficacy

Dextromethorphan

30–120 mg 4 times a day

May have a role in treating neuropathic pain in patients who have developed tolerance or a lower pain threshold due to central sensitization

In > 90% whites, rapid metabolism via hepatic cytochrome P-450 2D6, reducing the therapeutic effect

Metabolism of dextromethorphan blocked by quinidine

Combination dextromethorphan/quinidine available for pseudobulbar affect in patients with amyotrophic lateral sclerosis

Oral sodium channel blockers

Mexiletine

150 mg once/day to 300 mg every 8 hours

Used only for neuropathic pain

For patients with a significant heart disorder, cardiac evaluation considered before the drug is started

Topical

Capsaicin 0.025–0.075% (eg, cream, lotion)

Apply 3 times a day

Some evidence of efficacy in neuropathic pain and arthritis

Capsaicin 8% patch

Up to 4 at one time‡

Causes a severe sunburn-like skin reaction; oral opioids often required for up to 1 week after application of capsaicin 8% to manage the worsening cutaneous pain

Meaningful pain relief for 3 months after a single application

EMLA

Apply 3 times a day, under occlusive dressing if possible

Usually considered for a trial if a lidocaine patch is ineffective; expensive

Lidocaine 5%

Daily

Available as patch

Other

Baclofen

20–60 mg 2 times a day

May act via GABA-B receptor

Helpful in trigeminal neuralgia; used in other types of neuropathic pain

Pamidronate (injection)

60–90 mg/month IV

Evidence of efficacy in complex regional pain syndrome

* Route is oral unless otherwise indicated.

† Newer antiseizure drugs have fewer adverse effects.

‡ Topical lidocaine 4–5% applied 1 hour before applying capsaicin can help limit irritation.

CBC = complete blood count; EMLA = eutectic mixture of local anesthetics; GABA =gamma-aminobutyric acid; NMDA =N-methyl-d-aspartate; WBCs = white blood cells.

Opioid analgesics can provide some relief but are generally less effective than for acute nociceptive pain; adverse effects may prevent adequate analgesia.

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

Other potentially effective treatments include

  • Spinal cord stimulation by an electrode placed epidurally for certain types of neuropathic pain (eg, chronic leg pain after spine surgery)

  • Electrodes implanted along peripheral nerves and ganglia for certain chronic neuralgias

  • Sympathetic blockade, which is usually ineffective, except for some patients with complex regional pain syndrome

  • Neural blockade or ablation (radiofrequency ablation, cryoablation, chemoneurolysis)

Treatment reference

Key Points

  • Neuropathic pain can result from efferent activity or from interruption of afferent activity.

  • 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, psychologic treatments, physical methods, neuromodulation, antidepressants or antiseizure drugs, analgesics, surgery), and recommend rehabilitation as appropriate.

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NOTE: This is the Professional Version. CONSUMERS: Click here for the Consumer Version
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