Neuropathic Pain
(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
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Root avulsions
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Painful traumatic mononeuropathy
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Painful polyneuropathy (including neuropathy due to diabetes or chemotherapy)
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Central pain syndromes (potentially caused by virtually any lesion at any level of the nervous system)
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Postsurgical pain syndromes (eg, postmastectomy syndrome, postthoracotomy syndrome, phantom limb pain)
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Complex regional pain syndrome (reflex sympathetic dystrophy and causalgia)
Etiology
Peripheral nerve injury or dysfunction can result in neuropathic pain. Examples are
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Mononeuropathies (eg, carpal tunnel syndrome, radiculopathy)
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Plexopathies (typically caused by nerve compression, as by a neuroma, tumor, or herniated disk)
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Polyneuropathies (typically caused by various metabolic neuropathies—see tables Causes of Peripheral Nervous System Disorders)
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
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Central pain (pain after central nervous system [CNS] injury)
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Phantom limb 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.
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
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
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).
Drugs for Neuropathic Pain
|
Class/Drug |
Dose* |
Comments |
Antiseizure drugs† |
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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 |
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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 |
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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 |
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Phenytoin |
300 mg once a day |
Limited data; 2nd-line drug |
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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 |
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Valproate |
250–500 mg 2 times a day |
Limited data, but strong support for treatment of headache |
Antidepressants |
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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 |
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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 |
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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 |
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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 |
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Clonidine |
0.1 mg once a day |
Also can be used transdermally or intrathecally |
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Tizanidine |
2–20 mg 2 times a day |
Less likely to cause hypotension than clonidine |
Corticosteroids |
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Dexamethasone |
0.5–4 mg 4 times a day |
Used only for pain with an inflammatory component |
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Prednisone |
5–60 mg once a day |
Used only for pain with an inflammatory component |
NMDA-receptor antagonists |
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Memantine |
10–30 mg once a day |
Limited evidence of efficacy |
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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 |
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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 |
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Capsaicin 0.025–0.075% (eg, cream, lotion) |
Apply 3 times a day |
Some evidence of efficacy in neuropathic pain and arthritis |
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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 |
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EMLA |
Apply 3 times a day, under occlusive dressing if possible |
Usually considered for a trial if a lidocaine patch is ineffective; expensive |
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Lidocaine 5% |
Daily |
Available as patch |
Other |
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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 |
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Pamidronate (injection) |
60–90 mg/month IV |
Evidence of efficacy in complex regional pain syndrome |
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* Route is oral unless otherwise indicated. |
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† Newer antiseizure drugs have fewer adverse effects. |
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‡ Topical lidocaine 4–5% applied 1 hour before applying capsaicin can help limit irritation. |
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CBC = complete blood count; EMLA = eutectic mixture of local anesthetics; GABA =gamma-aminobutyric acid; NMDA =N-methyl-d-aspartate; WBCs = white blood cells. |
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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
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Spinal cord stimulation by an electrode placed epidurally for certain types of neuropathic pain (eg, chronic leg pain after spine surgery)
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Electrodes implanted along peripheral nerves and ganglia for certain chronic neuralgias
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Sympathetic blockade, which is usually ineffective, except for some patients with complex regional pain syndrome
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Neural blockade or ablation (radiofrequency ablation, cryoablation, chemoneurolysis)
Treatment reference
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1. Finnerup NB, Attal N, Haroutounian S, et al: Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol 14 (2):162–173, 2015. doi: 10.1016/S1474-4422(14)70251-0.
Key Points
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Neuropathic pain can result from efferent activity or from interruption of afferent activity.
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Consider neuropathic pain if patients have dysesthesia or if pain is out of proportion to tissue injury and nerve injury is suspected.
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Treat patients using multiple modalities (eg, psychologic treatments, physical methods, neuromodulation, antidepressants or antiseizure drugs, analgesics, surgery), and recommend rehabilitation as appropriate.
Drugs Mentioned In This Article
| Drug Name | Select Trade |
|---|---|
Dextromethorphan |
DELSYM |
Amitriptyline |
No US brand name |
Oxcarbazepine |
TRILEPTAL |
Dexamethasone |
OZURDEX |
Carbamazepine |
TEGRETOL |
nortriptyline |
AVENTYL |
Desipramine |
NORPRAMIN |
Venlafaxine |
EFFEXOR XR |
Pamidronate |
AREDIA |
Prednisone |
RAYOS |
Pregabalin |
LYRICA |
Tizanidine |
ZANAFLEX |
Gabapentin |
NEURONTIN |
Duloxetine |
CYMBALTA |
Capsaicin |
QUTENZA |
lidocaine |
XYLOCAINE |
Phenytoin |
DILANTIN |
Memantine |
NAMENDA |
Clonidine |
CATAPRES |
baclofen |
LIORESAL |
