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Neuropathic pain (NP) is defined by the International Association for the Study of Pain as “pain initiated or caused by a primary lesion or dysfunction in the nervous system.”1 NP can occur because of dysfunction or disease of the nervous system at the peripheral and/or central level.2 NP can be very severe and disabling, with significant functional, psychological, and social consequences. Regardless of the underlying cause of NP, common treatment goals are to decrease pain and/or improve function.
NP is often classified by etiology or by the presumed site of neurologic involvement (central or peripheral). However, both peripheral and central nervous system lesions may contribute to most types of chronic NP.3 More complex classification systems based on symptoms, signs, anatomical distribution, or hypotheses regarding etiologies have been proposed, but it is not clear if such classifications are accurate or reproducible. A mechanistic classification may be the preferred approach, but current knowledge of the pathophysiology of NP is incomplete, and multiple mechanisms may be involved.4
NP is characterized by continuous or intermittent spontaneous pain, typically characterized by patients as burning, aching, or shooting. The pain may be provoked by normally innocuous stimuli (allodynia). NP is also commonly associated with hyperalgesia (increased pain intensity evoked by normally painful stimuli), paresthesia, and dysesthesia.4
Up to 3% of the general population reports NP at some time.5 The prevalence of different types of NP varies widely.6 NP is most commonly associated with painful diabetic neuropathy, post-herpetic neuralgia (PHN), or lumbar nerve root compression.6 Diabetic neuropathy occurs in approximately 10% of persons with diabetes.7 Prevalence of diabetic neuropathy increases with age, worsening glycemic control, and duration of diabetes. The most common form of diabetic peripheral neuropathy is a distal symmetric polyneuropathy.8 PHN is defined as pain persisting or recurring at the site of acute herpes zoster 3 or more months after the acute episode.9 It occurs in up to 25% of patients following an episode of shingles.10 Symptomatic spinal stenosis and lumbar disc herniation with nerve root compression occur in approximately 3% and 4% of patients with low back pain, respectively.11 Other causes of NP include cancer-related pain, spinal cord injury, post-stroke pain, HIV-associated neuropathy, and phantom limb pain. Uncommon but potentially debilitating NP conditions include trigeminal neuralgia (incidence 4/100,000 population).12 In the U.S., health care and disability-related costs associated with NP are estimated at almost $40 billion annually.13
| Drug | Trade Name(s) | Labeled indications for neuropathic pain | Recommended daily dosing for neuropathic pain | Range of daily doses used in RCTs of neuropathic pain (median) | FDA warnings/cautions* |
|---|---|---|---|---|---|
| Gabapentin, pregabalin, SNRIs, and topical lidocaine patch or gel | |||||
| Antiepileptics | |||||
| Gabapentin | Neurontin® | Postherpetic neuralgia | Start at 300 mg, titrate to900 mg, increase up to1800 mg (divided TID) | 900–3600 mg (1800 mg) | Central nervous system adverse events in pediatric patients with epilepsy. |
| Pregabalin | Lyrica® | Diabetic neuropathy Postherpetic neuralgia | Diabetic neuropathy: Start at 150 mg, increase up to 300 mg (divided TID) Postherpetic neuralgia: Start at 150 mg, increase up to 75 to 150 mg BID, or 50 to 100 mg TID in patients with creatinine clearance of at least 60 mL/min | 75–600 mg (300 mg) | Angioedema, hypersensitivity reactions |
| SNRI antidepressants | |||||
| Duloxetine | Cymbalta® | Diabetic neuropathy | 60 mg once daily; consider lower starting dose and gradual increase in patients with renal impairment | 20–120 mg (90 mg) | Increased suicidality in children, adolescents, and young adults with major depressive disorder and other psychiatric conditions. Risk of serotonin syndrome when SNRIs and triptans are used together. |
| Venlafaxine | Effexor® Effexor XR® | None | NA | 37.5–225 mg (75 mg) | |
| Topical analgesic | |||||
| Lidocaine patch 5% | Lidoderm® | Postherpetic neuralgia | Up to 3 patches for up to 12 hours within a 24-hour period | 5%, up to 3 patches | Accidental exposure in children Excessive dosing by applying patch longer than or to a larger area than recommended |
| Lidocaine topical gel 5% | Anestacon® Xylocaine® | None | NA | 5% | |
| Other medications for neuropathic pain | |||||
| Antiepileptics | |||||
| Carbamazepine | Tegretol® Tegretol XR® | Trigeminal neuralgia | Start at 100 mg BID, increase up to a maximum of 1200 mg daily (divided BID). Most patients are maintained on 400–800 mg daily. Attempt to reduce dose to minimum effective level, or discontinue, at least every 3 months. | 500–2400 mg (1000 mg) | |
| Lamotrigine | Lamictal® | None | NA | 200–600 mg (350 mg) | Teratogenicity: Possible risk of cleft lip or palate |
| Topiramate | Topamax® | None | NA | 75–600 mg (258 mg) | Use is associated with metabolic acidosis |
| Oxcarbazepine | Trileptal® | None | NA | 600–1800 mg (900 mg) | Serious dermatological reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN |
| Valproic acid/divalproex | Depakote® Depakene® | None | NA | 600–2400 mg (1000 mg) | BOXED WARNING: Teratogenicity |
| Tricyclic antidepressants | |||||
| Amitriptyline | Elavil® | None | NA | 10–150 mg (70 mg) | Increased suicidality in patients with depression |
| Desipramine | Norpramin® | None | NA | 50–200 mg (184 mg) | |
| Nortriptyline | Pamelor® | None | NA | 25–100 mg | |
| Imipramine | Tofranil® | None | NA | 50–150 mg (75 mg) | |
| Doxepin | Sinequan® | None | NA | No trials | |
| SSRI antidepressants | |||||
| Citalopram | Celexa® | None | NA | 40 mg | Increased suicidality in patients with depression |
| Fluoxetine | Prozac® | None | NA | 40 mg | |
| Paroxetine | Paxil® | None | NA | No trials | |
| Sertraline | Zoloft® | None | NA | No trials | |
| Escitalopram | Lexapro® | None | NA | No trials | |
| NMDA receptor antagonist | |||||
| Dextromethorphan | Several | None | NA | 40.5–439 mg (270 mg) | BOXED WARNING: Misuse of amphetamines may cause sudden death and serious cardiovascular adverse events. FDA notification: There have been five recently reported deaths of teenagers that may be associated with the abuse/ over-consumption of powdered dextromethorphan sold in capsules |
*Please see package inserts and FDA labeling information for more detailed and specific cautions and black box warnings for medications included in this review.
The purpose of this review is to compare the effectiveness and harms of gabapentin, pregabalin, duloxetine, venlafaxine, and topical lidocaine (patch or gel) for neuropathic pain. The Oregon Evidence-based Practice Center wrote preliminary key questions, identifying the populations, interventions, and outcomes of interest, and based on these, the eligibility criteria for studies. These were reviewed and revised by representatives of organizations participating in DERP. The participating organizations of DERP are responsible for ensuring that the scope of the review reflects the populations, drugs, and outcome measures of interest to both clinicians and patients. The participating organizations approved the following key questions to guide this review:
What is the comparative effectiveness of pregabalin, gabapentin, serotonin-norepinephrine reuptake inhibitors (SNRIs), and topical lidocaine (patch or gel) versus each other for neuropathic pain?
What is the comparative effectiveness of pregabalin, gabapentin, SNRIs, or topical lidocaine (patch or gel) versus other drugs (other antiepileptics, tricyclic antidepressants, selective serotonin reuptake inhibitors [SSRIs], or dextromethorphan) for neuropathic pain?
What are the comparative harms of pregabalin, gabapentin, SNRIs, and topical lidocaine (patch or gel) for neuropathic pain?
What are the comparative harms of pregabalin, gabapentin, SNRIs, or topical lidocaine (patch or gel) versus other drugs (other antiepileptics, tricyclic antidepressants (including tertiary versus secondary amines), selective serotonin reuptake inhibitors [SSRIs], or dextromethorphan) for neuropathic pain?
What are the comparative effectiveness and harms of dual therapy with pregabalin, gabapentin, an SNRI, or topical lidocaine (patch or gel) plus a tricyclic antidepressant or another antiepileptic versus monotherapy with a tricyclic antidepressant or another antiepileptic?
Are there differences in effectiveness or harms of drugs used to treat neuropathic pain based on demographics, comorbidities, or drug-drug interactions?
