Treatment of Neuropatic Pain. Medscape

Abstract and Introduction
Abstract

Neuropathic pain is a common symptom associated with peripheral neuropathy and can be as or more disabling than the effects of nerve damage from the neuropathy. Though treatment of the underlying pathophysiology causing neuropathies may not be possible, treatment of neuropathic pain is. The author reviews the major medications used, dosing schedules, and data from randomized controlled trials.

Introduction

Neuropathic pain is a common symptom expressed by patients who have a variety of causes for their neuropathy. It is thought to be due to pathologic changes in, or damage to, neurons in the peripheral or central nervous system.[1]

This disrupts the normal pain signaling process and can cause sensitization or spontaneous neuronal activity in the nervous system. The neural activity is perceived as pain.
There are effective medications available for the treatment of neuropathic pain; however, many patients do not achieve a satisfactory response or experience intolerable side effects.
Several organizations have published guidelines for the pharmacologic management of neuropathic pain.[2–5]

These guidelines are fairly consistent and emphasize the importance of medication efficacy, patient comorbidities, potential side effects and drug interactions, abuse potential, and cost when considering a medication for the treatment of neuropathic pain.
The data for a large number of drugs used to treat neuropathic pain are reviewed and suggestions to optimize patient use and effect are provided. Several drugs will be discussed for off-label indications.

Calcium Channel Alpha-2-delta Ligands

Gabapentin (Neurontin®, Pfizer Pharmaceuticals) and pregabalin (Lyrica®, Pfizer Pharmaceuticals) are structurally similar to gamma-aminobutyric acid (GABA), although they do not bind to GABA receptors. They are thought to exert their beneficial effects on neuropathic pain by binding to the α-2-delta subunit of voltage-dependant calcium channels. This leads to reduction of the influx of calcium into neurons throughout the central nervous system (CNS).[3]
This in turn may decrease the release of glutamate, norepinephrine, and substance P.[5]

Gabapentin (Neurontin®)

Gabapentin is an antiepileptic drug (AED) studied for various types of neuropathic pain. It is FDA-approved for the treatment of PHN and as adjunct therapy for partial onset seizures.[11]
Clinical trials have shown positive results for the treatment of PHN and painful polyneuropathy, and mixed results for the treatment of painful diabetic neuropathy and phantom limb pain.
Gabapentin was not effective in studies of complex regional pain syndrome, chemotherapy-induced neuropathy, and HIV neuropathy.[6] Gabapentin is recommended as a first-line treatment option for painful polyneuropathies, postherpetic neuralgia, and central neuropathic pain by the AISP, EFNS, and CPS.[2–5]

Gabapentin can be initiated at doses of 100 to 300 mg at bedtime or 100 to 300 mg three times daily.
The dose should be titrated by 100 to 300 mg every 3 to 7 days as tolerated to a maximum dose of 3600 mg per day.
The usual effective dose is 1800 mg to 3600 mg per day, which may take several weeks to achieve. Because of the slow dose titration, an adequate trial may take more than 2 months.[5]
It has minimal drug interactions because it is not hepatically metabolized and does not inhibit or induce hepatic enzymes.
However, a dose reduction is required in patients with renal insufficiency. It may also help improve sleep.

Sedation is the most common dose-limiting side effect and is minimized by initiating with a lower dose and titrating more gradually.[6]
Somnolence and dizziness are the most common side effects, and can often be managed by a slow titration.
The elderly are more prone to these side effects and gabapentin may increase the risk of falls and worsen cognitive impairment in this patient population.[5]
The slow-dose titration and onset of action, three times daily dosing schedule and side effects of sedation, edema, dizziness, and weight gain may limit the use of gabapentin for some patients.

A Cochrane review[12] included trials of gabapentin for the treatment of different types of chronic pain.
This analysis included four placebo-controlled trials (281 patients) of gabapentin 900 to 3600 mg daily for the treatment of painful diabetic neuropathy.

The combined NNT for effective pain relief in these four studies was 4.3 (95% CI 3.5–5.7); that is, 64% of patients improved on gabapentin compared with 28% on placebo.
Three control studies comparing gabapentin to amitriptyline for the treatment of painful diabetic neuropathy were also reported.
One study of 25 patients showed similar efficacy with gabapentin (900–1800 mg per day) or amitriptyline (25–75 mg per day).
A second study of 25 patients concluded that gabapentin (1200–2400 mg per day) was superior to amitriptyline (30–90 mg daily), but these results were not statistically significant.
The third study included only seven patients who had benefit from gabapentin in a previous study. The results of this study were not evaluable.[12]

A recent crossover design study[13] compared nortriptyline (maximum dose of 100 mg daily), gabapentin (maximum dose of 3600 mg daily), and a combination of both in 56 patients with painful diabetic neuropathy or PHN.
Participants received each treatment for 6 weeks followed by a one week taper and a one-week washout phase.
Pain scores were significantly lower during the combination phase than for either treatment alone.
Gabapentin monotherapy and nortriptyline monotherapy were similarly effective. Dry mouth was more common with nortriptyline and difficulty concentrating was more common with gabapentin.

Pregabalin (Lyrica®)

Pregabalin is thought to have a mechanism of action similar to gabapentin. It is FDA-approved for the treatment of painful diabetic neuropathy, PHN, and fibromyalgia and as adjunct therapy for partial onset seizures.
Its efficacy is established in randomized controlled trials for the treatment of painful diabetic neuropathy and PHN; however, some trials in these conditions have also shown negative results.[6]

Pregabalin is initiated at a dose of 50 mg three times daily or 75 mg twice daily. The total daily dose can be titrated in increments of 150 mg every 3 to 7 days as tolerated to a maximum dose of 600 mg per day.
However, doses greater than 300 mg have not consistently shown additional benefit for the treatment of neuropathic pain conditions.[6] A lower initial dose and slower taper may help minimize sedation.
Pregabalin has a faster tolerable titration than does gabapentin and twice daily rather than three times per day dosing.
Pregabalin has minimal drug interactions and no hepatic metabolism. It can help with comorbidities such as insomnia and anxiety.[6]

The side effects associated with pregabalin also appear to be similar to those associated with gabapentin, including sedation, edema, dizziness, and weight gain and occur more frequently at higher doses.
A small percentage of patients reported euphoria when taking pregabalin, leading to its Schedule V Controlled Substance classification in the United States.[6]

A Cochrane review assessed the efficacy of pregabalin for chronic pain.
The NNT for greater than 50% pain relief over baseline with 600 mg/day was 5.0 (95% CI 4.0–6.6) for painful diabetic neuropathy (six studies, 1360 patients) and 5.6 (95% CI 3.5–14) for central neuropathic pain (two studies, 176 patients).

The NNT for greater than 50% pain reduction at a lower dose of 300 mg per day was 7.5 (95% CI 5.1–14) for painful diabetic neuropathy (two studies, 341 patients).
The results were similar when only studies of greater than 8-week duration were included.

The NNH causing discontinuation due to side effects with 600 mg/day was 8.8 (95% CI 6.8–12) in painful diabetic neuropathy trials (six studies, 1351 patients), and not significantly different from placebo in central neuropathic pain trials.
For a lower dose of 300 mg per day, the NNH was 16 (95% CI 9.9 to 37) for painful diabetic neuropathy (four studies, 823 patients).


Topical Lidocaine

Topical lidocaine is thought to reduce discharges of small afferent nerve fibers by blocking voltage-gated sodium channels.[3] It is available in gel and transdermal patch formulations. The transdermal patch is FDA approved for treatment of PHN.[14]

Lidocaine 5% transdermal patch was effective in randomized controlled trials of patients with allodynia due to PHN or peripheral neuropathies of other etiologies.[6]

A lidocaine gel formulation was effective in patients with PHN and allodynia, but can also be considered when the transdermal patch is not available, is not tolerated, or is too expensive.[5]

NeuPSIG recommends topical lidocaine as a first-line option for the treatment of localized peripheral neuropathic pain,[5] and the EFNS recommends it as first-line treatment of PHN with allodynia.

Topical lidocaine is considered a second-line treatment option for localized neuropathic pain by the CPS.[4]

A maximum of three patches can be applied to the painful area once every 24 hours and left in place for 12 hours.
Prior to removing the release liner, the patches can be cut to fit the affected area.[14]

Topical lidocaine is well tolerated and minimal systemic absorption occurs at the recommended dose.[5]
No dose titration is necessary to reach an effective dose.[6]

Lidocaine patches are effective only for the area where the patch is applied, and are not helpful for central neuropathic pain or to treat polyneuropathy that occurs over a large area.[6]
Application site irritation may occur.
Although systemic absorption is unlikely, topical lidocaine should be used with caution in patients with hepatic dysfunction, and those taking class I antiarrhythmic medications such as mexiletine.[5]

Increased absorption or drug accumulation may occur when the patch is applied for longer periods of time or over larger areas than recommended, in small patients, and in patients with kidney insufficiency.[14]


Opioid Analgesics

Randomized controlled trials have shown beneficial effects of opioids (including oxycodone, methadone, morphine, and levorphanol) for the treatment of DPN, PHN, painful polyneuropathy, and phantom limb pain.[6]

Comparative trials have shown similar benefit with opioids when compared with TCAs and gabapentin, but more frequent side effects occurred with opioids.[6] NeuPSIG recommends opioids as second-line medications when an adequate response is not achieved with first-line medications or as a first-line option when immediate pain relief is necessary and short-term for acute neuropathic pain.[5]

The EFNS recommends opioid medications as second- or third-line options for painful diabetic neuropathy, PHN, and central neuropathic pain because of limited trials assessing long-term safety and abuse potential.[2]

The Canadian Pain Society recommends opioids (excluding methadone) as third-line agents for the treatment of painful diabetic neuropathy, PHN, and other neuropathic pain conditions.

Methadone is considered a fourth-line agent because of limited clinical evidence, difficulty with titration, and regulatory status in Canada.[4]

The appropriate dose is widely variable from patient to patient and depends on prior opioid exposure.
The typical initial dose is 10 to 15 mg of morphine or equianalgesic dose every 4 hours or as needed.

After 1 to 2 weeks the total daily dose can be converted to an equianalgesic dose of a longer acting opioid medication such as transdermal fentanyl, extended release oxycodone, or extended release morphine.

A scheduled long-acting opioid is typically preferred. If pain is not improved after an adequate trial, the medication should be tapered and discontinued.[5]

Compared with other medications, opioids typically have a quick onset of pain relief. Opioid medications are particularly useful for short-term use to treat acute exacerbations or during the titration phase of a first-line medication.[5]

There are several disadvantages associated with the use of opioid medications.
They are often poorly tolerated. Common side effects include sedation, constipation, and nausea. Constipation typically does not improve over time and a bowel regimen may be required.
These medications can increase risk of falls and cognitive problems in elderly patients.
Rare but serious side effects include hypogonadism, immunologic changes, and hyperalgesia.

Opioids are associated with a risk of misuse or addiction of 5% to 50% in other chronic pain conditions. Risk factors for abuse include a history of or current substance abuse, major psychiatric disorders, and family history of substance abuse.[5]

A Cochrane review of 23 studies assessed the efficacy of opioid medications for the treatment of neuropathic pain.[15]

The majority of these studies assessed treatment for less than 24-hour duration, single doses, or intravenous (IV) administration, but nine studies were 8 to 70 days in duration and included 460 patients with various types of neuropathic pain (painful diabetic neuropathy, PHN, and phantom limb pain).

The opioid medications studied were morphine (four trials), oxycodone (three trials), methadone (two trials), and levorphanol (one trial).

The opioid medications were superior to placebo in all placebo-controlled studies. A meta-analysis of the seven studies with suitable data concluded that overall opioid medications were associated with a reduction in pain intensity of 13 points on a scale of 0 to 100.
The most common side effects were nausea, constipation, sedation, and vomiting. The NNH for drug discontinuation was 16.7 (95% CI 9.1–100).