Treatment of Neuropathic Pain

Kristen Jefferies, Pharm.D.

Disclosures

Semin Neurol. 2010;30(4):425-432. 

In This Article

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).

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