Calcium channel-blocking anticonvulsants gabapentin and pregabalin are safe and relatively well tolerated. They can be used as first-line agents for PHN, starting with a low dosage and titrating up, based on effectiveness and tolerability.
Gabapentin is FDA approved for the treatment of PHN. The starting dosage is 100 to 300 mg taken at night, titrated as needed by 100 to 300 mg every 3 to 5 days, to as high a dosage as 1800 to 3600 mg/d in 3 or 4 divided doses. In 2 large, randomized controlled trials, gabapentin produced a statistically significant reduction in pain ratings and improved sleep and quality of life.14,15 Adverse effects include somnolence, dizziness, peripheral edema, visual adverse effects, and gait and balance problems.
Because gabapentin is excreted by the kidneys, take care when using it in patients with renal insufficiency. Gabapentin clearance is linearly related to creatinine clearance and is decreased in the elderly and in individuals with impaired renal function. Hence, the gabapentin dose and the frequency of dosing must be adjusted in these patients.
In patients on hemodialysis, plasma gabapentin levels can be maintained by giving a dose of 200 to 300 mg 4 hours after hemodialysis.16
Extended-release gabapentin. The FDA recently approved an extended-release gabapentin formulation for PHN. Approval was based on a 12-week pivotal study and 2 adjunct studies. In a multicenter, randomized, double-blind, parallel-group, placebo-controlled, 12-week study evaluating the efficacy, safety, and dose response of 3 doses, extended-release gabapentin was effective at 1200 mg/d dosing. The initial recommended dose is 600 mg, once daily for 3 days, followed by 600 mg, twice daily, beginning on Day 4.17 The premise is that the extended-release preparation improves bioavailability of the active drug and, therefore, reduces the incidence of adverse effects, compared with regular gabapentin.
Overall, evidence is mixed. Two randomized controlled trials of extended-release gabapentin showed benefit (ie, reduced pain score on a numerical rating scale) with twice-a-day dosing (600 mg in the morning and 1200 mg at night), compared with a once-daily 1800-mg dose as well as placebo, for reduction in intensity of pain18 and specific pain quality.19 In another trial, however, extended-release gabapentin, 1800 mg once daily, did not show any benefit compared with placebo.20
Pregabalin is also FDA approved for PHN. The effective dosage range is 150 to 600 mg/d. Pregabalin provided significantly superior pain relief and improved sleep scores compared with placebo in 776 patients with PHN.21 Adverse effects include weight gain, dizziness, and somnolence. Titrate the dosage slowly in the elderly.
Sodium channel-blocking anticonvulsants topiramate, lamotrigine, carbamazepine, oxcarbazepine, levetriacetam, and valproic acid are not FDA approved for PHN. These agents may be a treatment option, however, for patients with PHN who do not respond to conventional therapy. In an 8-week randomized controlled trial, patients treated with divalproex sodium (valproic acid and sodium valproate), 1000 mg/d, experienced significant pain relief compared with placebo-treated patients.22 Adverse effects included vertigo, hair loss, headache, nausea, and diarrhea.
Tricyclic antidepressants, including amitriptyline, desipramine, and nortriptyline, might work by (1) inhibiting norepinephrine and serotonin uptake, (2) sodium-channel blockade, or (3) another mechanism that is unclear. Although amitriptyline is the most studied tricyclic antidepressant for PHN, available evidence and clinical experience suggest that nortriptyline and desipramine have comparable efficacy and are better tolerated.23,24
Key Point Available evidence and clinical experience suggest that nortriptyline and desipramine have comparable efficacy and are better tolerated than amitriptyline for PHN. |
Nortriptyline and desipramine are preferred in frail and elderly patients. Start therapy with 10 to 25 mg nightly, titrating as tolerated every 2 weeks to 75 to 150 mg as a single daily dose. Adverse effects include dry mouth, fatigue, dizziness, sedation, urinary retention, orthostatic hypotension, weight gain, blurred vision, QT interval prolongation, constipation, and sexual dysfunction.
Serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressants. Use of such agents as duloxetine and venlafaxine in PHN patients is extrapolated from their proven efficacy in treating diabetic neuropathy and other neuropathic pain conditions. Try duloxetine if your patient does not respond to or tolerate a tricyclic. The recommended dosage is 60 to 120 mg/d in 2 divided doses.24
Two randomized, 12-week, double-blind, placebo-controlled trials using duloxetine 60 mg once a day and 60 mg twice a day for diabetic peripheral neuropathy concluded that 120 mg was safe and effective in treating diabetic peripheral neuropathy, but 120 mg was not as well tolerated as 60 mg once a day.25
Monitor liver function periodically in patients taking duloxetine. Alternatively, you can give venlafaxine; the recommended dosage is 75 to 225 mg/d.26