Pharmacotherapy for Neuropathic Pain in the Elderly: Focus on Postherpetic Neuralgia
Postherpetic neuralgia (PHN) is the most common complication of herpes zoster (HZ) infection, also known as shingles, which is caused by reactivation of the latent varicella zoster virus in the sensory nerve ganglia.1-3 The skin rash consists of blisters along the sensory region of the affected ganglia and is often preceded or accompanied by acute pain or itching. Pain that persists for at least 3 months after resolution of the rash is called PHN, and in some individuals, this condition can linger for months or even years.2-4
Age is the predominant predictor of PHN,2,3 with its prevalence markedly increasing with age, ranging from 8% at age 50 to 54 years to 21% at age 80 to 84 years.5 PHN can lead to insomnia, chronic fatigue, depression, anxiety, anorexia, weight loss, social isolation, and loss of function.6 A study of neuropathic pain in older adults concluded that 28% of adults 70 to 79 years of age and 35% of adults 80 years or older have peripheral neuropathy.7
This article provides an update on the prevention of PHN and pharmacotherapies used to treat it. In the previous issue of Clinical Geriatrics, we examined the pharmacotherapies for diabetic peripheral neuropathy (DPN).8 The aim of these articles is to provide clinicians with a comprehensive overview of the pharmaceuticals that can be used to manage two of the most common forms of neuropathic pain in geriatric patients: DPN and PHN. When treatments for PHN are properly prescribed and used, they can significantly improve the quality of life in elders suffering from this debilitating condition.
Prevention of Postherpetic Neuralgia
There is a high incidence and increased risk of PHN morbidity among the elderly4,9; thus, prevention is imperative in this population. Treatment of acute shingles with antiviral agents (ie, acyclovir, valacyclovir, famciclovir, brivudin) within 72 hours of rash appearance has some effect at preventing the subsequent development of PHN. It also relieves the pain of acute zoster and prevents subsequent scarring.4 However, despite these benefits, studies suggest that only 25% to 50% of patients receive antiviral agents at an early stage.9
Vaccination has been shown to markedly decrease the morbidity associated with HZ and the incidence of PHN for a mean duration of at least 3 years.10,11 The HZ vaccine has been approved by the US Food and Drug Administration (FDA) and by the European Medicines Agency (EMA) for individuals aged 50 years and older. It is contraindicated in immunocompromised patients, children, and pregnant women. A 2007 study by Pellissier and colleagues indicates that vaccination of the elderly is likely to be cost-effective from the healthcare–payer perspective.12 The Shingles Prevention Study Group,10 which enrolled 38,546 adults 60 years or older in a randomized, double-blind, placebo-controlled trial of an investigational live attenuated HZ vaccine, found that use of the HZ vaccine reduced the incidence of HZ by 51.3% (P<.001), reduced the burden of illness from HZ by 61.1% (P<.001), and reduced the incidence of PHN by 66.5% (P<.001). The most common adverse events observed with vaccination occurred at the local injection site (48% in vaccine recipients vs 16% in placebo recipients; P<.05), whereas systemic adverse events occurred in 6.3% of vaccine recipients and in 4.9% of placebo recipients (P<.05). Headache was the most frequently reported adverse event.
Treatment of Postherpetic Neuralgia
Several of the same classes of drugs used for painful DPN can be used to treat PHN. This section provides an overview of agents that have demonstrated efficacy in relieving PHN. The data that follow are not specifically limited to elderly individuals, however, as many referenced studies also included younger patients.
Antidepressants
Tricyclic antidepressants (TCAs) are recommended as first-line therapy for PHN.13 The TCAs amitriptyline and desipramine inhibit the reuptake of norepinephrine and serotonin, block N-methyl-D-aspartate (NMDA) receptors, and block sodium and calcium channels.13-16
In one study, amitriptyline 25 mg daily started within 48 hours of the onset of HZ rash resulted in a 50% decrease in pain prevalence at 6 months.17 A randomized, double-blind trial compared the TCAs desipramine and amitriptyline, both titrated to a maximum dose of 150 mg daily, with the selective serotonin reuptake inhibitor (SSRI) fluoxetine, titrated to a maximum dose of 60 mg daily. All three agents showed efficacy in reducing pain among patients with PHN, but desipramine had the best results, producing pain relief in 80% of subjects.18
Nortriptyline has a favorable safety profile compared with amitriptyline. Nortriptyline is typically started at 10 mg daily and titrated up weekly in increments of 10 mg daily. TCAs should be continued at their full dose for 3 months after the pain has disappeared, then tapered off gradually. The patient should be warned to restart (or increase the dose) immediately if the pain recurs.13 Use of amitriptyline is not recommended in older adults because of its anticholinergic side effects, such as orthostatic hypotension and cardiac arrhythmias. Older adults who have neuropathy are at increased risk of adverse events from TCAs, especially falls and cognitive decline.
Anticonvulsants
The anticonvulsants gabapentin and pregabalin, which are effective in treating DPN, have also been shown to be effective in treating PHN.
Gabapentin. Gabapentin is another recommended first-line therapy for PHN.13 Gabapentin should be given three times daily in doses titrated up over a few weeks until an average of 400 mg three times daily is reached. In most patients, gabapentin is remarkably free of side effects, so large doses can often be tolerated (even up to 3600 mg daily), although a daily total between 900 mg and 1800 mg is usually adequate.
A 10-week, randomized, double-blind, placebo-controlled, multicenter trial compared gabapentin extended release (g-ER; total daily dose, 1800 mg), either once daily or as divided doses (DDs), with placebo in 407 patients with PHN.19 Of these patients, 400 were included in the intent-to-treat population (g-ER once daily; n=134; g-ER DD, n=135; placebo, n=131). There were no statistically significant differences between groups in the average daily pain scores. Treatment-related adverse events in the groups treated with g-ER occurred in 31% of patients. The most common adverse events in the g-ER once daily and DD groups included dizziness (10% vs 15%), headache (4% vs 7%), somnolence (3% vs 7%), and peripheral edema (5% vs 5%). The investigators concluded that the primary efficacy end point for this study of g-ER was not met, most likely due to the unexpectedly large placebo response. Outcomes on secondary end points suggest the potential efficacy of g-ER once daily.19
Another randomized, double-blind, placebo-controlled study showed g-ER administered twice daily was more effective and safe than once-daily g-ER in the treatment of pain associated with PHN.20 Common adverse events in the g-ER once daily, twice daily, and placebo groups, respectively, were dizziness (22.2%, 11.3%, and 9.8%) and somnolence (9.3%, 7.5%, and 7.8%). The results suggest that g-ER, especially when administered twice daily, has the greatest effect on sharp, dull, sensitive, and itchy pain.21
Pregabalin. Pregabalin is recommended by the American Academy of Neurology as a level 1 treatment for PHN.22,23 The efficacy of pregabalin for this indication was established in three double-blind, placebo-controlled, multicenter clinical trials involving patients with PHN and in one randomized, double-blind, placebo-controlled study involving patients with chronic neuropathic pain, including PHN.23-26 In these trials, pregabalin was found to significantly decrease pain and improve sleep.
Pregabalin treatment can be started at a dose of 150 mg daily (divided into two or three smaller doses). Slow titration is preferred for elderly patients. Based on individual patient response and tolerability, the dose may be increased to 300 mg daily after an interval of 3 to 7 days, and if needed, to a maximum dose of 600 mg daily after an additional 7-day interval.
Opioid Analgesics
Opioids are widely used to treat cancer–related pain. Their use in the treatment of nonmalignant neuropathic pain remains limited due to concerns about prescribing opioids, including fears of addiction, tolerance, physical dependence, and side effects, especially respiratory failure. In addition, physicians may be apprehensive about government regulations related to prescribing opioids.
The efficacy of opioids in PHN has been documented in several studies.27-30 Oxycodone (controlled release) has been found safe and effective in treating moderate to severe pain caused by PHN.28,29 In a double-blind, placebo-controlled, randomized, crossover trial, 76 patients with PHN were scheduled to undergo three treatment phases (opioid, TCA, and placebo), each lasting approximately 8 weeks.30 Of these patients, 50 completed two phases and 44 completed all three. Mean daily maintenance doses were morphine
91 mg or methadone 15 mg and nortriptyline 89 mg or desipramine 63 mg. Opioids and TCAs reduced pain more than placebo (P<.001), with no appreciable effect on any cognitive measure. The trend favoring opioids over TCAs did not reach statistical significance (P=.06), and reduction in pain with opioids did not correlate with that observed following TCA treatment. Opioid and TCA treatments provided greater pain relief (38% and 32%, respectively) than placebo (11%; P<.001).30
Constipation is a major and expected side effect of opioid use that can negatively affect pain management and quality of life; thus, constipation should be prevented and managed immediately when it occurs. Prophylactic use of laxatives is the standard of care at the start of any opioid therapy.31
Lidocaine Patch
The 5% lidocaine patch is FDA approved to treat pain associated with PHN. Topical application of lidocaine is well tolerated. Previous reviews have concluded that lidocaine should be a first-line adjunctive treatment for PHN. The topical use of lidocaine provided significant pain relief in two randomized trials, although patient response may be delayed.3,32 One study revealed that PHN-related medical costs may be lower for patients using lidocaine patches.33 In a recent UK-based study, the 5% lidocaine patch proved more cost-effective than pregabalin at treating the pain of PHN.34 The results of this study cannot be applied to the United States, however, because the cost of the medications differs between countries.
Capsaicin Patch
The 8% capsaicin patch is approved in Europe for the treatment of peripheral neuropathic pain in nondiabetic adults and in the United States for the treatment of PHN.35 Capsaicin is a substance naturally found in chili peppers that confers a sensation of heat. The patch is a single 1-hour application that is repeated every 90 days as needed. In contrast, other agents must generally be taken or applied daily. The capsaicin patch works locally by stimulating and then inactivating C-nociceptors.35 Randomized, double-blind, multicenter trials in adults with PHN showed that a single 60-minute application of the 8% capsaicin patch reduced the Numeric Pain Rating Scale (NPRS) scores (0 = no pain; 10 = severe pain) from baseline to a significantly greater extent than a low-concentration (0.04%) capsaicin control patch during weeks 2 to 8 of use.35 The efficacy of the capsaicin dermal patch was maintained for up to 1 year in extension studies, during which patients could receive up to four more applications.
In a multicenter, double-blind, parallel-group trial, 402 patients who had PHN for at least 6 months were randomly assigned to one 60-minute application of NGX-4010 (a high-concentration 8% capsaicin dermal patch) or to a low-concentration (0.04%) capsaicin control patch.36 Patients had an average baseline NPRS score of 3 to 9. The percentage change in baseline NPRS scores in weeks 2 through 8 was the primary outcome measure. Patients who received the 8% capsaicin patch (n=206) experienced a significantly greater reduction in pain during weeks 2 through 8 than patients given the control patch (n=196). The mean changes in NPRS score were -29.6% versus -19.9% (difference, -9.7%; 95% CI, -15.47 to -3.95; P=.001). The patients using NGX-4010 had significant improvements in pain during weeks 2 to 12 (mean change in NPRS score, -29.9% vs -20.4%; difference, -9.5; 95% CI -15.39 to -3.61; P=.002). One 60-minute application of the 8% capsaicin patch provided rapid and sustained pain relief in patients with PHN, with minimal local side effects.36
A recent meta-analysis of topical capsaicin to treat neuropathic pain included six randomized controlled trials (389 total participants) that compared the regular application of low-dose (0.075%) capsaicin cream with placebo cream. The number needed to treat for any pain relief over 6 to 8 weeks was 6.6 patients (4.1 to 17 patients treated). The same meta-analysis reviewed two studies (709 total participants) comparing a single application of a high-dose (8%) capsaicin patch with a placebo patch. The number needed to achieve a reduction in pain of at least 30% over 12 weeks was 12 patients (6.4 to 70 patients treated). Local skin reactions were more common with capsaicin, but these were usually tolerable and attenuated with time. The investigators concluded that capsaicin, either as a repeated application of a low-dose (0.075%) cream or a single application of a high-dose (8%) patch, may provide a degree of pain relief to some patients with painful neuropathic conditions such as PHN.37 Moreover, because it is simple to use and has fewer systemic side effects, it should always be the first thearpy tried in elderly patients.
Combination Therapies for Neuropathic Pain
Up to 50% of patients receiving monotherapy for neuropathic pain are left with significant residual pain.38 Because monotherapy provides only partial pain relief and neuropathic pain is caused by multiple mechanisms, multimodal analgesia for neuropathic pain syndromes may be the optimal approach.39
In a double-blind crossover trial, 56 patients with daily painful DPN or PHN were randomized in a 1:1:1 ratio to receive oral gabapentin, nortriptyline, or both.40 During each 6-week treatment period, drug doses were titrated toward a maximum tolerated dose. Mean daily NPRS scores were 5.4 (95% CI, 5.0 to 5.8) at baseline. At the maximum tolerated dose, mean pain scores were 3.2 (2.5 to 3.8) for gabapentin, 2.9 (2.4 to 3.4) for nortriptyline, and 2.3 (1.8 to 2.8) for combined treatment. Pain scores with combination treatment were significantly lower than with gabapentin (-0.9; 95% CI, -1.4 to -0.3; P=.001) or nortriptyline alone (-0.6; 95% CI, -1.1 to -0.1; P=.02). The most common adverse event was dry mouth, which was significantly less frequent in patients taking gabapentin than in those taking nortriptyline (P<.0001) or combination treatment (P<.0001). The investigators concluded that combined gabapentin and nortriptyline treatment seems to be more efficacious than either drug given alone for neuropathic pain secondary to DPN or PHN.40
In another randomized, double-blind, placebo-controlled, 4-period crossover trial, patients with DPN or PHN, who had a mean baseline NPRS score of 5.72, received daily active placebo (lorazepam), sustained-release morphine, gabapentin, or a combination of gabapentin and morphine; each was given orally for 5 weeks.41 Mean daily NPRS scores at a maximum tolerated dose of the study drug were as follows: 4.49 with placebo, 4.15 with gabapentin, 3.70 with morphine, and 3.06 with the gabapentin-morphine combination (P<.05). Total scores on the short form of the McGill Pain Questionnaire (uses a scale from 0 to 45, with higher numbers indicating more severe pain) at a maximum tolerated dose were 14.4 with placebo, 10.7 with gabapentin, 10.7 with morphine, and 7.5 with the gabapentin-morphine combination (P<.05). The maximum tolerated doses of morphine and gabapentin were lower (P<.05) when they were combined. The gabapentin-morphine combination resulted in a higher frequency of constipation than gabapentin alone (P<.05) and a higher frequency of dry mouth than morphine alone (P<.05).41
Pregabalin-oxycodone therapy was evaluated in patients with DPN or PHN in a randomized, double-blind, placebo-controlled, parallel-group study.42 After a 7-daily washout period, 62 patients were randomized to receive oxycodone 10 mg daily or placebo for 1 week. Patients were then started on open-label pregabalin (75 mg, 150 mg, 300 mg, and 600 mg daily) according to a forced titration dosage regimen, while continuing the same dosage of oxycodone or placebo for 4 weeks. Similar levels of overall efficacy in relieving PHN and painful DPN were observed between the pregabalin-oxycodone groups and the pregabalin-placebo groups. Although this study supports the effectiveness of pregabalin in the treatment of PHN and painful DPN, it also shows that the addition of a low dose of oxycodone, did not enhance the pain-relieving effects of pregabalin.42
Epidural Injection of Steroids and Local Anesthetics
A randomized controlled trial based in the Netherlands assessed the effectiveness of a single epidural injection of steroids and local anesthetics at preventing PHN in older patients with HZ.43 In the trial, 598 patients 50 years of age and older with acute HZ (rash <7 days) below dermatome C6 were randomized to receive standard therapy (oral antiviral agents and analgesics) or standard therapy plus one epidural injection of methylprednisolone acetate 80 mg and bupivacaine 10 mg. The primary end point was the proportion of patients with HZ–associated pain at 1 month. In the study, 48% of patients in the epidural group reported pain at 1 month compared with 58% in the control group (relative risk [RR], 0.83; 95% CI, 0.71 to 0.97; P=.02). After 3 months, these values were 21% and 24%, respectively (RR, 0.89; CI, 0.65 to 1.21; P=.47). The authors concluded that a single epidural injection of steroids and local anesthetics is not effective at preventing long-term PHN.
Conclusion
Uncontrolled pain in elders may cause cognitive dysfunction, depression, insomnia, gait disturbances, falls, anorexia, social withdrawal, and dependence in activities of daily living and instrumental activities of daily living. FDA-approved drugs for PHN include pregabalin, the 5% lidocaine patch, and gabapentin. NMDA receptors, sodium channels, voltage-gated calcium channels, and inhibitory neurotransmission are involved in the pathophysiology of neuropathic pain and are important targets for improving treatment and developing effective drug combinations. Because research on neuropathic pain has not included enough patients 65 years and older, more research is needed in this age group. When treating elders, the goal is to optimize their function and mobility. Prevention is the most effective approach for PHN, and vaccination markedly decreases both the morbidity associated with HZ and the incidence of PHN. Combination therapy for neuropathic pain is gaining momentum because it produces better outcomes with a smaller dose of each drug, and it should be considered for older adults.
Dr. Mahmoud is Geriatric Fellow, University of Connecticut Center on Aging, Farmington; and Dr. Tampi is Associate Clinical Professor of Psychiatry, Yale University School of Medicine, New Haven, CT.
The authors report no relevant financial relationships.
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