ABSTRACT: Prompt treatment of herpes zoster with an antiviral such as acyclovir does not prevent post-herpetic neuralgia, but it can reduce the pain and duration of the disorder, particularly in older patients. Agents used to treat post-herpetic neuralgia include gabapentin, tricyclic antidepressants, lidocaine patches, capsaicin, and opioids. Effective treatment often requires the use of multiple medications. When you select a regimen, consider whether your patient is at heightened risk for adverse drug effects and whether he or she has comorbid disorders, such as depression, that might be amenable to treatment with the same medication used for post-herpetic neuralgia. Patients with intense pain and dysfunction are more likely to have a protracted disease course; early, aggressive intervention is warranted in this setting. For patients who continue to have disabling pain despite treatment, consider intrathecal corticosteroid or lidocaine injections or referral to a pain management center or specialist.
Post-herpetic neuralgia is a common complication of herpes zoster (shingles). Nearly 1 million cases occur each year in the United States, and the incidence is expected to rise as baby boomers age.1
Until the early 1990s, tricyclic antidepressants (TCAs) were the only effective treatment available. Since then, evidence supporting the use of gabapentin, opioids, and lidocaine patches has emerged. Still, management of the condition can be frustrating for both patient and physician because no single modality produces excellent pain control and the majority of patients do not respond to medical treatment.
The approach we describe here is guided by the patient's susceptibility to adverse drug effects, the presence of comorbid illness, and the severity of the disease. Such an approach ameliorates symptoms and increases functional capacity while minimizing risk.
Shingles pain typically resolves by 3 months; however, in a small percentage of patients, pain persists in the affected dermatome after skin lesions have healed. Post-herpetic neuralgia is a clinical diagnosis based on the history and physical examination. It should be high on the differential diagnosis of pain that occurs at the site of a healed shingles lesion. Post-herpetic neuralgia causes neuropathic pain that is described as burning and paroxysmal and is accompanied by itching and allodynia. The pain and dysfunction associated with the condition are generally mild and self-limited but can be severe, long-lasting, and debilitating enough to cause insomnia and impair daily functioning.
The main risk factors for the development of post-herpetic neural- gia after a shingles attack are presented in Table 1. Of these, the most notable are advanced age and a severe shingles attack. The Web site at http://www.shingles.mgh.harvard.edu has a useful post-herpetic neuralgia risk calculator based on expert opinion and evidence-based research.2 Among patients older than 55 years who have shingles, post-herpetic neuralgia develops in 11.7%.3
PREVENTION OF POST-HERPETIC NEURALGIA
Varicella-zoster virus (VZV) vaccine may help decrease the incidence of post-herpetic neuralgia. However, most older adults have been infected with wild-type VZV, not vaccine-type VZV; thus, they remain at risk for shingles and subsequent post-herpetic neuralgia despite vaccination.
Prompt treatment of shingles with acyclovir-ideally within 72 hours-does not prevent post-her- petic neuralgia, but it does reduce the pain and duration of the disorder, especially in patients older than 60 years.4 The number needed to treat (NNT) to ameliorate post-herpetic neuralgia in patients over 60 years of age by treating shingles with acyclo- vir is between 3.2 and 17.5 The acyclovir prodrugs, famciclovir and valacyclovir, have a more convenient dosing schedule than acyclovir but are no more effective. Dosage recommendations for these antivirals are provided in Table 2.
Acyclovir and similar agents have no role in the treatment of post-herpetic neuralgia; they are useful only in acute shingles. Treatment of shingles with corticosteroids has no effect on post-herpetic neuralgia.6
Treatment of shingles with an NSAID or opioid may reduce the risk of post-herpetic neuralgia because of decreased pain intensity.6 Apart from this, NSAIDs are not an effective treatment for post-herpetic neuralgia.7
Treatment of shingles with amitriptyline helps ameliorate post-herpetic neuralgia (NNT, 5.1), and a low dose is usually well tolerated.8 In patients with shingles who are at increased risk for post-herpetic neuralgia, consider a 25-mg dose of amitriptyline at bedtime.
AGENTS USED TO TREAT POST-HERPETIC NEURALGIA
Gabapentin. Variousanticonvulsants have been used to treat neuropathic pain with mixed results. Two recent randomized, controlled trials (RCTs) demonstrated that gabapentin effectively treats pain and sleep disturbance caused by post-herpetic neuralgia.9,10 In these studies, significantly more patients treated with gabapentin showed improvement in pain ratings, quality of life, and sleep than did those who were not treated. Patients who received gabapentin had an average reduction in pain of 43.2% compared with 12.1% in the placebo group. The NNT for reduction of pain based on these 2 studies is between 2 and 3, and the effective starting dosage is in the range of 900 to 1200 mg/d.
The most common adverse effects of gabapentin are somnolence, dizziness, nausea, and ataxia (Table 3).11 Many of these side effects are transient, and none led to patient withdrawal from either study. No causal relationship has been established between gabapentin and any specific, life-threatening organ toxicity.12
The FDA has approved gabapentin for the treatment of post-herpetic neuralgia, and in 2003 the members of the Fourth Annual Conference on the Mechanism and Treatment of Neuropathic Pain designated gabapentin as a first-line medication for the treatment of post-herpetic neuralgia.13 A recommended target dosage of gabapentin is 1800 mg/d because this is the dosage at which most patients in the gabapentin RCTs showed benefit. Only a few additional patients in the gabapentin studies benefited from dosages of 3600 mg/d.14
When you increase the dosage, titrate gradually to reduce side effects, as detailed in Table 2.12 However, faster titration schedules will reach goal dosages sooner and may be considered in patients who have tolerated the drug well in the past. Patients who take gabapentin should experience some improvement within 8 weeks.15 Avoid abrupt cessation of high-dose gabapentin because rapid withdrawal can produce anxiety, insomnia, diaphoresis, and palpitations.16
Tricyclic antidepressants. Three RCTs of the TCAs nortriptyline and amitriptyline demonstrate that they ameliorate post-herpetic neuralgia with a NNT of 2 to 3.17 Both have similar efficacy, costs, and dosing schedules; however, in a head-to-head trial, nortriptyline was better tolerated than amitriptyline.18 In some studies of chronic neuropathic pain, low doses of TCAs were as effective as high doses and had fewer side effects; nonetheless, the greatest impact of TCAs on post-herpetic neuralgia is in the improvement of sleep, and this effect occurs at higher doses.19
TCAs are effective for treatment of depression, which is associated with increased pain scores in patients who have chronic pain.20,21 Prescribing a TCA for post-herpetic neuralgia and comorbid depression effectively treats both conditions.
Gabapentin or a TCA? There are no RCTs that directly compare TCAs with gabapentin. TCAs and gabapentin appear equally effective for treating post-herpetic neuralgia. Therefore, the decision to treat with a TCA or gabapentin remains a clinical decision based on the side-effect profiles and costs of the agents in ques-tion rather than their effectiveness. Gabapentin is more expensive than the TCAs but is better tolerated. Both TCAs and gabapentin have a "number needed to harm" (NNH) for minor adverse effects of 2.7, but gabapentin is associated with no major adverse events. On the other hand, TCAs have a NNH for major adverse effects (as defined by withdrawal from treatment in a clinical trial) of 17.22 TCAs have side effects that range from common anticholinergic effects to life-threatening arrhythmias, and there is also a growing body of evidence that long-term use of TCAs may contrib- ute to myocardial infarction.23,24 TCAs may be a good choice in younger patients, but gabapentin is safer in older patients.
Another clinically important difference between gabapentin and TCAs is the dosing frequency. Gabapentin is dosed 3 times a day, so you can expect less than perfect adherence to this regimen.25
Lidocaine patches and capsaicin. The only other medication besides gabapentin to have an FDA indication for post-herpetic neuralgia is the lidocaine 5% patch. Three studies found that the lidocaine patch produced a statistically significant reduction in pain intensity; however, the effect was temporary, lasting 12 hours with each application.26-28 The lidocaine patch has an excellent safety profile, because systemic absorption is negligible. Patches are popular medication vehicles, and undoubtedly patients derive some satisfaction from placing a "numbing" medication directly on a painful area. However, the lidocaine patch is expensive, and solid evidence of clinically relevant pain relief is lacking.17
Capsaicin cream has been shown to ameliorate post-herpetic neuralgia, but only slightly and in a minority of patients.29 Many patients do not tolerate capsaicin cream because of skin reactions and a burning sensation at the application site. Capsaicin must be applied for 2 to 6 weeks before pain control takes effect.
Opioids. Not long ago, it was believed that opioids had no place in the treatment of neuropathic pain. Their utility in post-herpetic neuralgia has since been validated in two RCTs.17,30 At least moderate pain relief and sleep improvement were reported by 58% of patients who took sustained-release oxycodone compared with 18% of those who took placebo, with an NNT of 2.1. No improvement was observed in mood or physical functioning; however, patients preferred treatment with opioids to TCAs or placebo.
In trials, opioids did not cause addiction or tolerance in patients who had neuropathic pain, and no negative effect on cognitive function or respiratory depression was noted.31 The effective dosing range for controlled-release oxycodone in one RCT was 10 to 99 mg/d, with an average of 37 mg/d.
Effective treatment of post-herpetic neuralgia often requires multiple medications. When one agent alone does not control a patient's pain (which is usually the case), add a second. The addition of an opioid to a TCA or gabapentin regimen is a common type of combination therapy. In theory, these medications should have additive or synergistic effects because they all have different mechanisms of action.
An alternative approach is to begin with combination therapy. One strategy is to prescribe lidocaine 5% patches-which have a rapid onset of action and no titration period-and either gabapentin or nortriptyline at an increasing dosage. Combination therapy is a powerful and commonly used approach to post-herpetic neuralgia. In many cases, it is preferable to monotherapy because of the low individual success rates of agents when used alone.15
Unfortunately, published data on combination therapy are scanty. There are no specific contraindications to combining anticonvulsants, antidepressants, topical anesthetics, and analgesics. However, keep in mind the potential for increased adverse effects when multiple medications are prescribed-especially in elderly patients, who may experience cognitive side effects.
In addition to medications, some patients use nondrug modalities to treat post-herpetic neuralgia. Current evidence is insufficient to determine whether transcutaneous electric nerve stimulation, acupuncture, biofeedback, or nerve blocks are effective. These methods lack adequate RCTs to support their use. Surgical and chemical sympathectomy can cause more harm than good. Intrathecal corticosteroid and lidocaine injections are effective; however, reserve them for patients in whom medical treatment has failed and who continue to have disabling pain.
Effective treatment of post-herpetic neuralgia often requires the use of several modalities. A multimodal, multidisciplinary approach might include psychological or behavioral interventions. Referral to a pain management center or pain specialist is advisable when treatment is ineffective or when medication dosages are higher than you are comfortable prescribing.
OVERALL TREATMENT APPROACH
A logical approach to the treatment decision-making process is delineated in the Algorithm. Determine which adverse effects you are most concerned about in your patient and eliminate the agents with those effects from consideration. Next, look for coexisting illnesses, such as depression, that may be amenable to treatment with the same medication used to treat post-herpetic neuralgia. The aggressiveness of treatment can then be determined by the severity of disease. Patients with more intense pain and dysfunction are at increased risk for a protracted course of post-herpetic neuralgia.32 Thus, severe disease requires early, aggressive intervention. Consider combination therapy if the side effects of both drugs and their addition to the patient's current medications are safe.
Most medications currently available for post-herpetic neuralgia produce only partial improvement; thus, it is important to establish reasonable goals of therapy with your patient. For example, improved sleep and functioning are more tangible and realistic goals than total elimination of pain. Post-herpetic neuralgia generally improves with time, so reevaluate the patient frequently and be prepared to discontinue treatment when the pain resolves. n
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