US Pharm. 2006;4:44-50.

Herpes zoster (HZ), or shingles, is a reactivation of the varicella zoster virus (VZV or varicella) characterized by a painful rash of small blisters on a strip of skin anywhere on the body. Occasionally, the pain may continue for a prolonged period even after the rash is gone, known as postherpetic neuralgia (PHN). Shingles is often a debilitating disease in the acute stage and even after resolution. While there is no cure, pharmacotherapy has been the mainstay of treatment for shingles but may be associated with side effects (e.g., sedation, constipation, mood swings). A new vaccination completed phase III trials in April 2005 and will likely bring hope to the many people who suffer from shingles. Until then, patient education and contemporary pharmacotherapy will continue to be modestly effective. The goal of this article is to give pharmacists a better understanding of the epidemiology, pathophysiology, clinical features, and treatment of shingles and PHN.

Epidemiology
VZV, also known as chickenpox, infects more than 90% of Americans by adolescence.1 Nearly the entire population will be infected with VZV by age 60.1 Reactivation of VZV later in life produces HZ. Shingles affects 10% to 20% of the population at a rate of 131 per 100,000 individuals every year.1 A study reported that the lifetime incidence of HZ in Caucasians is twice that in African-Americans and has no preference regarding gender.2 Complications from HZ infection result in as many as 10,000 hospitalizations and approximately 100 deaths every year.2 Elderly individuals and people who are immunocompromised (e.g., those with HIV or AIDS), receiving immunosuppressive therapy,  or have experienced a primary infection in utero or in early infancy are at high risk for complications of HZ.1

Pathophysiology
Shingles is a neurocutaneous disease caused by the reactivation of VZV from a latent infection of dorsal sensory or cranial nerve ganglia.1 Chickenpox is a highly contagious disease, with high infection rates during childhood. VZV has the ability to establish a latent infection for the lifetime of the carrier and retains the capacity after many decades to emerge at unpredictable times and cause shingles. The precise mechanism of VZV reactivation is unclear but appears to be related to a diminution of host immunity or to impairment of the reticuloendothelial system that accompanies aging. Thus, all patients with HZ have had chickenpox in the past, even though the manifestation of the infection may have been extremely mild and perhaps not remembered.3

HZ may involve sensory ganglia along with cutaneous nerves. The thoracic portions of the spine are most frequently affected, equally followed by the lumbar and cervical portions. Viral replication of HZ spreads both centrally and peripherally along the cutaneous neuron and dorsal root ganglia. When reaching the skin, HZ replicates in the lower layers of the epidermis where it disrupts normal cellular processes. Host immune and inflammatory responses further contribute to cellular injury.1-3

Clinical Features of Shingles            
The clinical features of HZ may follow progression through three stages: prodromal, active, and chronic. However, it is common for patients not to experience all three stages. The prodromal phase seems to be the most commonly experienced. During this phase, constant or intermittent burning, tingling, itching, or various types of pain often precede rash by a few hours to several days. While the prodromal phase and the presence of cutaneous nerve fibrils indicate that HZ infection is present in the sensory ganglia, a loss of sensation can also occur.3

The acute phase is considered the active phase and follows the prodromal phase, which involves the development of characteristic skin lesions. Development of rash, especially in elderly patients, may be accompanied by generalized malaise, headache, low-grade fever, and nausea. Mild encephalopathy and severe pain may also accompany these symptoms. The active phase is initially characterized by erythematous papules and edema. Papules progress to vesicles in 12 to 24 hours and to pustules within one to seven days. The pustules eventually dry and fall off within 14 to 21 days, leaving behind erythematous macular lesions. 1,3,4 The chronic phase is unlike any of the other phases and occurs mostly in the elderly. Many patients develop PHN, which is most likely to result during the chronic stage.1,3,4




Postherpetic Neuralgia
Although the overall prevalence of PHN is 10% to 15%, nearly half of all individuals over age 70 who have experienced HZ have had pain lasting more than one year. 4,5 Patients with PHN may have constant pain (e.g., burning, aching, throbbing), intermittent pain (e.g., stabbing, shooting), or pain experienced after a nonpainful stimulus (i.e., allodynia). These subtypes of pain may produce chronic fatigue, sleep disorders, depression, anorexia, weight loss, and social isolation. Activities of daily living, such as dressing and bathing, are often impaired in elderly patients with PHN. Less frequent chronic complications of PHN include impaired vision, hearing, vertigo, facial paresis (Ramsay Hunt syndrome), and meningoencephalitis.4,5

While the exact etiology of PHN remains unclear, it has been attributed to viral-induced edema, inflammation, and hemorrhage of the dorsal root ganglia. Neuralgia may also develop secondarily due to enhanced sympathetic vasospastic ischemia in the root ganglion.4,6 Diagnosis of PHN is made clinically, based on the persistence of pain in a dermatological pattern long after the vesicle eruption has healed.

Although VZV is highly contagious, it is generally self-limited. However, if the VZV is reactivated and leads to shingles, more aggressive pain management, symptomatic relief and, occasionally, antiviral agents may be used in treatment.

Management of Shingles
A combination of nonpharmacologic therapy and medication is the most effective approach for managing HZ. Education about the illness may help eliminate anxiety and fear associated with the disease. Social support, adequate rest and physical activity, proper nutrition, and local therapy can help manage HZ. Pharmacologic approaches include the use of antiviral therapy, antidepressants, anti-inflammatory agents, anticonvulsants, and systemic and topical analgesics individualized to each patient's needs.6,7 Neuropathic pain may be unresponsive to opiates. Some patients with PHN will benefit from simple analgesics, such as acetaminophen and NSAIDs.

Antiviral Therapy: Therapy with antiviral agents can reduce the pain of acute PHN and help with the healing process. A recent review article found that when initiated within 72 hours of rash onset, oral acyclovir decreases the incidence and severity of neuropathic pain.8 Antiviral agents may be beneficial while new lesions are actively being formed but are unlikely to be helpful after lesions have crusted.8 However, the effectiveness of antiviral agents in preventing PHN is under debate; numerous studies have been conducted, but the results have been variable. The approved dose of acyclovir for the treatment of shingles is 800 mg five times/day for seven to 10 days. The newer analogs of acyclovir, such as famciclovir (Famvir/Novartis) or valacyclovir (Valtrex/Glaxo), may also be used and only need to be administered two to four times daily. Compliance to acyclovir may be difficult since five doses per day are required.6-8 All antivirals must be initiated within 72 hours, and ideally, within 24 hours, to be effective.

Tricyclic Antidepressants: Tricyclic antidepressants (TCAs) are considered the mainstay of therapy for PHN, although their side effects limit their usefulness. While their mechanism is unclear, TCAs inhibit central nervous system reuptake of norepinephrine and serotonin and may increase the inhibition of nociceptive signals from the periphery. In a study that compared amitriptyline to lorazepam in the treatment of PHN, amitriptyline demonstrated moderately significant pain relief over lorazepam.7,8 However, due to the overwhelming anticholinergic side effects of TCAs (i.e., dry mouth, urinary retention, blurry vision, and constipation), they are not recommended in the elderly. A typical initial dose of amitriptyline for neuropathic pain is 25 mg at bedtime, which may be slowly increased as tolerated to 100 mg/day. Less anticholinergic TCAs, such as nortriptyline, may be preferred since they are better tolerated than amitriptyline.

Corticosteroids: Systemic corticosteroids are the therapies most widely recommended by dermatologists to control cutaneous eruptions and pain.8 While several different routes of administration have been studied in the acute phase of PHN, oral corticosteroids appear most useful. Oral prednisone 40 mg daily tapered over three weeks, decreasing by 10 mg weekly, is effective at reducing the duration of HZ and associated symptoms. However, additional studies have found that the benefits of corticosteroids in patients older than 60 years is questionable, and adjuvant therapy such as antivirals should be used concomitantly.7,8 The side effects of systemic corticosteroids such as prednisone should be familiar to pharmacists. Short-term adverse reactions include mood swings, hyperglycemia, appetite changes, and hypokalemia (arising from mineralocorticoid activity). Chronic steroid therapy may be associated with adrenal suppression, impaired wound healing, cataract formation, skin thinning, and osteopenia or osteoporosis. Since the risk of side effects increases with the dosage and duration of steroid therapy, patients should be maintained on steroids only as long as clinically necessary.

Gabapentin: The anticonvulsant gabapentin (Neurontin/Pfizer) is approved for the treatment of PHN. The drug works by reducing spontaneous neuronal firing through membrane-stabilizing effects. Anticonvulsants were originally introduced for the treatment of epilepsy but have been found to be useful for neuropathic pain. In a randomized, double-blind, placebo-controlled study, gabapentin was effective in the treatment of pain and sleep interference associated with PHN.9 Patients' mood and quality of life generally improve with gabapentin therapy. Gabapentin is associated with a variety of side effects, including sedation, dizziness, somnolence, and memory disturbances. Rare adverse effects with gabapentin include liver toxicity and thrombocytopenia. The dosage for gabapentin for the treatment of PHN is as follows: day 1, 300 mg; day 2, 300 mg two times/day; and day 3, 300 mg three times/day. The dose may be titrated to between 1,800 and 3,600 mg/day as needed for pain relief. Daily doses greater than 1,800 mg do not generally show increased benefit.

Capsaicin: The topical analgesic capsaicin is thought to produce analgesia by depletion of substance P, a nocigenic peptide associated with pain. Topical application of capsaicin can cause burning and erythema, but has been found to produce moderate relief when applied four times daily.10,11 The recommended strength of capsaicin is 0.075% (Zostrix HP/Rodlen Laboratories), and it must be applied directly to areas of pain three to four times daily. Patients should be instructed to wear gloves when applying the medication, wash hands immediately after application, and discontinue use if severe burning or intense itching occurs. 

Transdermal Lidocaine: Lidocaine 5% patch (Lidoderm/Endo Pharmaceuticals) is also useful for local pain associated with PHN. The patch may remain in place for up to 12 hours, and up to three patches may be applied in a single application in any 24-hour period. The most common side effects of lidocaine are skin redness or rash.

Prospects for Shingles Vaccination
The morbidity of HZ could be reduced if a safe and effective preventive treatment were available. Zostavax (zoster vaccine live/Merck) is an investigational shingles vaccine. In a recent placebo-controlled clinical trial, the vaccine reduced the total burden of pain and discomfort caused by shingles by 61%, the incidence of PHN by 67%, and the overall incidence of shingles cases by 51%. 12 The study was conducted in more than 38,500 men and women ages 60 years and older. Participants were enrolled from 1998 to 2001, with the follow-up completed in 2004. Enrollment criteria included history of chickenpox (varicella) or residency in the United States for more than 30 years. Patients were excluded if they were immunocompromised or unable to adhere to the specific requirements of the protocol. More than 95% of participants completed the study.12 The rates of serious adverse events were low, and the number and types of serious adverse events were similar in the vaccine and placebo groups. Erythema and rash around the injection site were common adverse effects.

Conclusion
Shingles is often a confusing and frustrating disease, especially for patients. Current treatment options focused on relieving the symptoms of PHN include TCAs, analgesics, anticonvulsants (gabapentin), and topical agents such as capsaicin and lidocaine. Since shingles often affects elderly patients, it is especially important that pharmacists be aware of the adverse effect profile of these medications. Pharmacists should educate patients and advise them if drug interactions are anticipated or if adverse effects are suspected. Baseline pain intensity and the nature of pain (e.g., tingling, burning) should be used to assess the effectiveness of pharmacotherapy for PHN. Although the management of shingles is primarily symptomatic and supportive, since antivirals may not reduce the incidence of the disease, HZ vaccination holds promise for the future.

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