Herpes Zoster and Postherpetic Neuralgia

Siddarth Thakur

Robert H. Dworkin

Rajbala Thakur

The objective of this chapter is to provide an overview of the clinical presentation and management of herpes zoster and its most common complication in immunocompetent patients, postherpetic neuralgia (PHN). Herpes zoster is a viral infection caused by the reactivation of the varicella-zoster virus (VZV). The primary varicella infection occurs when the patient contracts chicken pox. Following the resolution of chicken pox, the virus then remains dormant in dorsal sensory ganglia and cranial nerve ganglia for years to decades. Individuals are asymptomatic while the virus is dormant, and reactivation of VZV results in a characteristic and usually painful vesicular dermatomal rash. Some patients with herpes zoster develop PHN, and this persisting neuropathic pain can last for years.

Herpes zoster afflicts millions of older adults worldwide each year and causes significant suffering and disability because of both the acute pain that occurs in association with the rash and the chronic pain that is present in those patients who develop PHN. VZV-induced neuronal destruction and inflammation causes pain that interferes with activities of daily living and reduces quality of life. Contemporary advances have improved our ability to both diminish the incidence of these conditions as well was manage the remaining cases more effectively. These include the development of herpes zoster vaccines, consensus that antiviral therapy and aggressive pain management can reduce the burden of this disease, the identification of efficacious treatments for PHN, and the recognition of PHN as a study model for neuropathic pain research. An interesting ongoing development is recognition of phenotype-based identification of subsets of patients that may help clinicians make individualized therapeutic decisions.¹^,²^,³^,⁴

Clinical Picture and Natural History of Herpes Zoster

Herpes zoster is a neurodermatomal illness that does not cross the midline. Typically, a single dermatome is affected in immunocompetent patients, although in some cases, involvement of adjacent dermatomes can be seen due to normal variation of cutaneous innervation. In immunocompromised patients, there can be cutaneous dissemination and, rarely, visceral dissemination. The sequence of events described in the following sections is typically observed.

PRODROME

Herpes zoster may begin with fatigue, headache, or flu-like symptoms, including fever, neck stiffness, malaise, and nausea. This may be accompanied by unilateral dermatomal pain and abnormal sensations, including pruritus. The prodromal symptoms usually precede the appearance of a rash by 3 to 7 days, although longer periods have been reported. The prodrome probably occurs in association with the initiation of viral replication and the accompanying inflammatory response. This process results in ganglionitis as well as the destruction of neurons and supporting cells in the dorsal root ganglion (DRG) and accompanying dermatome.⁵^,⁶ In cases where patients experience a prolonged course of prodromal symptoms, diagnostic investigations are frequently undertaken to identify other medical conditions that may cause pain in the affected anatomic distribution. Common examples include pursuing the diagnosis of glaucoma in cases of herpes zoster ophthalmicus; sciatica in cases of sacral dermatomal involvement; and angina, renal colic, or cholecystitis in cases of truncal involvement. Diffuse or regional adenopathy is seen in a minority of cases and has not been correlated with any residual or long-term complications.

RASH

The reactivated virus replicates in the sensory ganglion and travels antidromically via the cutaneous nerves to the nerve endings at the dermoepidermal junction. Further replication in the skin results in tissue inflammation and necrosis which ultimately leads to the appearance of a rash in the same distribution as the prodrome. The rash is initially maculopapular and evolves into the classic appearance of grouped vesicle formations on an erythematous base. Regional lymphadenopathy may appear at this stage. Over the next 7 to 10 days, the lesions progress to a pustular rash. Open lesions will develop superficial crusting. Scabs are cleared within 2 to 3 weeks. Skin in the affected region may be left completely normal or may develop a patchwork of either hypo- or hyperpigmented scarring (Fig. 27.1).

PAIN

Pain often precedes or accompanies the herpes zoster rash.⁷^,⁸ Pain may be accompanied by other sensations such as itching, paraesthesias (i.e., nonpainful abnormal sensations that are not unpleasant), and dysesthesias (i.e., nonpainful abnormal sensations that are unpleasant). The timing of the pain may be constant or intermittent, and the quality of the pain is variously described as burning, throbbing, stabbing, electric shock-like, or various combinations of these. It is frequently associated with increased tactile sensitivity and allodynia (i.e., pain in response to a normally nonpainful stimulus). The pain may interfere with the patient’s sleep and other aspects of physical and emotional functioning. The acute pain associated with herpes zoster gradually resolves in most patients around the time that the rash resolves. Pain that persists beyond the acute phase of the rash is considered subacute herpetic neuralgia or PHN, depending on its duration. A distinction between these three phases of pain associated with herpes zoster has been identified and is useful in both clinical and research settings.⁹ Acute herpetic neuralgia has been defined as pain that occurs within 30 days of rash onset, subacute herpetic neuralgia as pain that persists beyond 30 days from rash onset but that resolves before the diagnosis of PHN can be made, and PHN as pain that persists for 120 days or more after rash onset (Fig. 27.2).

DISTRIBUTION OF HERPES ZOSTER

Thoracic dermatomes are the most commonly affected sites. These are followed, in order of incidence, by the ophthalmic division of the trigeminal nerve, other cranial nerves, and cervical, lumbar, and sacral dermatomes¹⁰ (Table 27.1). The reason for this pattern is not understood, but it has been speculated that this may reflect the characteristic distribution of the chicken pox rash. The pattern of rash seen in herpes zoster follows the same centripetal distribution observed with the primary varicella infection. Patients can develop lesions in the adjoining dermatomes, and much
less commonly, a diffuse cutaneous or even visceral dissemination can occur, most often in immunocompromised individuals.

FIGURE 27.1 Herpes zoster rash progression. (Reprinted from Weinberg JM. Herpes zoster: epidemiology, natural history, and common complications. J Am Acad Dermatol 2007;57(6 Suppl):S130-S135. Copyright © 2007 American Academy of Dermatology, Inc. With permission.)

CLINICAL VARIANTS

Herpes Zoster Ophthalmicus

Herpes zoster ophthalmicus (HZO) occurs in approximately 10% to 20% of herpes zoster cases.¹¹ The involvement of the ophthalmic branch of the fifth cranial nerve is five times as common compared with cases involving the maxillary or mandibular branches. The predilection for the ophthalmic branch may be due to more frequent trauma to that area with subsequent virus reactivation.¹² It is easily recognized by the presence of vesicles and erythema of the ipsilateral forehead and upper eyelid. HZO requires particularly prompt treatment and careful follow-up monitoring because of the possibility of ocular involvement, which occurs in approximately one-half of patients with HZO (Fig. 27.3).

Herpes Zoster Oticus (Ramsay-Hunt Syndrome)

This presentation of herpes zoster is relatively rare, but this may reflect, at least in part, a failure to properly recognize and diagnose cases. Classically, herpes zoster oticus begins with otalgia and the formation of herpetiform vesicles within the external ear canal. Associated findings that may be present include facial paralysis resulting from facial nerve (cranial nerve VII) involvement, auditory symptoms including unilateral deafness, and/or vestibular symptoms. This condition may also result from zoster of the 9th or 10th cranial nerves because the external ear has complex innervation by branches of several cranial nerves (V, VII, IX, and X) as well as vertebral nerves C2 and possibly C3.

FIGURE 27.2 Natural history of herpes zoster and postherpetic neuralgia.

Zoster Sine Herpete

Herpes zoster infections presenting with only dermatomal pain in the absence of rash have been described in the literature for many years.¹³^,¹⁴ The actual prevalence of this condition is unknown. Positive serology in the acute or convalescent phase is the only definitive way to establish the diagnosis in such patients. Given that it would be rare to perform the required serologic studies early in the disease course in most clinical settings, this diagnosis is rarely confirmed.

TABLE 27.1 Dermatomal Distribution of Herpes Zoster in Immunocompetent Patients

Thoracic: up to 50% of all cases

Cranial: 10%-20%

Cervical: 10%-20%

Lumbar: 10%-20%

Sacral: 2%-8%

Generalized: <1%

Diagnosis of Herpes Zoster

The diagnosis of herpes zoster is usually established based on the clinical findings of a characteristic dermatomal rash (Fig. 27.4) and the presence of associated pain. The differential diagnosis frequently includes contact dermatitis. Herpes simplex virus (HSV) infection must also be considered, particularly if sacral dermatomes are involved. The main differentiating features of an HSV infection are that it tends to occur predominantly around the mouth or genitalia, is more prevalent in younger patients versus the predilection for herpes zoster to afflict more elderly patients, and HSV has a propensity for recurrent outbreaks which are relatively rare in herpes zoster. In cases of atypical presentations or when there is confusion as to whether VZV or HSV is the pathogen, diagnosis can be confirmed by laboratory testing.

LABORATORY TESTING

Direct Immunofluorescence Assay

Direct immunofluorescence assay is often preferable to viral culture due to its low cost and rapid turnaround time, which can be within 1.5 hours. Sensitivity is approximately 90% but decreases if the lesions are beyond the vesicular stage.

FIGURE 27.3 Ophthalmic zoster. (Reproduced from Dworkin RH, Johnson RW, Breuer J, et al. Recommendations for the management of herpes zoster. Clin Infect Dis 2007;44[1]:S1-S26. Reproduced by permission of Infectious Diseases Society of America.)

FIGURE 27.4 Herpes zoster rash in the T2 dermatomal distribution. (Reproduced from Dworkin RH, Johnson RW, Breuer J, et al. Recommendations for the management of herpes zoster. Clin Infect Dis 2007;44[1]:S1-26. Reproduced by permission of Infectious Diseases Society of America.)

Viral DNA Testing

Viral DNA can be detected in the vesicle fluid and cutaneous tissue by polymerase chain reaction (PCR) technology. It has the advantage that it can be effective even on old and crusted lesions. It usually has a turnaround time of 1 day but can be completed in less than 5 hours with rapid real-time PCR.¹⁵ It is generally more expensive than other approaches and has exceptional sensitivity and specificity of near 100%.

Biopsy

A biopsy is not typically needed in clinical practice and should be reserved for difficult to diagnose cases. Histologic findings of ballooning degeneration and acantholysis of keratinocytes resulting in intraepidermal vesicles are common to all herpes infections. Multinucleated giant cells with accentuation of nuclear material at the periphery of the nuclei are present. Underlying leukocytoclastic vasculitis is often a prominent finding and helps differentiate zoster from other herpesvirus infections.

Testing for Underlying Disorders

If clinically indicated, testing for HIV or occult malignancy may be advisable, but this is typically not necessary and is not recommended on a routine basis.

Epidemiology of Herpes Zoster

The epidemiology of herpes zoster is primarily affected by a combination of the incidence of primary varicella infections as well as age and level of immunosuppression in the population. Herpes zoster is among the most common of neurologic illnesses, affecting about 1 million people in the United States annually.¹⁶ According to the Centers for Disease Control and Prevention (CDC), the lifetime incidence of herpes zoster in the United States is estimated to be 32%.¹⁷ A systematic review of global herpes zoster incidence rates found between 3 and 5 cases per 1,000 person-years in North America, Europe, and the Asia Pacific, with a precipitous increase beyond that noted with aging.¹⁸ At 60 years old, the incidence increases to 6 to 8/1,000 person-years and 8 to 12/1,000 person-years at 80 years of age. The findings were similar in a subsequent study of the incidence of herpes zoster in the United States.¹⁹

Accordingly, increasing age is the most potent risk factor for herpes zoster in both immunocompetent and immunocompromised individuals (Table 27.2). The decline in VZV-specific cell-mediated immunity is believed to drive the increase in herpes zoster observed in patients as they age.²⁰ There is a notable
increase in disease rates around 50 years of age,¹⁶ and the lifetime prevalence reaches approximately 50% in individuals living to be 85 years of age.²¹ There has also been a higher incidence in women, thought to be related to a combination of biologic factors (immunologic or hormonal) as well as differences in health seeking behaviors.¹⁹^,²²^,²³^,²⁴^,²⁵

TABLE 27.2 Factors Associated with an Increased Incidence of Herpes Zoster

Increasing age
Disease states

HIV

Lymphoproliferative disorders
Immunosuppressive therapy

After organ transplant

Chemotherapy

Steroid treatment
Possible association with

Caucasian vs. African American racial group

Psychological stress

Physical trauma

Immunocompromised individuals have a relatively high risk for developing herpes zoster.²⁶^,²⁷ Patients with a history of HIV infection, solid organ and bone marrow or stem cell transplantation, immunosuppressive chemotherapy, or systemic lupus erythematosus are 2 to 10 times more likely to develop herpes zoster compared to immunocompetent individuals.²⁷ Immunocompromised individuals also experience higher recurrence rates of zoster compared to those who are immunocompetent.²⁸

Other factors that appear to increase the risk for herpes zoster that are less well replicated include Caucasian versus African American racial group,²⁹ presence of elevated psychological stress,³⁰ physical trauma,³¹ and diabetes mellitus.³² Exposure to varicella antigen, either through contact with chicken pox or by vaccination, has a protective effect and reduces the incidence of herpes zoster.³³^,³⁴

The epidemiology of varicella and herpes zoster is likely to change as childhood vaccination against the primary infection alters the long established relationships between humans and this viral infection. The incidence of primary varicella infections has declined dramatically in the United States since the implementation of routine childhood vaccination.³⁵

It has been hypothesized that there will be an acceleration of incidence of herpes zoster beyond expectations in the future as the opportunities for subclinical immune boosting in aging adults, which result from exposure to VZV, will decline due to the decreased incidence of chicken pox.³⁶^,³⁷^,³⁸ To date, there is little evidence to support this hypothesis, as multiple studies have demonstrated rates of herpes zoster increasing across all adult age groups before the implementation of the varicella vaccine in 1996,³⁹ and that have continued since.²⁵^,²⁸^,⁴⁰^,⁴¹ Furthermore, the rates of herpes zoster are similar in areas with high levels of varicella vaccination and those without. One population-based study analyzed the incidence of herpes zoster over a 60-year period and noted an over fourfold increase was not likely related to introduction of the varicella vaccine.⁴² Furthermore, a decrease in the number of herpes zoster cases in children less than 10 years of age has been reported, presumably due to vaccination.²⁵^,⁴³ It is possible that there has not been enough time since the implementation of the recommended childhood varicella vaccination for the acceleration in zoster incidence to be observed.

FIGURE 27.5 Host factors in varicella-zoster virus (VZV) latency and reactivation. Varicella is the primary infection caused by VZV, and its resolution is associated with the induction of VZV-specific memory T cells (blue line). Memory immunity to VZV may be boosted periodically by exposure to varicella or silent reactivation from latency (red peaks). VZV-specific memory T cells decline with age. The decline below a threshold (black line below zoster threshold) correlates with an increased risk of zoster. The occurrence of zoster, in turn, is associated with an increase in VZV-specific T cells. The administration of zoster vaccine to older persons may prevent VZV-specific T cells from dropping below the threshold for zoster occurrence (dashed blue line). (Reprinted from Arvin A. Aging, immunity, and the varicella-zoster virus. N Engl J Med 2005;352[22]:2266-2267. Copyright © 2005 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.)

Eventually, as children immunized against VZV grow into adulthood, the number of adults infected with latent wild-type virus will decrease. Therefore, the incidence of herpes zoster is expected to decline as the live attenuated virus used in the varicella vaccine appears to be less likely to reactivate and cause herpes zoster.

Pathophysiology of Herpes Zoster and Mechanisms of Acute Pain

As noted earlier, herpes zoster most commonly manifests in the distribution of a single dorsal sensory or cranial nerve ganglion. Why the reactivation occurs in one ganglion when latent virus is present throughout the patient’s sensory ganglia is not clear. Declining cellular immunity is a major risk factor for reactivation of the virus, which is thought to occur when cell-mediated immunity falls below a critical level.²¹ This impression is supported by evidence that even individuals with adequate levels of serum antibodies to VZV antigen can, over time, exhibit T cells with reduced ability to proliferate and defend against VZV infections.⁴⁴ Hence, cell-mediated immunity appears to play a crucial role in preventing reactivation of latent VZV (Fig. 27.5). Common causes of decreased cellular immunity include increasing age, various diseases, and immune-suppressing medical interventions, all of which are known risk factors for herpes zoster.

During reactivation of the virus, newly synthesized viral particles are transported in a retrograde and anterograde fashion to the central and distal axons of the involved spinal or cranial sensory ganglion. Viral replication causes inflammatory and neural tissue injury in the affected dermatome,⁵ which can ultimately result in infectious hemorrhagic necrosis and subsequent neuronal loss and scarring centered in the sensory ganglion of affected cranial and peripheral nerves.⁴^,⁴⁵ Microscopic examination of the zoster affected ganglion shows significant hypocellularity and collagen scarring. The corresponding peripheral nerves may exhibit a long-lasting reduction in myelinated axons and increased numbers
of small unmyelinated axons. These structural changes contribute to the pain and other characteristic sensory findings along the corresponding sensory dermatomes of the involved ganglion. Excessive electrical activity in the damaged peripheral nociceptors is the major cause of pain in the acute herpes zoster infection. Although VZV is a sensory-specific virus, involvement of anterior horn cells, autonomic neurons, and leptomeninges can be observed as a result of a bystander effect,⁴⁶ with consequent muscle weakness, palsy, and/or pleocytosis of cerebral spinal fluid (CSF).

Complications Associated with Herpes Zoster

In general, the frequency and severity of complications are greater in older and immunocompromised individuals. The most common morbidity of herpes zoster in immunocompetent individuals is the development of PHN; this often severe pain can persist well beyond the resolution of herpes zoster. This complication is discussed in detail in the latter part of this chapter.

OPHTHALMIC COMPLICATIONS

The incidence of complications associated with HZO has been reported to be 2% to 6% of cases. A variety of complications have been described,¹¹ including retinitis, keratitis, iritis, scleritis, secondary glaucoma, and ptosis. These are obviously serious problems that can result in temporary or permanent deterioration in visual acuity or complete blindness. For these reasons, patients with ophthalmic zoster should be evaluated by an ophthalmologist as promptly as possible following diagnosis.

MOTOR NEUROPATHY

Motor nerve involvement is present in 5% to 15% of patients presenting with herpes zoster. Paresis in extraocular nerves, facial nerves, and a variety of other motor nerves has been described. Diaphragmatic paresis is not an uncommon occurrence with the involvement of the phrenic nerve, and intercostal nerve involvement may lead to paresis of intercostal muscles (Fig. 27.6). Involvement of cervical motor nerve roots may present as shoulder and arm weakness, and lower extremity weakness can occur when lumbosacral nerve roots are affected. In some cases, significant motor weakness may be the presenting symptom, and this can delay accurate diagnosis. In general, paresis improves with time and physical rehabilitation; however, the likelihood and completeness of muscle function recovery appears to decrease with older age and greater initial severity of the paralysis.

FIGURE 27.6 T8 motor neuropathy in an otherwise healthy 59-year-old man who presented with vesicles in the T8 distribution 4 weeks before this photo was taken. The patient was treated with an antiviral agent for 7 days and with analgesics as needed. As the rash resolved, this bulge became apparent; it is consistent with motor damage by varicella zoster virus to the muscles of the abdomen. (Reproduced from Dworkin RH, Johnson RW, Breuer J, et al. Recommendations for the management of herpes zoster. Clin Infect Dis 2007;44[1]:S1-26. Reproduced by permission of Infectious Diseases Society of America)

RARE NEUROLOGIC COMPLICATIONS

VZV is a common cause of aseptic meningitis with a sharp pleocytosis and elevated proteins evident on CSF studies. Most patients with VZV meningitis experience a complete resolution of the symptoms in 1 to 2 weeks,⁴⁷ although meningeal involvement can result in long-term sequelae from subsequent scarring of the involved neural structures. Myelitis and encephalitis are other rare central manifestations of reactivated VZV. VZV encephalitis can present as an acute delirium accompanied by few focal neurologic signs.⁴⁸ Factors that elevate the risk of central nervous system (CNS) involvement include the presence of altered immune function (e.g., HIV), cranial nerve or ophthalmic involvement, two or more prior zoster episodes, and evidence of cutaneous dissemination.⁴⁹ Although more common in immunocompromised patients, CNS involvement has also been reported in immunocompetent individuals⁵⁰ and in both children and adults.⁵¹ Herpes zoster may be a risk factor for Guillain-Barré syndrome developing within the 2 months following the rash.⁵²

DECREASED QUALITY OF LIFE

The acute pain associated with herpes zoster can cause significant suffering and is often accompanied by interference in the patient’s ability to carry out normal activities of daily living. In addition, acute pain is associated with the greater use of analgesic medications and their attendant side effects, most notably sedation and constipation.⁵³^,⁵⁴^,⁵⁵^,⁵⁶^,⁵⁷^,⁵⁸ The resultant impact of herpes zoster and related complications on health-related quality of life is at least as great as what has been found with other chronic diseases such as diabetes or congestive heart failure.⁵⁷

Treatment of Herpes Zoster

All patients should have a thorough medical evaluation with added attention to factors related to the individual’s immunocompetence. Patient education, reassurance, and supportive therapy are essential to allay fears and promote compliance with pharmacologic therapy. The primary goals of pharmacologic therapy are to reduce the severity and duration of pain, promote healing of skin lesions, prevent PHN, and decrease ongoing viral replication and shedding, thereby reducing the risk of transmission. Limiting viral replication has been shown to reduce the incidence and severity of acute pain associated with herpes zoster. The primary pharmacologic approaches include the use of antiviral therapy in conjunction with analgesic agents. Steroids have also been used, but their role is more controversial. The potential roles of neural blockade, neuroaugmentation strategies, and complementary and alternative medicine are also controversial.

PATIENT EDUCATION

It is important to educate patients and their family members about their disease. Patients and caretakers can be reassured that herpes zoster does not cause any illness in seropositive individuals who have contact with the patient. Herpes zoster does, however, pose a risk of viral transmission to individuals who do not have preexisting immunity to VZV. Given this, it is
important for patients with herpes zoster to avoid contact with individuals who are known to be seronegative for VZV or have known or suspected immune system impairment, especially if it is unclear whether they have a history of chicken pox. Patients should be counseled regarding maintaining appropriate nutrition and optimal levels of social and physical activities. In addition, patients should be told to keep the rash area clean and to avoid application of ointments or adhesive dressings because these can cause skin irritation and secondary infections. Patients should inform their physician if fever, confusion, or other significant constitutional symptoms develop and should return for further evaluation if rash healing appears delayed.

TABLE 27.3 Benefits of Antiviral Therapy¹⁷^,⁵⁹^,⁶²^,⁶³^,⁶⁵^,⁶⁶^,⁶⁷

Inhibition of viral replication
Reduces duration of viral shedding
Hastens rash healing
Decrease in degree of neural damage
Decreases severity and duration of acute pain
Decreases duration of postherpetic neuralgia

ANTIVIRAL THERAPY

Antiviral therapy has been shown to be efficacious in suppressing viral replication and also has beneficial effects on both acute and chronic pain (Table 27.3).⁵⁹^,⁶⁰^,⁶¹^,⁶²^,⁶³^,⁶⁴ Antiviral medication is recommended for all herpes zoster patients who are older than 50 years, have moderate to severe pain, have a moderate to severe rash, have ophthalmic involvement, or are immunocompromised.⁶⁸ In current clinical practice, most physicians prescribe antiviral therapy to all patients with herpes zoster because of the very favorable risk-benefit ratio of these medications. Antiviral treatment should be started as soon as possible; this should ideally be within 72 hours of the onset of rash, the inclusion criterion for initiating treatment in the clinical trials of antiviral agents in herpes zoster patients. The early initiation of antiviral therapy is intuitively logical and an important treatment objective. However, viral replication may continue beyond the third day after rash onset, suggesting that even delayed antiviral therapy may provide some benefit. Unfortunately, there are no well-designed clinical trials examining the efficacy of initiating antiviral therapy beyond 72 hours of rash onset. Two uncontrolled trials examined the effectiveness of antiviral treatment initiated at a later time, and the results suggested that such treatment may have beneficial effects.⁶⁵^,⁶⁹ In clinical practice, the diagnosis of herpes zoster is often not made within 72 hours of the onset of symptoms; nevertheless, it is important to identify patients who could still benefit from antiviral medication even when it is initiated relatively late in the disease course. One example of patients who warrant such later initiation of treatment is those with ophthalmic zoster. The duration of viral shedding from the ocular surface is highly variable⁷⁰ and may continue for a longer period of time. Immunocompromised patients, those with disseminated zoster, patients with neurologic complications, and possibly those with new lesions still forming should also be started on antiviral medication irrespective of whether they are beyond 72 hours of rash onset.

TABLE 27.4 Antiviral Medications for Herpes Zoster

Medication	Oral Bioavailability	Dosage	Duration of Treatment (Days)	Uncommon Side Effects	Special Considerations
Acyclovir	15%-30%	800 mg 5 times daily (every 4-5 h)	7-10	Neurotoxicity and nephrotoxicity	Additive nephrotoxic effects with cyclosporine
Famciclovir	77%	500 mg 3 times daily (approved dosage in United States; in some other countries, 250 mg 3 times daily is approved)	7		Probenecid, theophylline increase levels of famciclovir. Digoxin levels increased
Valacyclovir	55%	1,000 mg 3 times daily	7		Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome reported at dosages of 8,000 mg daily in immunocompromised patients
Foscarnet	NA	40-90 mg/kg IV for induction and 120 mg/kg/d for maintenance therapy	10-14 d for induction and variable duration for maintenance	Nephrotoxicity, neurotoxicity, neutropenia, anemia	Increased risk of nephrotoxicity with cyclosporine. Increased risk of seizures with ciprofloxacin
Brivudin^a		125 mg once daily	7		Contraindicated for patients treated with 5-fluorouracil or other 5-fluoropyrimidines because of drug interaction associated with severe and potentially fatal bone marrow suppression
NOTE: All antivirals are renally excreted; hence, dosage needs to be adjusted in patients with renal insufficiency, including patients on dialysis. Nausea and headache are common side effects.
^aNot available in the United States.

There are two main classes of antiviral medication, and these are differentiated by their reliance on viral phosphorylation to be activated. The first class of drugs is nucleoside analogues that require phosphorylation by viral thymidine kinase and includes acyclovir, brivudin, famciclovir, and valacyclovir (Table 27.4). These drugs are phosphorylated to a triphosphate form that impairs viral replication by inhibiting viral DNA polymerase. Acyclovir, famciclovir, and valacyclovir are all available in the United States and are approved by the U.S. Food and Drug Administration (FDA) for the treatment of herpes zoster. These medications are excreted renally, and dosages should therefore be adjusted in patients with renal insufficiency. Special dosing regimens are also needed in patients on dialysis. Although the dose necessary to treat HZV is higher than that for HSV, these medications have established safety and are generally well-tolerated. Acyclovir must be taken five times daily for 7 days, whereas famciclovir and valacyclovir are taken three times daily for 7 days. Thus, patient compliance with famciclovir and valacyclovir is likely to be considerably greater than with acyclovir, and this may translate to somewhat greater efficacy. Famciclovir and valacyclovir may also be somewhat better than acyclovir in reducing the incidence of prolonged pain.⁶⁶^,⁶⁷^,⁷¹ Although brivudin is currently
not available in the United States, it has been approved for the treatment of herpes zoster in several other countries; it is dosed once daily for 7 days.

The second class of antiviral medications is not dependent on viral phosphorylation. These agents noncompetitively inhibit viral DNA polymerase, and include vidarabine, foscarnet, and cidofovir. Foscarnet is useful in patients with known resistance to acyclovir due to lack of viral thymidine kinase, which can be seen in patients with AIDS or prolonged exposure to acyclovir (as in transplant patients). Hence, this agent plays an important role in treating infections in individuals with known resistance to acyclovir.

ANALGESIC TREATMENT

Antiviral therapy does not completely abolish the acute pain associated with herpes zoster, nor does it necessarily prevent PHN,²⁷ and supplemental analgesic medications are required in most patients. Effective analgesia improves patient comfort and may also reduce the risk of PHN beyond what is achieved by antiviral therapy alone.⁷²^,⁷³ These considerations argue for aggressive management of the acute pain associated with herpes zoster. A multimodal analgesic strategy should be used to balance efficacy, safety, and tolerability of the medication regimen. Unfortunately, well-designed studies to delineate which combinations of therapies are optimal have rarely been conducted. In lieu of focused studies, clinicians must use the available data, extrapolate available information, and individualize therapy based on patient-specific factors. The World Health Organization analgesic ladder can be applied as one useful analgesic strategy with well-proven efficacy and ease of application. Patients with mild pain can be started on acetaminophen alone or in combination with a mild opioid analgesic such as tramadol. Nonsteroidal anti-inflammatory drugs (NSAIDs) can also be used provided there are no contraindications to their use. Patients with moderate pain can be started on short-acting opioid medications and, if tolerated, can be converted to a timed-release preparation if clinically warranted. Opioids have not been well-studied in patients with herpes zoster, but one small clinical trial did show that controlled-release oxycodone was superior to placebo in relieving acute pain within the first 2 to 3 weeks of rash onset, although the small sample size precluded an evaluation of the effect of this treatment on the development of PHN.⁷⁴

If acute pain in herpes zoster patients is not adequately controlled with the mentioned analgesics, other medications that have demonstrated efficacy in the treatment of chronic neuropathic pain can also be used in combination with antiviral therapy.⁶⁸ Gabapentin, pregabalin, and tricyclic antidepressants such as nortriptyline and desipramine can be considered in patients when conventional analgesic medications are not adequate in managing acute pain. Studies are limited, but a single-dose trial of 900 mg of gabapentin versus placebo did demonstrate a reduction in acute pain over 6 hours in patients with herpes zoster.⁷⁵ Both gabapentin and pregabalin would seem like reasonable alternatives because they not only have efficacy in the treatment of PHN but have also demonstrated efficacy in reducing pain and analgesic requirements in some acute pain conditions.⁷⁶^,⁷⁷

Although tricyclic antidepressants have not been wellstudied in patients with herpes zoster, they have proven efficacy in chronic neuropathic pain and are additional rational choices for treating acute pain associated with herpes zoster. Dual reuptake inhibitors (selective serotonin and norepinephrine reuptake inhibitors) can be considered in lieu of tricyclic antidepressants given their more favorable side effect profiles. Both duloxetine and venlafaxine have demonstrated efficacy in painful diabetic peripheral neuropathy⁷⁸^,⁷⁹ and could thus be considered a potential therapy for the treatment of acute pain in patients with herpes zoster.

A pragmatic approach is to start with a short-acting opioid in combination with acetaminophen or an NSAID. Gabapentin or pregabalin can then be added if conventional analgesics are not entirely effective. Many clinicians would use one of these medications rather than a tricyclic antidepressant because of their generally safer side effect profile. The analgesic regimen should be tailored based on the individual patient’s needs and tolerances (Table 27.5). Frequent follow-up and reassessment are vital to assess efficacy and tolerability while titrating analgesic therapy.

CORTICOSTEROIDS

The use of corticosteroids in the treatment of herpes zoster has been controversial.⁸⁰^,⁸¹ One placebo-controlled trial demonstrated a benefit in terms of significantly accelerated return of uninterrupted sleep, cessation of analgesic therapy, and return to normal activity in patients treated with the combination of a corticosteroid and acyclovir as compared to those treated with acyclovir alone.⁸¹ The patients in this trial were 60 years of age on average and possessed no contraindications to corticosteroid treatment. Based on these results, the addition of oral corticosteroids can be considered in healthy older adults with moderate-to-severe pain unrelieved by antiviral therapy and analgesics, provided there are no contraindications to steroid use.

Oral steroids are empirically used in VZV-induced facial nerve palsy or other cases of cranial neuritis, although there is limited evidence supporting the effectiveness of such treatment. It must be emphasized that corticosteroids should not be used alone in herpes zoster and must be initiated in combination with antiviral therapy.

Lidocaine Patch

A 5% lidocaine patch is traditionally used for PHN pain and approved by the FDA for the same indication. A randomized placebo-controlled study showed that lidocaine patches reduced pain associated with herpes zoster⁸²; based on this information and the excellent side effect profile of lidocaine patches, their use can be considered. The patch should only be applied to intact skin after the initial rash has completely healed.

NEURAL BLOCKADE

Although no conclusive and strong recommendations can be made for the use of any invasive interventions due to lack of consistent data, if pain is not controlled with medical management, referral to a pain specialist should be considered for possible interventions. These may include neuraxial injections of local anesthetics and steroids, neuraxial local anesthetic infusion, paravertebral blocks, or sympathetic blocks. All these interventions have been used for years in clinical practice, but few controlled studies have been conducted to systematically examine their effects on herpes zoster acute pain or the development of PHN. As per NeuPSIG recommendations, moderate quality of available evidence provided the basis for a weak recommendation for the use of epidural or paravertebral blocks with local anesthetic and steroids injections for herpes zoster pain.⁸³ These guidelines were based on three RCTs.⁸⁴^,⁸⁵^,⁸⁶ One of the RCTs⁸⁴ found significant reduction in acute pain following a single epidural injection of steroid and local anesthetic within the first month after rash onset as compared to standard therapy alone. The incidence of developing PHN, however, was not reduced in this study. A more recent systematic review and meta-analysis also showed a favorable outcome with the use of interventional procedures for the management of acute herpes zoster related pain; in addition, these authors also addressed the role of interventions in reducing the incidence of PHN.⁸⁷^,⁸⁸ The findings suggest that nerve blocks do shorten the duration of acute pain in
herpes zoster and repeat or continuous epidural blocks and paravertebral blocks reduce the likelihood of PHN. Single stellate ganglion blocks fail to decrease the incidence, but multiple blocks may have a beneficial effect in this regard.⁸⁷^,⁸⁸ The exact mechanism by which sympathetic or somatic blocks could prevent PHN or lessen its severity is poorly understood. The sympathetic nervous system is important in mediating pain in some neuropathic pain conditions. It has been hypothesized that in the acute phase of herpes zoster, inflammation induces intense stimulation of the sympathetic nervous system leading to reduced intraneural blood flow with resultant neuronal hypoxia and endoneural edema. Other putative mechanisms of sympathetic nervous system involvement include the formation of ephaptic connections between the sensory system and the sympathetic system as well as the upregulation of adrenoreceptors. These phenomena could result in inappropriate activation of primary nociceptive fibers in response to sympathetic nervous system activation. Blockade of sympathetic nerves with local anesthetics may reverse these effects. It is also hypothesized that these interventions may favorably affect the progression of herpes zoster acute pain to PHN because the effective treatment of acute pain may prevent the development of PHN or at least decrease the severity of subsequent PHN.

TABLE 27.5 Pharmacologic Options that Can Be Considered for Treatment of Acute Pain in Herpes Zoster

Medication	Initial Dose	Titration	Maximum Daily Dose	Side Effects
Acetaminophen	500-1,000 mg every 6 h as needed	Not needed	2.6 g in elderly; 4 g in younger patients	Liver toxicity with prolonged use; avoid alcohol use
NSAIDs (dosages given are for ibuprofen)	400 mg every 6 h as needed	Not needed	2,400 mg	Gastrointestinal side effects, CV and renal toxicity, and increased bleeding tendency
Opioid analgesics (dosages given are for oxycodone)	5 mg every 4 h as needed	Increase by 5 mg 4 times daily every 2 d as tolerated; dosage can be converted to extended-release opioid analgesic combined with shortacting medication as needed	No maximum dosage with careful titration	Nausea/vomiting, constipation, sedation, dizziness
Tramadol	50 mg once or twice daily	Increase by 50-100 mg daily in divided doses every 2 d as tolerated; dosage can be converted to extended release preparation combined with immediate release one as needed.	400 mg daily (100 mg 4 times daily); for patients >75 y of age, 300 mg daily in divided doses	Nausea/vomiting, constipation, sedation, dizziness, seizures, postural hypotension
Gabapentin	300 mg at bedtime or 100-300 mg 3 times daily	Increase by 100-300 mg 3 times daily every 2 days as tolerated	3,600 mg daily (1,200 mg 3 times daily; reduce if renal function is impaired)	Sedation, dizziness, peripheral edema
Pregabalin	75 mg at bedtime or 75 mg twice daily	Increase by 75 twice daily every 3 days as tolerated	600 mg daily (300 mg twice daily; reduce if renal function is impaired)	Sedation, dizziness, peripheral edema
Tricyclic antidepressants, especially nortriptyline	25 mg at bedtime	Increase by 25 mg daily every 2-3 days as tolerated	150 mg daily	Sedation, dry mouth, blurred vision, weight gain, urinary retention
Oral corticosteroid (dosages given for prednisone)	60 mg daily for 7 days	After 60 mg daily for 7 days, decrease to 30 mg daily for 7 days, then decrease to 15 mg daily for 7 days, and then discontinue.	60 mg daily	Gastrointestinal distress, nausea, changes in mood, edema
NOTE: Dose of opioids, pregabalin, and tricyclic antidepressants can be reduced in frail elderly individuals. Consider a screening electrocardiogram for patients with preexisting cardiac disease. CV, cardiovascular; NSAID, nonsteroidal anti-inflammatory drugs. Adapted from Dworkin RH, Johnson RW, Breuer J, et al. Recommendations for the management of herpes zoster. Clin Infect Dis 2007;44(1):S1-S26. Reproduced by permission of Infectious Diseases Society of America.

In conclusion, we do not make a strong recommendation for routine use of interventions for acute herpes zoster pain. Interventions can be considered if the pain is not well controlled, or if pharmacotherapy results in intolerable side effects. The use of local interventions should be carefully considered, and the type of intervention should be guided by the patient’s condition and the provider’s expertise.

COMPLEMENTARY AND ALTERNATIVE MEDICINE

Complementary and alternative medicine modalities are becoming increasingly popular in patients with acute as well as chronic pain conditions and herpes zoster, and related pain syndromes are no exception. Integrative (complementary) therapies include meditation, hypnosis, relaxation therapy, imagery, music therapy, magnet therapy, dietary and herbal supplements, and acupuncture. There are no reliable data available that will help make strong and specific recommendations in the treatment of zoster-related pain with these approaches.

Acupuncture has been examined in small studies for the treatment of herpes zoster pain. One of the mechanisms of action is thought to be associated with endorphin release at both the spinal and supraspinal levels. In a small randomized study, subjects were randomized to receive weekly acupuncture treatment versus standard therapy including pregabalin, local anesthetic injections for all patients and opioids for patients who had intractable pain.⁸⁹ Patients in the acupuncture arm were only allowed acetaminophen as a rescue analgesic. No significant differences were observed between the groups in terms of mean pain reduction, incidence of PHN or total pain burden, concluding that acupuncture could have similar efficacy as conventional analgesic therapies. Although this study alone does not provide high-quality evidence to support the routine use of acupuncture, it does provide some evidence as to the potential role of acupuncture in the treatment of acute herpes pain.

SPINAL CORD STIMULATION

Spinal cord stimulation (SCS) has been tried in a case series of four patients with active herpes zoster and reported to be effective.⁹⁰ It is difficult to extrapolate these results to routine clinical practice as the majority of patients with herpes zoster have resolution of their symptoms as part of the natural history of the disease; hence, authors do not recommend this modality of treatment for acute zoster.

Prevention of Herpes Zoster

CHILDHOOD VACCINATION

The propensity to develop herpes zoster and PHN can ultimately be traced back to an individual’s primary varicella infection. Thus, one obvious prevention strategy would include the prevention of the primary VZV infection through the use of varicella vaccination in childhood. Two types of vaccines are approved by the FDA for vaccination in children from 12 months to 12 years of age; both are based on the Oka virus. The first agent is a single-antigen vaccine, and the more recent vaccine is a combination product and protects against multiple childhood infections (i.e., measles, mumps, rubella, and varicella). The current recommendations for routine immunization of immunocompetent children are two doses of varicella vaccine (either single antigen or combined product) with the first dose at 12 to 15 months, followed by a second dose at 4 to 6 years of age.⁹¹ The live attenuated Oka vaccine virus establishes latency in sensory ganglia, like wild-type VZV, but it appears to cause herpes zoster much less frequently. Hence, childhood varicella vaccination should eventually result in an overall decrease in the incidence of herpes zoster and PHN.

VARICELLA-ZOSTER IMMUNOGLOBULIN

Temporary passive immunization may be required in specific circumstances. The CDC currently recommends administration of purified varicella-zoster immune globulin preparation, VariZIG (Cangene Corp, Winnipeg, Canada), to prevent or modify clinical illness in immunocompromised or pregnant seronegative persons and a select group of infants with recent exposure to patients with chicken pox or zoster. VariZIG should be administered as soon as possible, ideally within 96 hours of exposure to provide maximum benefit, but it may be used within 10 days.⁹² Treatment with VariZIG should be followed by vaccination in eligible patients 5 months after administration.

HERPES ZOSTER VACCINATION FOR ADULTS

Herpes zoster is caused by reactivation of VZV from a single sensory ganglion. The precise mechanism of reactivation is not known but thought to be due to waning VZV specific cell-mediated immunity. Therefore, adult vaccination can confer the immunologic boost to prevent herpes zoster and the associated pain, suffering, and decreased quality of life.

In 2006, a live attenuated Oka virus-based varicella vaccine was approved by the FDA for adults 60 years of age or older. The approval was based on the results of the Shingles Prevention Study—a large, multicenter, randomized, placebo-controlled trial—that established efficacy and safety of a single-dose herpes zoster vaccination.³³ The results of the trial indicated that the herpes zoster vaccine reduces the likelihood of developing herpes zoster in immunocompetent individuals 60 years of age or older. Important results of this study included a decrease in the incidence of herpes zoster by 51.3%, a reduction in the overall burden of illness (BOI) by 61.1%, and a decrease in the incidence of PHN by 66.5%.⁹³ Subsequently, in order to investigate the durability of benefit from vaccination, the Short-Term Persistence Substudy (STPS) was performed by the same group of investigators.⁹⁴ The study was designed to evaluate efficacy up to 7 years postvaccination. The major findings included a drop in efficacy in herpes zoster BOI by 11%, 6.4% for PHN incidence, and 11.7% for herpes zoster incidence. The results regarding incidence for BOI and incidence of herpes zoster were significant through 5 years postvaccination leading the authors to conclude the persistence of efficacy at 5 years but the benefit beyond that time point was unclear. To address this question, the same group performed the Long-Term Persistence Substudy (LTPS) evaluating patients 7 to 11 years postvaccination.⁹⁵ All participants in the prior two studies had been vaccinated, leaving no controls to use for comparison. Therefore, the authors used regression models to estimate incidences of herpes zoster and PHN, finding that efficacy of the vaccine continued to decline. Only for herpes zoster BOI was efficacy retained at 10 years, efficacy for incidence of herpes zoster persisted through year 8. The findings from the LTPS have been supported by an analysis of over 175,000 vaccinated individuals from an integrated health care organization, which found the effectiveness of the vaccine drops from 68.7% in the first year to 4.2% in the 8-year postvaccination.⁹⁶ In order to address the issue of waning efficacy the logical next step would be evaluation of a “booster” dose of vaccine. In fact, that work has been initiated and demonstrated enhanced VZV-specific cell-mediated immunity in individuals >70 years of age who received a second dose of varicella zoster vaccine.⁹⁷ The findings are promising and support further investigation of the use of booster doses to prevent herpes zoster.

Recently, a novel glycoprotein-based herpes zoster subunit vaccine has been developed, potentially for adults older than 50 years and immunocompromised hosts. It has been evaluated in two phase 3, large, international, multicenter, randomized, placebo-control trials. The first demonstrated an overall vaccine efficacy against herpes zoster of 97.9 % for those 70 years or older and 97.2% for all individuals greater than 50 years of age.⁹⁸ The second looked specifically at those 70 years of age or older and found an overall vaccine efficacy of 89.9%.⁹⁹ A pooled analysis from the two trials demonstrated an 88.8% vaccine efficacy against PHN for individuals greater than 70 years of age and 91.2% for those greater than 50 years of age. The results from these studies are very encouraging and the vaccine is currently under review by the FDA.

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