Herpes zoster: etiology, clinical features and treatment options, and case report

Herpes zoster: etiology, clinical features and treatmentoptions, and case reportShrikant Mali

Herpes zoster is a painful vesicular rash resulting

from reactivation of the virus that also causes

chickenpox – Varicella zoster virus. Typically, the rash

runs its course in a matter of 4–5 weeks. The pain,

however, may persist months, even years, after the

skin heals. This phenomenon is known as postherpetic

neuralgia. Conventional therapies include prescription

antivirals, corticosteroids, and analgesics, both oral

and topical. Here I present a case report of post

herpetic neuralgia patient with discussion about

etiology, pathology and treatment options. Egypt J Oral

Maxillofac Surg 3:91–100 �c 2012 The Egyptian

Association of Oral & Maxillofacial Surgeons.

Egyptian Journal of Oral & Maxillofacial Surgery 2012, 3:91–100

Keywords: acyclovir, herpes zoster, neuralgia, postherpetic neuralgia, shingles

Oral and Maxillofacial Surgery, CSMSS Dental College, Aurangabad,Maharashtra, India

Correspondence to Shrikant Mali, MDS, Oral and Maxillofacial Surgery,CSMSS Dental College, Aurangabad, Maharashtra, IndiaE-mail: [email protected]

Received 30 January 2012 accepted 3 May 2012

IntroductionHerpes zoster (HZ) is the reactivated form of the

varicella zoster virus (VZV), the same virus responsible

for chickenpox. HZ is more commonly known as shingles,

from the Latin cingulum for ‘girdle’. This is because a

common presentation of HZ involves a unilateral rash

that can wrap around the waist or torso like a girdle.

Similarly, the name zoster is derived from classical Greek,

referring to a belt-like binding (known as a zoster) used

by warriors to secure armor [1].

Case reportA 60-year-old male patient reported to the department of

oral and maxillofacial surgery, CSMSS Dental College and

Hospital, Aurangabad, with a chief complaint of pain and

rashes on the right side of his face. On examination,

multiple vesicles and rashes were found on the lower lip,

angle of the mandible region, in front of the ear, lateral to

the eye, and intraorally on the lateral border of the tongue

and the floor of the mouth.

The patient reported prodromal signs of fever and

malaise 3–4 days before the appearance of rashes. These

rashes then became pustules, which formed crusts. The

patient reported unilateral pain along the distribution of

the trigeminal nerve of the right side. He also reported

lack of sleep because of pain. Because of unilateral pain

and rashes along the nerve distribution, coupled with

prodromal signs, a diagnosis of HZ was made.

Treatment with acyclovir 800 mg five times a day was

started. Combiflam was also started to combat pain.

Antiviral treatment was carried out for 7 days. The

patient responded well to acyclovir and the rashes

disappeared after 7–10 days. However, he developed

severe neuralgic pain along the course of the trigeminal

nerve on the right side. Trigger zones were the cheek, the

skin below the infraorbital ridge, and the intraoral buccal

mucosa. The patient did not shave for fear of activating

trigger zones. On the basis of the clinical findings and

history of HZ, a diagnosis of postherpetic neuralgia

(PHN) was made as a complication of HZ.

Treatment with carbamazapine 200 mg three times a day

was started to control neuralgic pain. The patient

responded well and pain was relieved. This treatment

was continued for 1 month. On completion of 1 month,

carbamazapine tables were discontinued and the patient

was fine.

DiscussionThere is no way to predict who will develop HZ, when

the latent virus may reactivate, or what may trigger its

reactivation. However, the elderly and those with

compromised immunity – such as those who have

undergone organ transplantation or recent chemotherapy

for cancer, or individuals with HIV/AIDS – are at a greater

risk for developing HZ. Between 10 and 20% of normal

(immunocompetent) adults will get shingles during their

lifetime. This figure increases markedly to 50% for those

older than 85 years of age [1].

Spontaneous pain, pain induced by trivial stimuli, and

altered sensation accompany HZ and may continue long

after its characteristic rash has healed – a condition

known as PHN. Many approaches have been proposed to

treat the pain of acute zoster, to avert its progression to

PHN, and to alleviate PHN. Few of these approaches

have been shown to be beneficial, and PHN remains a

source of frustration for both patients and physicians [2].

Etiology and pathology [1–4]

VZV is one of eight known herpes viruses that infect

humans. Its structure is characterized by an icosahedral

nucleocapsid surrounded by a lipid envelope. Double-

stranded DNA is located at its center. The virus is

B150–200 nm in diameter and has a molecular weight of

B80 million.

During its viremic phase, cell-associated VZV gains access

to epidermal cells, causing the typical varicella rash. The

virus then enters the sensory nerves in mucocutaneous

sites and travels by retrograde axonal transport to the

sensory dorsal-root ganglia adjacent to the spinal cord,

where the virus establishes permanent latency in

Case report 91

2090-097X �c 2012 The Egyptian Association of Oral & Maxillofacial Surgeons DOI: 10.1097/01.OMX.0000418695.06506.6c

Copyright © The Egyptian Association of Oral and Maxillofacial Surgeons. Unauthorized reproduction of this article is prohibited.

neuronal cell bodies. Latent VZV is present in B1–7% of

sensory ganglion neurons, with less than 10 genomic

copies per infected cell. Seeding of the dorsal-root ganglia

might also occur during viremia. The magnitude of

viremia, the number of skin lesions, and the burden of

VZV that establishes latency during primary varicella

infection might be linked. As with other members of the

herpes virus family, VZV is noninfectious in its latent

form, but can reactivate at a later time to form intact

virions in the involved sensory neurons. These virions

then migrate to the skin through axons, spread from cell

to cell, and penetrate the epidermis. In its full clinical

expression, zoster causes pain, which is followed by a

vesicular rash distributed across closely overlapping

dermatomes of the involved sensory nerve roots.

The triggers for the reactivation of VZV have not been

identified and probably involve multiple factors. However,

specific components of cell-mediated immunity (CMI)

play an important role in controlling the development of

zoster by preventing reactivation within the neuron or the

full clinical expression of reactivated VZV as zoster. The

effectiveness of these protective components of CMI is

well maintained in immunocompetent individuals during

childhood and early adulthood. These CMI components are

believed to be partially or substantially maintained by

periodic immunologic boosting. ‘Endogenous boosting’

might occur in response to the subclinical reactivation of

latent VZV or to the development of zoster itself, and

‘exogenous boosting’ might occur in response to exposure

to VZV circulating in the population as chickenpox.

Primary infection is clinically identified as varicella or

chickenpox. VZV is ubiquitous and highly contagious,

with initial exposure typically occurring during childhood.

The virus enters the host through the respiratory system,

replicates at an undefined site (presumably the naso-

pharynx), infiltrates the reticuloendothelial system, and

eventually makes its way into the bloodstream. Evidence

of viremia is manifested by the scattered nature of the

telltale skin lesions on the body.

The usual incubation period for varicella is 14–16 days,

with communicability ranging from 10 to 21 days after

initial exposure. An individual can no longer transmit VZV

once the final skin lesions have crusted. Indirect

transmission (through an immune third person) is not

believed to occur.

Once the initial outbreak has subsided, VZV then retreats

into the dorsal-root ganglia, where it can remain dormant

for years until some excitatory factor triggers reactivation.

Fig. 1

Crusted healed lesions on the chin along with erythematous lesionsafter acyclovir therapy.

Fig. 2

Erhythomatous maculopapular unilateral rashes seen on the cheek,temple, and angle of the mandible area.

92 Egyptian Journal of Oral & Maxillofacial Surgery 2012, Vol 3 No 2


The associated outbreak is then clinically identified as HZ

or shingles. Microscopic examination of select dorsal-root

ganglia tissue during active HZ shows the presence of

hemorrhage, edema, and lymphocytic infiltration. Figure 1

shows the typical progression of VZV from varicella to

zoster [3–5].

Reduced cellular immunity places an individual at risk for

HZ, hence the susceptibility of immunocompromised

individuals and the elderly. It has been proposed that one

reason why VZV may not recur as frequently as other herpes

viruses, such as Herpes simplex virus, type 1 (HSV-1),

or Herpes simplex virus, type 2 (HSV-2), is that genes

involved in the reactivation of HSV are missing in VZV.

Signs and symptoms [1–5]

The classic presentation of HZ starts with a prodrome of

mild-to-moderate burning or tingling (or in some cases

numbness) in or under the skin of a given dermatome, often

accompanied by fever, chills, headache, stomach upset, and

general malaise. Within 48–72 h from the prodrome, an

erythematous, maculopapular rash forms unilaterally along

the dermatome and rapidly develops into vesicular lesions

reminiscent of the original chickenpox outbreak. The pain

associated with shingles varies in intensity from mild to

severe, such that even the slightest touch or breeze can

elicit excruciating spasms. The lesions usually begin to dry

and scab 3–5 days after appearing Figs 2–4.

Prodromal stage – sensations such as burning, tingling,

etching, boring, prickly, and knife like occurring along the

nerve distribution.

Active stage – rash forms after a few hours to several days,

with malaise, low-grade fever, and headache.

Rash changes from papules and edema to vesicles in

12–24 h and to pustules in 1–7 days.

Pustules dry and form crusts that fall off in 14–21 days

and leave erythematous lesions leading to hypopigmenta-

tion or hyperpigmentation.

Intraoral lesions appear after cutaneous lesions.

Pain and dysasthesia are minimal during the active stage.

However, during crusting, it returns.

Chronic stage PHN – constant deep pain, sharp shock

like a tic.

Radiating dysasthesia with trigger zones.

Differential diagnosis – trigeminal neuralgia, maxillary

sinusitis, periodic migrainous neuralgia, atypical facial pain.

HZ typically erupts within one or two adjacent derma-

tomes, with thoracic, cervical, and ophthalmic involve-

ment being the most common.

Most patients report a deep aching or burning pain,

altered sensitivity to touch (paresthesia) that may be

Fig. 3

Vesicular lesion on the ventral surface of the tongue, ulcerative lesionseen near the tonsillar area.

Fig. 4

Erythematous and vesicular lesions bluish black in color on the lateralsurface of the tongue.

Herpes zoster Mali 93


painful (dysesthesia), exaggerated responses to stimuli

(hyperesthesia), or electric shock-like pain.

Pain induced by otherwise trivial stimuli (allodynia),

unbearable itching, and escalating pain in response to

repeated stimulation (windup pain) are also reported.

These abnormal sensations resolve or persist unpredic-

tably, making it difficult to draw absolute distinctions

between pain associated with zoster and PHN. Pain-

induced disruption of sleep, mood, and work contributes

toward the impact of zoster on the quality of life, in both

the short and the long term.

Zoster rash is typically unilateral and does not cross the

mid-line, erupting in one or two adjacent dermatomes.

The frequency of zoster occurrence in different derma-

tomes has been evaluated in certain studies. In general,

thoracic, cervical, and ophthalmic involvements are most

common. Small numbers of lesions can occur outside the

primary or adjacent dermatome.

A common and potentially debilitating consequence of

zoster is PHN, a persistent pain after resolution of the

rash. Pathologic observations believed to distinguish PHN

from uncomplicated zoster include axonal and cell body

degeneration, atrophy of the spinal cord dorsal horn,

scarring of the dorsal-root ganglion, and loss of epidermal

innervation of the affected area. Some experts believe that

this neuronal damage might be caused by ongoing viral

replication. In addition, consensus is lacking on the criteria

required to distinguish the quality, duration, or underlying

pathophysiology of pain occurring with zoster versus PHN.

Therefore, the duration of pain used to define PHN has

been inconsistent, ranging from any duration after resolu-

tion of the rash to periods from greater than 30 days to

greater than 6 months after the onset of rash.

The nature of PHN pain varies from mild to excruciating

in severity, constant, intermittent, or triggered by trivial

stimuli. Approximately half of patients with zoster or

PHN describe their pain as ‘horrible’ or ‘excruciating’,

ranging in duration from a few minutes to constant on a

daily or an almost daily basis. The pain can disrupt sleep,

mood, work, and activities of daily living, adversely

impacting the quality of life, and leading to social

withdrawal and depression. Anecdotes of suicide among

patients with PHN have been reported. Among patients

experiencing zoster, predictors of PHN include the

occurrence and severity of pain both before and after

the onset of the rash, the extent of the rash, trigeminal or

ophthalmic distribution, and the occurrence of viremia.

In addition to PHN, zoster is associated with a variety of

other complications. Among patients with zoster, 10–25%

have eye involvement, called herpes zoster ophthalmicus

(HZO). HZO can occur when reactivation involves the

nasociliary branch of the trigeminal nerve, sometimes

preceded by the presence of zoster vesicles on the nose

(Hutchinson sign). Keratitis occurs in approximately two-

thirds of patients with HZO, often causing corneal

ulceration. Other complications include conjunctivitis,

uveitis, episcleritis and scleritis, retinitis, choroiditis,

optic neuritis, lid retraction, ptosis, and glaucoma.

Extraocular muscle palsies also occur. Prolonged or

permanent sequelae of HZO include pain, facial scarring,

and loss of vision.

An uncommon complication of zoster is Ramsay Hunt

syndrome, a peripheral facial nerve palsy accompanied by

zoster vesicles on the ear, hard palate, or tongue. The

pathophysiology of this complication involves the reacti-

vation of VZV in the geniculate ganglion of the facial

nerve. Additional signs and symptoms of Ramsey Hunt

syndrome can include pain, vertigo, hearing loss, sensi-

tivity to sound, tinnitus, and loss of taste. Many patients

do not recover completely. Idiopathic facial palsy (Bell’s

palsy) might be caused by inapparent VZV reactivation.

Occasionally, zoster can cause motor weakness in

noncranial nerve distributions, called zoster paresis. The

mechanism has not been determined. The weakness

develops abruptly within 2–3 weeks after onset of the

rash and can involve the upper or the lower extremities.

Diaphragmatic paralysis has also been described. The

prognosis of zoster paresis is good. Zoster can also result

in autonomic dysfunction, causing urinary retention and

colon pseudo-obstruction.

Rarely, patients will experience acute focal neurologic

deficits weeks to months after resolution of the zoster

rash, involving the trigeminal distribution contralateral to

the initial rash. This ischemic stroke syndrome, termed

granulomatous angiitis, is believed to be caused by the

direct extension of VZV from the trigeminal ganglion to

the internal carotid artery or its branches, resulting in

inflammation. Mortality from this syndrome is substan-

tial. Other rare neurologic complications of zoster include

myelitis, aseptic meningitis, and meningoencephalitis.

The prognosis for these conditions is good, although

encephalomyelitis can be life threatening. Guillain–Barre

syndrome has also been reported in association with

zoster.

In immunocompromised individuals, zoster initially

might present typically. However, the rash tends to be

more severe and its duration may be prolonged. One

specific risk for patients with some immunosuppressive

conditions is dissemination of the zoster rash. True

cutaneous dissemination generally occurs only among

immunocompromised patients, occurring in up to 37% of

zoster cases in the absence of antiviral treatment.

Dissemination usually begins with a dermatomal rash;

however, the rash sometimes begins with no primary

dermatomal involvement.

The risk for neurologic zoster complications is generally

increased in immunocompromised individuals. These

complications, which can be aggressive and even fatal,

include myelitis, chronic encephalitis, ventriculitis, me-

ningoencephalitis, and cranial palsies. However, the risk

for PHN is not appreciably increased among immuno-

compromised patients who develop zoster.

Diagnosis [1–5]

The diagnosis of zoster might not be possible in the

absence of rash (e.g. before rash or in cases of zoster sine

herpete). Patients with localized pain or altered skin



sensations might undergo evaluation for kidney stones,

gallstones, or coronary artery disease until the zoster rash

appears and the correct diagnosis is made. In its classical

manifestation, the signs and symptoms of zoster are

usually distinctive enough to make an accurate clinical

diagnosis once the rash has appeared. Occasionally, zoster

might be confused with impetigo, contact dermatitis,

folliculitis, scabies, insect bites, papularurticaria, candidal

infection, dermatitis herpetiformis, or drug eruptions.

More frequently, zoster is confused with the rash of the

HSV, including eczema herpeticum. The accuracy of

diagnosis is lower for children and younger adults in

whom the incidence of zoster is lower and its symptoms

are less often classic.

In some cases, particularly in immunosuppressed indivi-

duals, the location of rash appearance might be atypical or

a neurologic complication might occur well after resolu-

tion of the rash. In these instances, laboratory testing

might clarify the diagnosis. Tzanck smears are inexpen-

sive and can be used at the bedside to detect multi-

nucleated giant cells in lesion specimens, but they do not

distinguish between infections with VZV and HSV. VZV

obtained from lesions can be identified using tissue

culture, but this can take several days and false-negative

results occur because viable virus is difficult to recover

from cutaneous lesions. Direct fluorescent antibody

staining of VZV-infected cells in a scraping of cells from

the base of the lesion is rapid and sensitive. Direct

fluorescent antibody and other antigen-detection meth-

ods can also be used on biopsy material, and eosinophilic

nuclear inclusions (Cowdry type A) are observed on

histopathology. PCR techniques performed in an experi-

enced laboratory can also be used to detect VZV DNA

rapidly and sensitively in properly collected lesion

material, although VZV PCR testing is not available in

all settings. A modification of PCR diagnostic techniques

has been used at a few laboratories to distinguish wild-

type VZV from the Oka/Merck strain used in the licensed

varicella and zoster vaccines.

In immunocompromised individuals, even when VZV is

detected by laboratory methods in lesion specimens,

differentiation of chickenpox from disseminated zoster

might not be possible by physical examination or

serologically. In these instances, a history of VZV exposure,

a history that the rash began with a dermatomal pattern,

and the results of VZV antibody testing at or before the

time of rash onset might help guide the diagnosis.

Zoster transmission [1–5]

Zoster lesions contain high concentrations of VZV that

can be spread, presumably by the airborne route, and

cause primary varicella in exposed susceptible individuals.

Localized zoster is only contagious after the rash erupts

and until the lesions crust. Zoster is less contagious than

varicella.

Pain

The pain associated with acute zoster and PHN is

neuropathic and results from injury of the peripheral

nerves and altered central nervous system signal processing.

After the injury, peripheral neurons discharge sponta-

neously, have lower activation thresholds, and show

exaggerated responses to stimuli. Axonal regrowth after

the injury produces nerve sprouts that are also prone to

unprovoked discharge.

The excessive peripheral activity is believed to lead to

hyperexcitability of the dorsal horn, resulting in exagger-

ated central nervous system responses to all input.

These changes may be so complex that no single

therapeutic approach will ameliorate all the abnormalities.

Histopathological features [2,3]

In acute zoster, the skin is inflamed and already partially

denervated, and the dorsal-root ganglion shows inflam-

mation, hemorrhagic necrosis, and neuronal loss.

Inflammation in the peripheral nerves may persist for

weeks to months and usually leads to demyelination,

wallerian degeneration, and sclerosis.

Ultimately, there may be scarring of the skin, peripheral

nerves, and dorsal-root ganglia.

Pathologic changes are also evident in the central nervous

system during zoster. They include acute degeneration of

the dorsal horn of the spinal cord, unilateral segmental

myelitis and leptomeningitis, and the involvement of

spinal cord segments at levels adjacent to the affected

skin. In patients who have had zoster, atrophy of the

dorsal horn has been found at autopsy in those with PHN,

but not in those without PHN.

Complication

Neurologic Guillian–Barre syndrome, encephalitis, mye-

litis, ramsay hunt syndrome, horner’s syndrome.

The four main domains of complications (excluding

PHN) identified in patients with acute HZ.

Antiviral agents [2–8]

The first line of treatment and the most widely used agents

for zoster infection are antiviral agents. As nucleoside

analogs, they block viral replication. Antiviral agents

accelerate healing in the acute phase of illness by reducing

the duration of viral shedding as well as time to crusting

and scabbing. In addition, they prevent the formation of

new lesions. Pharmacotherapy with antiviral agents must be

initiated within 72 h of symptom onset (i.e. rash) for

maximum effectiveness. Any delay in administration may

result in neuronal destruction – leading to the derange-

ments of the central nervous system that are responsible for

the neuropathic pain syndrome associated with PHN.

However, a course of therapy with an antiviral agent is

recommended beyond the 72-h window, especially in

immunosuppressed patients as well as those with ophthal-

mic zoster. Administration of an antiviral agent is

recommended for 7–10 days – although it is acceptable to

extend treatment to up to 15 days, especially for individuals

who are immunosuppressed.

Ideally, antivirals should be administered until no new

lesions have been observed for about 2 days. Acyclovir,



valacyclovir, and famciclovir are available antiviral agents.

Valacyclovir is the prodrug of acyclovir; famciclovir is the

prodrug of penciclovir.

Acyclovir

Oral acyclovir is used for the management of acute HZ. It is

also commonly used in immunosuppressed patients or those

with central nervous system disease. Intravenous acyclovir

may be administered to immunosuppressed patients 72 h

after rash onset. Acyclovir is initially phosphorylated by only

the viral thymidine kinase; therefore, it is active only within

cells infected with the VZV. Cellular kinases metabolize the

monophosphate to the triphosphate form, which acts as

a competitive inhibitor of viral DNA polymerase.

Placebo-controlled trials four to six have shown that oral

acyclovir shortens the duration of viral shedding, halts the

formation of new lesions, and accelerates the rate of

healing, reducing the severity of acute pain.

Malaise was the most frequent adverse effect with both

acyclovir (11.5%) and placebo (11.1%). Adverse effects

associated with intravenous acyclovirare are local pro-

blems such as phlebitis or inflammation. Transient

elevations in serum creatinine may also be observed.

Oral acyclovir has a limited oral bioavailability of 10–30%,

which necessitates frequent dosing. The recommended dosing

for oral acyclovir is 800 mg five times a day for 7–10 days.

Valacyclovir

Valacyclovir is the L-valyl ester of acyclovir. It is rapidly

converted into acyclovir after oral administration and, in

humans, results in three to five times greater bioavail-

ability than that of acyclovir. The recommended dose of

this medication is 1 g three times daily for 7 days, with

each gram of valacyclovir yielding B700 mg acyclovir and

300 mg of the essential amino acid valine.

Famciclovir

Famciclovir is the diacetyl, 6-deoxy ester of penciclovir,

which is a guanosine nucleoside analog. Metabolism of

the prodrug to penciclovir begins with uptake by

intestinal cells and is completed by the liver.

The current recommended dose is 500 mg three times

daily. Famciclovir has been shown to accelerate zoster

lesion healing and viral shedding. Famciclovir at 250 mg

three times daily for 7 days was as effective as – and had a

more favorable safety profile than – acyclovir at a dosage

of 800 mg five times daily for 7 days. Moreover,

famciclovir at a dose of either 750 mg once daily or

500 mg twice daily plus 250 mg once daily is as effective

as acyclovir 850 mg five times daily. Thus, famciclovir is as

effective as acyclovir when administered only once a day,

a regimen that leads to better patient compliance.

Limitations of antiviral agents

As reported previously, therapy must be initiated within

72 h of rash onset for maximal effectiveness. Finally,

although they may reduce the duration of PHN, they do

not function prophylactically.

Oral corticosteroids [2,5–7]

As an adjuvant option in the treatment of patients with

acute zoster infection, oral corticosteroids have been

shown to ameliorate the inflammatory characteristics of

this condition, cosmetically improving the rash. Moreover,

oral corticosteroids have been shown to reduce acute pain

but not the chronic pain associated with PHN.

Finally, corticosteroids are associated with upper gastro-

intestinal adverse events such as dyspepsia, and they have

been shown to exacerbate diabetes, hypertension, and

osteoporosis. These adverse effects are especially un-

desirable among older patients, the majority of indivi-

duals in whom zoster infection is diagnosed.

Pharmacotherapeutic options for postherpetic

neuralgia [2,4–8]

Treatment goals include alleviating the pain associated

with PHN and improving the quality of life, allowing the

patients to maintain sleep, physical activity, and nutri-

tion. Tricyclic antidepressants(TCAs), anticonvulsants,

opioid analgesics, and topical agents are recommended

first-line therapies for PHN.

Neuroactive agents [2,4–8]

TCAs are important components of therapy for PHN.

Because of their ability to block the reuptake of

norepinephrine and serotonin, these drugs may relieve

pain by increasing the inhibition of spinal neurons

involved in pain perception.

Amitriptyline decreases neuronal reuptake of both

norepinephrine and serotonin. In one trial, desipramine,

a selective inhibitor of norepinephrine reuptake, also

significantly reduced pain at 3 and 6 weeks.

Serotonin-selective drugs are of little value in the

treatment of PHN.

Adverse reactions to TCAs, including confusion, urinary

retention, postural hypotension, and arrhythmias, limit

their usefulness in older patients, and plasma concentra-

tions should be monitored to ensure compliance and help

determine the optimal dose.

Lorazepam, postulated to inhibit neurotransmission in

the spinal cord and brain stem, also proved inferior to

amitriptyline in a controlled trial.

The phenothiazine chlorprothixene is of no value, but in

controlled studies, other phenothiazines combined with

TCAs resulted in the partial relief of pain.

In a double-blind, controlled study, carbamazepine reduced

lancinating pains but was ineffective for continuous pain.

The combination of clomipramine and carbamazepine led

to only partial relief in a controlled trial, and combinations

of other antidepressant and anticonvulsant drugs had some

benefit in uncontrolled trials.

Tricyclic antidepressants [2,4–8]

They block the reuptake of norepinephrine and serotonin.

Thus, they may relieve pain by increasing the inhibition of

spinal neurons involved in pain perception. Animal studies

have shown that TCAs may also work as sodium channel



antagonists within the peripheral nervous system, another

mechanism that may be responsible for pain relief.

Amitriptyline was found to be superior to lorazepam, and

nortriptyline hydrochloride, a metabolite of amitriptyline,

was also found to be effective in ameliorating the pain

associated with PHN. However, physicians prefer nor-

triptyline to amitriptyline because the former has fewer

anticholinergic effects.

Adverse events associated with TCAs, which are mainly

because of anticholinergic effects, include sedation,

confusion, urinary retention, dry mouth, blurred vision,

postural hypotension, and arrhythmia. These adverse

events limit the usefulness of TCAs for the treatment of

older patients.

Anticonvulsants [2,4–8]

Two anticonvulsants are indicated for the treatment of

PHN: gabapentin and pregabalin. Anticonvulsants are

believed to work in neuropathic pain syndromes because

they are involved in membrane stabilization, which reduces

neuronal derangement. Although gabapentin’s mechanism

of action is currently unknown, it appears to be indepen-

dent of aminobutyric acid receptors. It is lipophilic and

penetrates the blood–brain barrier (Tables 1 and 2).

Adverse events that occurred more frequently in the

gabapentin group compared with those in the group

receiving placebo were somnolence, dizziness, ataxia,

peripheral edema, and infection. Pregabalin was initially

reported to be effective in alleviating neuropathic and

nociceptive pain in a variety of animal models.

Opioid analgesics [2,4–8]

The opioid analgesics morphine and methadone were

found to be as effective as the TCAs nortriptyline or

desipramine in a randomized double-blind, placebo-

controlled cross-over trial. Intravenous morphine sulfate

infusions have been shown to be effective in reducing the

pain and hyperalgesia of PHN.

Adverse events observed with opioids are minimal and

include constipation, nausea, loss of appetite, dizziness,

and drowsiness. A theoretical limitation to the use of

opioids is the potential for addiction.

Topical treatment [2,4–8]

Topical treatment is also a good therapeutic option for

patients in whom systemic treatment is contraindicated.

Topical treatment is currently divided into three groups:

combined aspirin and NSAID formulations, local analge-

sics, and capsaicin cream.

Topical nonsteroidal anti-inflammatory drugs [2,4–8]

NSAIDs applied topically are useful in the treatment of

patients with zoster during the active and early post-

herpetic phase of illness because pain symptoms are

associated with tissue trauma and inflammation as well as

an increased level of tissue prostaglandins.

NSAIDs inhibit cyclooxygenase, decreasing the synthesis

of prostaglandins. Thus, there has been a recent focus on

developing topical NSAIDs, such as powdered aspirin in

chloroform or ethyl ether, to treat patients for PHN.

Over-the-counter creams and topical indomethacin, diclofe-

nac, and benzydamine hydrochloride cream have also been

investigated for their pain-alleviating properties in PHN.

Topical aspirin has been shown to be superior to placebo in

reducing PHN, whereas other topical NSAIDs such as

indomethacin, diclofenac, and benzydamine have not.

Analgesics [2,4–8]

A topical lidocaine 5% patch is a targeted peripheral

analgesic that is indicated for the treatment of patients

with PHN. When four patches were applied for up to 24 h,

the systemic absorption of lidocaine from the patch was

Table 1 Treatment categories for postherpetic neuralgia

Group 1 Group 2 Group 3 Group 4

Medium to high efficacy, goodstrength of evidence, and low levelof side effects

Lower efficacy than those listed ingroup 1, or limited strength ofevidence, or side effect concerns

Evidence indicating no efficacycompared with placebo

Reports of benefit limited to class IVstudies

GabapentinLidocaine patchOxycodone or morphine sulfate,

controlled releasePregabalinTricyclic antidepressants

Aspirin in cream or ointmentCapsaicin, topicalMethylprednisolone, intrathecal

AcupunctureBenzydamine creamDextromethorphanIndomethacinLorazepamMethylprednisolone, epiduralVincristine iontophoresisVitamin EZimelidine

BiperidinCarbamazepineChlorprothixeneCryocauteryDorsal root entry zone lesionExtract of Ganoderma lucidumHe–Ne laser irradiationKetamineMethylprednisolone, iontophoresisMorphine sulfate, epiduralNicardepinePiroxicam, topicalStellate ganglion blockTriamcinolone, intralesional

Table 2 Impact of Herpes zoster and postherpetic neuralgia onquality of life 6

Physical Fatigue, anorexia, weight loss, reduced mobility,physical inactivity, insomnia

Psychological Depression, anxiety, emotional distress, difficultyconcentrating, fear

Social Withdrawal, isolation, change in social role,attendance at fewer social gatherings, lossof independence

Functional Dressing, bathing, eating, mobility, traveling,cooking, housework, shopping



minimal in healthy adults and even lower among patients

with PHN, thus eliminating adverse systemic events.

Capsaicin [2,4–8]

Capsaicin cream is also indicated for the treatment of

patients with PHN. At high concentrations, capsaicin

depletes substance P, a principal peptide neurotransmitter.

This depletion first causes a burning sensation, and then

anesthetic effects. Capsaicin cream is the only drug

approved by the Food and Drug Administration for the

treatment of PHN.

Natural treatment options [1]

As with conventional protocols, the objective of natural

therapeutics in the prevention and treatment of HZ and

PHN is to aid healing of skin lesions, reduce pain, and prevent

complications. An underlying goal for the use of natural

therapies is to strengthen CMI, thereby allowing the body’s

natural defense mechanisms to control the virus and prevent

recurrence. Natural therapies can provide solutions to

effectively manage herpes viruses, prevent and treat complica-

tions, and minimize the risk of developing viral resistance.

Dietary/multiple-nutrient effects

The incidence of HZ increased considerably after the age

of 50 years. Maintaining adequate nutrition is one

contributing factor to ensuring healthy CMI.

Vitamin A [9,10]

Vitamin A functions both as a fat-soluble vitamin and as a

hormone, contributing to the visual pigment rhodopsin and

controlling gene transcription that allows for the normal

proliferation and differentiation of epithelial cells. Vitamin

A is a key immune modulator, involved in the synthesis of

lymphocytes, neutrophils, cytokines, and immunoglobulins.

Vitamin A deficiency has been associated with increased

susceptibility to numerous infectious diseases, and is of

particular concern in patients undergoing bone marrow

transplants. An observational trial on 120 bone marrow

transplant patients has shown an association between an

increased incidence of hyporetinolemia and an increased

risk of HZ infection.

Enzyme therapy [11,12]

Before the introduction of acyclovir, pancreatic enzyme

preparations were used effectively in Germany as a

treatment for HZ. The suspected mechanisms of action

for the enzyme formula included stimulating the break-

down of immune complexes and enhancing CMI.

Other nutritional considerations

Nutrients such as vitamin C, vitamin E, lysine, and zinc

have shown potential in the treatment of HSV-1 and

HSV-2. Consequently, they may also be helpful against

HZ, although evidence for this is primarily in the realm of

anecdotal reports and speculative extrapolation.

Licorice (Glycyrrhiza glabra) [13–17]

Licorice is one of the most widely used herbs in

traditional medicine, spanning many generations and

several continents. Its properties as an anti-inflammatory,

mucoprotectant, and antiviral agent may be potentially

valuable in the treatment of HZ. One constituent,

glycyrrhizin, inhibits virus growth and may also inactivate

viral particles. It has shown antiviral activity in vitroagainst various forms of herpes virus, including VZV, and

induces interferon production both in vitro and in vivo.

When glycyrrhizin is taken orally, it is converted into

glycyrrhetinic acid, with loss of its systemic antiviral

effects. However, as a topical agent, both glycyrrhizin and

licorice may provide antiviral activity, and as such may be

beneficial in cases of both HSV and HZ. Further

investigation of this application is warranted.

Madonna Lily (Lilium candidum) [18,19]

In northern Italy, traditional folk medicine identifies

L. candidum as a herbal treatment for HZ. Bulbs of

cultivated L. candidum have yielded successful results

when fried in olive oil and applied externally as a poultice

on HZ lesions. Its healing properties are believed to be a

result of the presence of eight spirostanolsaponins and

two furostanolsaponins identified in the bulb of the plant.

Reishi Mushroom (Ganoderma lucidum) [20,21]

A few small studies have examined the effect of

G. lucidum, either by itself or in combination with other

herbs, for the treatment of HZ or PHN. One case study

on two patients with HZ and two patients with PHN

showed that administration of hot-water-soluble extracts

of G. lucidum (36–72 g dry weight/day) led to a consider-

able decrease in pain.

Bi Phaya Yaw (Clinacanthus nutans) [22]

A small shrub found in Southeast Asia, has long been used

in Thailand as a traditional medicine for snake and insect

bites and various skin ailments. Several small studies have

examined its benefit for HZ. One randomized, placebo-

controlled trial was carried out on 51 HZ patients using a

topical preparation of C. nutans extract applied five times

daily for 7–14 days until the lesions were healed. The

number of patients with lesions crusting within 3 days

and healing within 7–10 days was significantly higher in

the experimental group than in the placebo group

(P < 0.01); the pain scores were significantly reduced as

well. No side effects were reported with the medication.

Honey/propolis [23–26]

Since ancient times, bee products, specifically honey and

propolis, have been recognized in traditional medicine as

aids in wound healing. Today, their healing properties for

select herpes viruses are being confirmed in both the

laboratory and the examination room; they may prove to

be beneficial in the management of HZ.

A small, nonblinded, cross-over study comparing the

topical application of honey with acyclovir cream on

patients with HSV found a significantly shorter duration

of episodes and faster healing time when using a honey

application versus the antiviral drug. Similarly, a rando-

mized, blinded-investigator study, comparing the use

of a topical propolis ointment with acyclovir and placebo

for 90 patients with confirmed HSV, concluded that after

10 days, a significant number of patients in the propolis



group (24/30) had healed, compared with those in the

acyclovir (14/30) or the placebo (12/30) group. These

findings coincide with in-vitro studies proposing the

potential antiviral property of propolis against HSV.

Sangre de Grado (Croton lechleri) [27]

Extracts of Sangre de Grado have shown activity against a

number of viruses, including influenza, parainfluenza,

hepatitis A and B, and HSV-1 and HSV-2.

Aloe (Aloe vera) [28,29]

Topical administration of A. vera has been used widely for

wound healing. Aloe emodin, an anthraquinone prepared

from A. vera, was shown in vitro to inactivate HSV-2. In

another study, acemannan (another ingredient of Aloe)

was reported to act synergistically with acyclovir against

HSV in vitro.

St John’s wort (Hypericum perforatum) [30–33]

St John’s wort is widely known in traditional medicine to

be an effective treatment for viral infections and afflictions

related to the nerves. In terms of its effect on herpes

viruses, several studies have shown promising results.

Hypericum species have been observed in vitro to show

potent antiviral activity against HSV-1. In addition, two

double-blind, placebo-controlled studies have shown the

efficacy of an orally administered H. perforatum extract

against HSV.

Other treatment options

Traditional Chinese Medicine Acupuncture has long been

considered as an effective therapy for pain management.

Preliminary studies have shown that Chinese medicine

may show promise when used in conjunction with

conventional therapies in the management of PHN. A

variety of different treatment methods are available;

these fall into the following five main categories:

(1) Treatment according to the pathogenic factor.

(2) Treatment according to the channels involved.

(3) Treatment of the local area.

(4) Use of empirical points.

(5) Ear acupuncture.

Transcutaneous electrical nerve stimulation [5,7]

The use of transcutaneous electrical nerve stimulation

therapy has been beneficial in the management of PHN.

In one review, the use of combination therapy consisting

of amitriptyline, topical capsaicin, and transcutaneous

electrical nerve stimulation was recommended for the

treatment of PHN over antiviral therapy.

Nonpharmacologic interventions [5]

Neurosurgical procedures are treatments of last resort for

intractable pain. In small studies, electrical stimulation of

the thalamus and anterolateral cordotomy to interrupt the

spinothalamic tract led to relief in patients with PHN.

Electrocoagulation of well-defined areas of the dorsal root

has been attempted, but the procedure has a substantial

risk of prolonged hemiparesis and sensory deficits, and a

recent consensus conference did not advocate its use.

A phenomenon known as ‘counterirritation’ has been

reported to relieve PHN by reintroducing normal

inhibition of the small fibers in the spinal cord.

Data from small studies suggest that ethyl chloride spray,

which evaporates rapidly and causes a freezing sensation,

and transcutaneous electrical nerve stimulation provide

partial to complete relief of pain in some patients with

PHN.

ConclusionMany options are available to the clinician for the

treatment of HZ and PHN, albeit with variable degrees

of success. Antiviral agents, such as acyclovir, valacyclovir,

and famciclovir, have been shown to reduce both the pain

and the healing time of skin lesions associated with HZ,

but have marginal success in the prevention and

treatment of PHN. Corticosteroids may be used for pain

management in HZ, but do not seem to be effective in

the prevention of PHN. Analgesics provide effective

temporary pain relief for both HZ and PHN. Nerve block

injections offer more long-term pain relief in both

conditions, provided they are administered early in the

course of the disease. TCAs may provide pain relief in

cases of PHN, but require at least 3 months for positive

effects. The potential for antiviral resistance, particularly

in immunosuppressed individuals, is of growing concern,

as this group is at a greater risk of developing HZ and

PHN. Furthermore, the increased cost of antiviral therapy

can represent a financial obstacle for at-risk individuals to

obtain conventional medication. These issues underscore

the need to investigate and identify alternative ther-

apeutic options.

Although vitamin A deficiency appears to be associated

with increased susceptibility to HZ in immunosup-

pressed individuals, further investigation is required to

determine whether a causal relationship exists. Enzyme

therapy may serve as an effective alternative to acyclovir.

The topical use of capsaicin in the management of pain

has been shown to be effective in PHN, whereas topical

applications of licorice extract, Madonna lily bulb, and

C. nutans have been used in the treatment of skin lesions

associated with HZ; further investigation is required to

determine clinical efficacy. Small case studies using hot-

water-soluble extracts of reishi mushroom by itself or in

combination with other herbs indicate potential benefit

in both HZ and PHN. As with the other herbs

mentioned, further rigorous investigation is required to

determine clinical relevance.

AcknowlegdementsConflicts of interest

There are no conflicts of interest.

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Herpes zoster: etiology, clinical features and treatment options, and case report

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