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N Engl J Med. Author manuscript; available in PMC 2016 March 13.
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Published in final edited form as:

N Engl J Med. 2013 July 18; 369(3): 255–263. doi:10.1056/NEJMcp1302674.

Herpes Zoster
Jeffrey I. Cohen, M.D.
Medical Virology Section, Laboratory of Infectious Diseases, National Institutes of Health,
Bethesda, Maryland

Abstract
A 65-year-old man presents with a rash of 2 days duration over the right forehead with vesicles
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and pustules, a few lesions on the right side and tip of the nose, and slight blurring in the right eye.
The rash was preceded by tingling in the area and is now associated with aching pain. How should
this patient be evaluated and treated?

THE CLINICAL PROBLEM

Primary infection with varicella-zoster virus (VZV) results in chickenpox, manifested by
viremia with a diffuse rash and seeding of multiple sensory ganglia where the virus
establishes life-long latency. Herpes zoster is caused by reactivation of latent VZV from
cranial nerve or dorsal root ganglia with spread of virus along the sensory nerve to the
dermatome. There are more than 1 million cases of herpes zoster in the United States each
year with an annual rate of 3 to 4 cases per 1000 persons. Studies suggest that the incidence
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of herpes zoster is increasing.1 Unvaccinated persons who live to age 85 have a 50% chance
of developing herpes zoster. Up to 3% of patients with zoster require hospitalization.

The major risk factor for herpes zoster is increasing age. With increasing time after
varicella, there is a reduction in the level of T cell immunity to VZV2 which, unlike virus-
specific antibodies, correlates with protection from zoster. The risk is higher in women than
men, in whites than blacks, and in persons with a family history of herpes zoster.3
Chickenpox that occurs in utero or early in infancy, at a time when the cellular immune
system is not fully matured, is associated with herpes zoster in childhood.
Immunocompromised persons with impaired T cell immunity, including organ and
hematopoietic stem cell transplant recipients, persons receiving immunosuppressive therapy,
and patients with lymphoma, leukemia, or HIV infection, are at increased risk of developing
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herpes zoster and having more severe disease.

Postherpetic neuralgia (PHN), or pain persisting after the rash has resolved (often defined
specifically as pain persisting 90 days or more after onset of rash), is a feared complication
of herpes zoster. The pain may persist for many months or even years; it may be severe and

Address reprint requests to Dr. Cohen at the Laboratory of Infectious Diseases, National Institutes of Health, Bldg. 50, Rm. 6134, 50
South Drive, MSC1807, Bethesda, Maryland 20892-1807, or at jcohen@niaid.nih.gov.
The views expressed here are those of the author and not necessarily those of US government.
No potential conflict of interest relevant to this article was reported. Disclosure forms provided by the authors are available with the
full text of this article at NEJM.org.
 Cohen Page 2

interfere with sleep and activities of daily living, resulting in anorexia, weight loss, fatigue,
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depression, withdrawal from social activities and employment, and loss of independent
living. Depending on age and the definition used, ten to 50% of persons with herpes zoster
develop PHN. The risk increases with increasing age (particularly over age 50) and is
greater in persons with severe pain at the onset of herpes zoster or severe rash with a large
number of lesions.

Various neurologic complications have been reported to occur with herpes zoster including
Bell’s palsy, the Ramsay-Hunt syndrome, transverse myelitis, transient ischemic attacks, or
stroke.4 In addition, ophthalmologic complications of zoster occurring in the V1 distribution
of the trigeminal nerve can include keratitis, scleritis, uveitis, or acute retinal necrosis (Table
1). Immunocompromised persons can develop additional complications including
disseminated skin disease, verrucous skin lesions, acute or progressive outer retinal necrosis,
chronic zoster, or infection with acyclovir-resistant VZV. In these patients the disease can
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involve multiple organs (e.g. lung, gastrointestinal tract, brain) and patients may present
with hepatitis or pancreatitis several days before the rash appears.5

STRATEGIES AND EVIDENCE

EVALUATION
The rash of herpes zoster is dermatomal and does not cross the midline, consistent with
reactivation from dorsal root or cranial nerve ganglia. The thoracic, trigeminal (Fig. 1A),
lumbar, and cervical dermatomes are the most frequent sites of rash, although any area of
the skin can be involved. In non-immunocompromised persons, a few scattered lesions
outside the affected dermatome are not unexpected. The rash is often preceded by tingling,
itching, and/or pain for 2 to 3 days, which can be continuous or episodic. Depending upon
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the location and severity, this prodromal pain may lead to misdiagnosis and costly testing.
The rash begins as macules and papules which evolve into vesicles and then pustules (Fig.
1B). New lesions appear over 3 to 5 days, often with filling in of the dermatome despite
antiviral treatment. The rash usually dries with crusting in 7 to 10 days. Some persons have
pain in the absence of a rash, termed zoster sine herpete, which is difficult to diagnose and
may lead to numerous unnecessary tests or procedures. Immunocompromised patients may
have disseminated rashes with viremia and new lesions occurring for up to 2 weeks. The
characteristics of pain associated with herpes zoster may vary. Patient may have paresthesias
(e.g. burning or tingling), dysethesias (altered or painful sensitivity to touch), allodynia (pain
associated with non-painful stimuli) or hyperesthesia (exaggerated or prolonged response to
pain). Pruritis is also commonly associated with herpes zoster.
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DIAGNOSIS
Most cases of herpes zoster can be diagnosed clinically, although direct
immunofluorescence for VZV antigen or PCR for VZV DNA in cells from the base of
lesions after they are unroofed may be needed for atypical rashes. In a study comparing PCR
with other diagnostic methods, the sensitivity and specificity of PCR was 95% and 100%
respectively, and, using immunofluorescent VZV antigen testing, was 82% and 76%,
respectively.6 The most common condition mistaken for zoster is herpes simplex virus,

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which can recur in a dermatomal distribution; accordingly, when patients present with
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“recurrent zoster,” atypical lesions, or are immunocompromised with disseminated skin

lesions, specific testing for both VZV and herpes simplex virus is often useful. VZV has
been demonstrated in saliva of persons with zoster, although such testing does not currently
have a demonstrated role in clinical practice.7

PCR of the cerebrospinal fluid (CSF) has been used for diagnosis of CNS vasculopathy;
demonstration of an increase in the ratio of anti-VZV antibody in CSF to that in the blood is
more sensitive.4 PCR of the blood may be helpful for diagnosis of visceral zoster in
immunocompromised persons who present with hepatitis or pancreatitis without a rash.5
PCR of blood or CSF for VZV has been used for diagnosis of zoster sine herpete.

TREATMENT AND PREVENTION

Antiviral Therapy—Antiviral therapy is recommended for herpes zoster for certain non-
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immunocompromised patients and all immunocompromised patients (Table 2). Other

persons might also benefit from antiviral therapy, although their risk of complications from
zoster is lower. Three guanosine analogs- acyclovir, valacyclovir, and famciclovir- have
been licensed by the Food and Drug Administration (FDA) for treatment of herpes zoster
(Table 3). Oral bioavailability and levels of antiviral drug activity in the blood are higher
and more reliable in those receiving thrice daily valacyclovir or famciclovir than for
acyclovir 5 times daily. This is important, because VZV is less sensitive than herpes simplex
virus to acyclovir, valacyclovir, or famciclovir. These antivirals hasten resolution of lesions,
reduce new lesion formation, reduce virus shedding, and decrease severity of acute pain
(Table 3). For example, in the largest randomized, double-blind trial of acyclovir for zoster,
oral acyclovir given within 47 hours of onset shortened the mean time for the last day of
new lesion formation, loss of vesicles, and full crusting by 0.5 days, 1.8 days, and 2.2 days,
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respectively, compared with placebo.10 In another large trial, acyclovir reduced duration of
virus shedding by 0.8 days compared with placebo.11 In a meta-analysis of several
randomized, controlled trials, antivirals did not significantly reduce the incidence of PHN19
and they are not approved for prevention of PHN by the FDA. Valacyclovir or famciclovir
have been shown to be superior to acyclovir for reducing pain associated with herpes zoster
in some studies.14,15 Valacyclovir is comparable to famciclovir in terms of efficacy for
reducing acute pain and accelerating healing.20 As compared with acyclovir, valacyclovir
and famciclovir require fewer daily doses, but are more expensive. While controlled trials
have initiated treatment within 72 hours of onset of the rash, and treatment is recommended
to start within this interval and as early as possible, many experts recommend that if new
skin lesions are still appearing or complications of herpes zoster are present, treatment
should be initiated even if the rash began more than 3 days prior. Treatment is usually given
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for 7 days in the absence of complications of herpes zoster. Intravenous acyclovir is

recommended for immunocompromised persons who require hospitalization or for persons
with severe neurologic complications. Foscarnet is used for immunocompromised patients
with acyclovir-resistant VZV.

Corticosteroids—The use of corticosteroids with antiviral therapy for uncomplicated

herpes zoster remains controversial. Randomized controlled trials have demonstrated

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benefits of a tapering course of predisone21 or prednisolone12, including reducing acute

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pain,12,21 improving performance of activities of daily living,21 accelerated early healing,12

and time to complete healing in one21 but not another study.12 The addition of
corticosteroids to antiviral therapy has not been shown to reduce the incidence of PHN.
Owing to their immunosuppressive properties, corticosteroids should not be administered for
herpes zoster without concomitant antiviral therapy. Corticosteroids should generally be
avoided in patients with hypertension, diabetes mellitus, peptic ulcer disease, or
osteoporosis; particular caution is warranted in elderly patients, who are at increased risk of
serious adverse events with treatment. Prednisone is used for treatment of certain CNS
complications of herpes zoster such as vasculopathy or Bell’s palsy in non-
immunocompromised patients.

Acute pain associated with herpes zoster—Several medications have been used for
the treatment of acute pain associated with herpes zoster (Table 4). Nonsteroidal anti-
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inflammatory drugs or acetaminophen can be tried for patients with mild pain. Opioids, such
as oxycodone, are used for more severe pain associated with herpes zoster. Opioids were
more effective than gabapentin for herpes zoster pain in a randomized, placebo-controlled
trial.22 Gabapentin was shown in one,23 but not another22 controlled trial to reduce pain
associated with herpes zoster. Lidocaine patches reduced pain associated with herpes zoster
in a placebo-controlled trial, and should only be applied to intact skin, not to the area of the
rash.24 While tricyclic antidepressants have not been shown to be effective in randomized
controlled clinical trials for acute zoster pain, they have been used when opioids are
insufficient for pain.

Eye disease associated with zoster—Patients with zoster in the V1 distribution of the
trigeminal nerve (including lesions on the forehead and the upper eyelid) and either the tip
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of the nose or new visual symptoms should be evaluated by an ophthalmologist. Other

treatment may be needed in addition to antiviral therapy, including mydriatics to dilate the
pupil and reduce the risk of scarring (synechiae), topical corticosteroids for keratitis,
episcleritis, or iritis, medications to reduce ocular pressure for glaucoma, or intravitreal
antiviral therapy for immunocompromised patients with retinal necrosis.

Postherpetic neuralgia—Pain associated with PHN is often challenging to treat.

Detailed discussion of PHN management is beyond the scope of this article. In brief,
medications demonstrated in randomized trials to reduce pain associated with PHN include
topical lidocaine25, anticonvulsants (e.g. gabapentin26 or pregabalin27), opioids,28 tricyclic
antidepressants (e.g. nortriptyline29), and capsaicin30. Combined modalities, such as
gabapentin and nortriptyline31 or an opiate and gabapentin32 have been more effective for
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PHN than single agent therapy, but also confer greater risk of side effects. Even with
treatment, many patients do not have adequate relief of pain and referral to a pain specialist
can be helpful.

Prevention of Herpes Zoster—A live attenuated zoster vaccine is recommended by the

Advisory Committee on Immunization Practices in persons age 60 and older to prevent
herpes zoster and its complications, including PHN.9,33, Based on the results of a recent

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clinical trial, the vaccine is now approved by the FDA for use in persons age 50 or above to
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prevent herpes zoster.34 The efficacy of the vaccine to prevent herpes zoster is 70% in
persons aged 50 to 59, 64% in persons aged 60 to 69, and 38% in persons 70 or above.33–35
Vaccine efficacy for prevention of PHN is 66% in persons aged 60 to 69 and 67% in persons
70 or older.33,35 A follow-up study showed that the reduction in the risk of herpes zoster
remained significant for at least 5 years after vacation, though vaccine effectiveness declined
over time.36 Among vaccinated (as compared with unvaccinated) persons who develop
herpes zoster, pain was significantly shorter in duration and less severe.33 The vaccine can
be given to persons with a prior history of herpes zoster; in a recent report, rates of adverse
events associated with vaccination were similar between those who had prior zoster (mean
3.6 years prior to vaccination) and those with no history of zoster.37

The optimal timing of vaccination after an episode of zoster is uncertain. Since the risk of
recurrent zoster after a recent episode of the disease is relatively low,38 and the cellular
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immune response to VZV is similar during the first 3 years after receiving the zoster vaccine
and after having an episode of zoster,39 one might delay vaccination in immunocompetent
persons with a recent history of zoster providing that it is well documented by a health care
provider. The vaccine is contraindicated in persons with hematologic malignancies whose
disease is not in remission or have received cytotoxic chemotherapy within 3 months, in
persons with T cellular immunodeficiency (e.g. HIV infection with CD4 count ≤200/mm3 or
<15% of total lymphocytes), and in those receiving high dose immunosuppressive therapy
(e.g. ≥20 mg of prednisone daily for ≥2 weeks or anti-TNF therapy).

Infection Control—While herpes zoster is less contagious than varicella, patients with
zoster can transmit VZV to susceptible persons and cause varicella. Non-
immunocompromised persons with dermatomal zoster should be placed on contact
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precautions and lesions should be covered if possible;40 however, virus transmission has
occasionally been reported in such patients.41 Persons with disseminated lesions or
immunocompromised persons with herpes zoster should be placed on airborne and contact
precautions until all lesions have crusted.

AREAS OF UNCERTAINTY
Improved therapies are needed for pain associated with herpes zoster and PHN and to
prevent development of PHN after herpes zoster. Studies are needed to determine which
patients are at highest risk for PHN so that more aggressive therapy can be given. There is
uncertainty regarding the effectiveness of the zoster vaccine in persons ≥80 years old, the
safety and effectiveness of the vaccine in persons with immunocompromising conditions
that are currently considered contraindications to vaccination, the duration of immunity
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induced by the vaccine, and whether booster doses will be needed.

GUIDELINES
Recommendations have been published for the management of herpes zoster from a group
of experts8 and for prevention of herpes zoster by the Advisory Committee on Immunization
Practices.9 The present review is generally concordant with these recommendations.

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CONCLUSIONS AND RECOMMENDATIONS

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Whereas herpes zoster is often mild in healthy young persons, older individuals are at
increased risk of pain and complications including PHN, ocular disease, motor neuropathy,
or CNS disease. In the vast majority of cases, the diagnosis can be made clinically. Antiviral
therapy is most beneficial for persons with complications of zoster or at increased risks of
complications such as older persons and immunocompromised persons, and should be
initiated as soon as possible, and generally within 72 hours of the onset of rash. Valacyclovir
or famciclovir are preferred over acyclovir due to reduced frequency of dosing and higher
levels of antiviral drug activity. The patient described above should receive oral antiviral
therapy, medication for pain (e.g. opioid, with addition of gabapentin if needed), and prompt
referral to an ophthalmologist. He should also be advised to avoid contact with persons who
have not had varicella or have not received the varicella vaccine until his lesions have
completely crusted. I would recommend herpes zoster vaccination in the future to reduce his
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risk of recurrence, but would tend to defer this in an immunocompetant patient for
approximately 3 years, given that a zoster episode is expected to boost his cellular immune
response to VZV.

Acknowledgments
This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious
Diseases. I thank Drs. Adriana Marques and Michael Oxman for reviewing the manuscript.

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Take Home Points

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In the absence of zoster vaccine, persons who live to age 85 have a 50% chance of
developing herpes zoster.

Persons most likely to benefit from antiviral therapy for herpes zoster include those with
complications of zoster, and those at risk for complications including
immunocompromised persons, those ≥ 50 years old, and those with severe pain or severe
rash.
Antivirals hasten resolution of herpes zoster lesions and decrease severity of acute pain,
but have not been convincingly been shown to reduce the risk of postherpetic neuralgia.

Valacyclovir or famciclovir are preferred to acyclovir due to ease of dosing and higher
levels of antiviral drug activity.
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Patients with zoster and new visual symptoms should be evaluated by an ophthalmologist
to determine whether ocular-specific therapy is needed.

The zoster vaccine is approved by the FDA for persons ≥50 years old and is used in
persons with and without a history of zoster.
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Figure 1.
(A) Zoster in the ophthalmic (V1) branch of the trigeminal ganglia. Photograph courtesy of
Michael Oxman, M.D. (B) Vesicles and pustules in a patient with zoster. These are
representative photographs and are not from the case presented.
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Table 1

Selected Complications of Herpes Zoster in the Non-Immunocompromised Host

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Complication Manifestations Site of VZV reactivation

Aseptic meningitis Headache, meningismus Cranial nerve V

Bacterial superinfection Streptococcus, staphylococcus cellulitis Any sensory ganglia

Bell’s palsy Unilateral facial paralysis Cranial nerve VII

Eye involvement (herpes zoster Keratitis, episcleritis, iritis, conjunctivitis, uveitis, acute retinal Cranial nerve II, III, or V
ophthalmicus) necrosis, optic neuritis, acute glaucoma. (ophthalmic [V1] branch)

Hearing impairment Deafness Cranial nerve VIII

Motor neuropathy Weakness, diaphragm paralysis, neurogenic bladder Any sensory ganglia

Postherpetic neuralgia Pain persisting for 90 days after onset of rash Any sensory ganglia

Ramsay-Hunt syndrome Ear pain and vesicles in the canal, numbness of anterior tongue, Cranial nerve VII geniculate
facial paralysis ganglia and spread to cranial nerve
VIII
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Transverse myelitis Paraparesis, sensory loss, sphincter impairment Vertebral ganglia

Vasculopathy (encephalitis) Vasculitis of cerebral arteries, confusion, seizures, TIAs, stroke Cranial nerve V
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Table 2

Indications for Antiviral Treatment for Patients with Herpes Zostera

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≥50 years old

Moderate or severe pain

Severe rash

Involvement of the face or eye

Other complications of zoster

Immunocompromised persons

a
While antivirals may benefit additional patients with zoster, they are primarily recommended by experts for these 6 groups who either have
complications or who are at increased risk of complications from zoster.8,9
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Table 3

Antiviral Therapy for Herpes Zoster*

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Medication Dose Effects Observed in Side Effects

Controlled Trials

Nonimmunocompromised persons
Acyclovir (oral) 800 mg po 5 times Reduced time to last new lesion malaise
daily for 7–10 days formation, loss of vesicles, full crusting,
cessation of viral shedding; reduced
severity of acute pain10–12

Famiclovir (oral) 500 mg po 3 times Reduced time to last new lesion headache, nausea
daily × 7 days formation, loss of vesicles, full crusting,
cessation of viral shedding, cessation of
pain13,14

Valacyclovir (oral) 1 gm po 3 times daily Reduced time to last new lesion headache, nausea
× 7 days formation, loss of vesicles, full crusting,
cessation of pain15,16

Immunocompromised persons requiring

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hospitalization or severe neurologic

complications
Acyclovir (intravenous) 10 mg/kg iv every 8 Reduced time to last new lesion renal insufficiency
hrs × 7–10 days formation, full crusting, cessation of virus
shedding, cessation of pain; reduced
cutaneous dissemination, reduced visceral
zoser17,18

Foscarnet+ (for acyclovir-resistant VZV) 40 mg/kg every 8 hr not reported renal insufficiency,
until healed hypokalemia,
hypocalcemia,
hypomagnesemia,
hypophosphatemia,
nausea, diarrhea,
vomiting, anemia,
granulocytopenia,
headache

*
All drugsin this table are available as generics
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+
Not approved for this use by FDA
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Table 4

Medications commonly used for treatment of acute pain associated with herpes zoster*
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Medication Dose Titration Maximum Side Effects

Dose

Analgesics-opioid and non-opioid

Oxycodone 5 mg every 4 hrs as Increase by 5 mg 4 None specified, but Drowsiness, dizziness,
needed times daily every 2 do not exceed 120 mg constipation, nausea,
days as tolerated daily without pain vomiting
specialist

Tramadol 50 mg once or twice Increase by 50–100 400 mg daily; 300 mg Drowsiness, dizziness,
daily mg daily in divided dailyif >75 years old constipation, nausea,
doses every 2 days as vomiting
tolerated

Corticosteroids^
Prednisone 60 mg daily for 7 days, None 60 mg Gastrointestinal distress,
then decrease to 30 mg nausea, vomiting, mood
daily for 7 days, then changes, edema, glucose
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decrease to 15 mg intolerance, increased

daily for 7 days blood pressure

Anticonvulsants
Gabapentin 300 mg at bedtime or Increase by 100–300 3600 mg daily Drowsiness, dizziness,
100–300 mg 3 times mg 3 times daily ataxia, peripheral edema
daily every 2 days as
tolerated

Pregabalin 75 mg at bedtime or 75 Increase by 75 mg 600 mg daily Drowsiness, dizziness,

mg twice daily twice daily every 3 ataxia, peripheral edema
days as tolerated

Tricyclic antidepressants
Nortriptyline 25 mg at bedtime Increase by 25 mg 150 mg daily Drowsiness, dry mouth,
daily every 2–3 days blurred vision, weight
as tolerated gain, urinary retention

Topical therapy
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Lidocaine 5% patch One patch topically for None One patch for up to Local irritation; if
up to 12 hours to intact 12 hours within a 24- systemic absorption can
skin only hour period cause drowsiness,
dizziness

*
Modified from Dworkin RH, Johnson RW, Breuer J, et al. Recommendations for the management of herpes zoster. Clin Infect Dis. 2007;44 Suppl
1:S1–26, by permission of Oxford University Press.

This list provides examples and is not meant to be comprehensive

^
The use of corticosteroids is controversial as they are often poorly tolerated in older patients.
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