Neuralgia Pós-Herpética - UpToDate

05/09/2023, 08:23 Neuralgia pós-herpética - UpToDate
Postherpetic neuralgia
AUTOR: Erik Ortega, MD
EDITOR DE SEÇÃO: Jeremy M. Shefner, MD, PhD
EDITOR ADJUNTO: Richard P Goddeau, Jr, DO, FAHA
Divulgações do Colaborador
Todos os tópicos são atualizados à medida que novas evidências são disponibilizadas e nosso processo de revisão por
pares é concluído.
Revisão da literatura atualizada até: agosto de 2023.

Última atualização deste tópico: 25 de outubro de 2021.
INTRODUÇÃO
O vírus varicela-zoster (VZV) é o agente causador da varicela, ou "catapora", e do herpes

zoster, ou "cobreiro". O herpes zoster agudo geralmente se apresenta com uma erupção
cutânea dolorosa, mas autolimitada. Alguns pacientes podem continuar a sentir dor
durante meses a anos após a resolução da erupção cutânea, uma condição conhecida
como neuralgia pós-herpética (NPH).
A patogênese, epidemiologia, características clínicas, diagnóstico e tratamento da NPH são

revisadas aqui. Outros aspectos do VZV e da terapia aguda da infecção por herpes zoster
são discutidos separadamente. (Consulte “Epidemiologia, manifestações clínicas e
diagnóstico de herpes zoster” e “Tratamento de herpes zoster” .)
PATOGÊNESE
A inflamação associada ao herpes zoster agudo pode induzir fibrose e outras alterações
estruturais nos nervos que resultam em atividade espontânea capaz de manter a dor na
ausência de dano tecidual contínuo [1-5 ] . As alterações que podem contribuir para a dor
persistente da NPH incluem hiperexcitabilidade espinhal ou ganglionar e alterações pós-
infecciosas na expressão gênica neuronal [ 6,7 ].
O herpes zoster agudo que precede a NPH é causado pela reativação do vírus varicela-
zoster (VZV). O herpes zoster é caracterizado por inflamação hemorrágica do nervo
periférico, da raiz dorsal e do gânglio da raiz dorsal. À medida que a imunidade celular
diminui com a idade ou imunocomprometimento, o vírus pode ser transportado ao longo
dos nervos periféricos, produzindo uma neurite aguda [ 8,9 ]. A extensão central na
medula espinhal e nas leptomeninges também foi descrita [ 10 ]. Fibrose subsequente foi
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relatada no gânglio da raiz dorsal, raiz nervosa e nervo periférico após resolução do
processo agudo [ 11,12 ].
Existem três fases de dor associadas ao herpes zoster [ 13-15 ]:
● Acute herpetic neuralgia refers to pain preceding or accompanying the eruption of

rash that may persist for up to 30 days.
● Subacute herpetic neuralgia refers to pain that persists beyond healing of the rash
but that resolves within three months of onset.
● PHN refers to pain persisting beyond three months from the initial onset of the rash.
Autopsy data for cases of well-established PHN are limited. One study reported five cases,
three with severe PHN and two with no persistent pain [16]. Findings in patients with
persistent pain included dorsal horn atrophy as well as cellular, axonal, and myelin loss
with fibrosis in the sensory ganglion. Marked axonal and myelin loss in the nerve and/or
sensory root were found in patients both with and without persistent pain.
A search for responsible neurotransmitters in PHN has been difficult. Substance P is a

peptide implicated in the transmission of pain signals, while serotonin and norepinephrine
are neurotransmitters thought to play a role in the inhibition of pain signals. However,
studies of the affected dorsal horn and dermatomes from patients with PHN have failed to
demonstrate differences in cytokine profiles, levels of neurotransmitters, or opiate
receptors compared with the unaffected side [1,17,18].
Some have speculated that ongoing VZV viral replication after an acute infection might be
responsible for PHN [19]. However, in a randomized trial of 10 patients with severe PHN,
intravenous and oral acyclovir given for 56 days failed to influence the course of PHN [20].
EPIDEMIOLOGY AND RISK FACTORS
The probability of developing PHN increases with age. The best incidence data in older
patients come from the placebo arm of a large randomized trial that evaluated vaccination
against the varicella-zoster virus (VZV) [21]. In 334 patients 60 to 69 years of age who
developed herpes zoster and were followed for a median of 3.1 years, PHN occurred in 6.9
percent. By contrast, among 308 patients age 70 years or older who developed herpes
zoster, PHN occurred in 18.5 percent.
For adults younger than 60 years of age with herpes zoster, the risk of PHN is estimated to
be less than 2 percent [22]. PHN is rare in children.
The major risk factors for PHN are [23-27]:

● Age >60 years

● Severe or incapacitating pain with acute herpes zoster
● More severe rash with acute herpes zoster
Older age is also associated with increasing severity and persistence of PHN symptoms
[28]. The risk of PHN may increase with immunosuppression, although the evidence is not
entirely consistent [27,29,30].
CLINICAL MANIFESTATIONS
In most cases, PHN is a continuation of the pain that developed during an acute episode of
herpes zoster and never resolved. However, in some cases, PHN pain may develop months
to years after resolution of the initial acute event [31]. These episodes occur in the same
distribution as the initial rash and are typically precipitated by a specific trigger (eg, a
surgical procedure, tooth abscess).
The pain associated with PHN can be burning, pruritic, sharp, or stabbing and constant or
intermittent [13,32]. More than 90 percent of patients with PHN also report allodynia
(sensation of pain evoked by normally nonpainful stimuli such as light touch) [33].
The patient with PHN typically involves a specific nerve and localizes to a dermatome
( figure 1). Thoracic (typically T4 to T6), cervical, and trigeminal nerves are most
commonly affected with PHN [34]. Patients with PHN often report sensory deficits within
the affected dermatomes including areas of anesthesia or other specified deficits of
thermal, tactile, pinprick, or vibratory sensation [33]. Sensory deficits may extend beyond
dermatomal margins, but the contralateral dermatomes are unimpaired. Spontaneous
pain may predominate in cutaneous regions with lost or impaired sensation while allodynia
may be triggered in other regions with relatively preserved sensation.
On examination, the areas affected by PHN may show scarring related to the vesicular
eruption of the preceding acute herpes zoster infection or by areas of excoriation caused
by scratching.
The pain associated with acute herpes zoster and PHN can be severe and associated with
profound psychosocial dysfunction including impaired sleep, decreased appetite, and
diminished libido [32,35].
EVALUATION
Diagnosis — The diagnosis of PHN is made when localized neuropathic pain persists

beyond three months in the same distribution as a preceding documented episode of

acute herpes zoster. (See "Epidemiology, clinical manifestations, and diagnosis of herpes
zoster", section on 'Approach to diagnosis'.)
In atypical cases of PHN, the characteristic, localized, and persisting pain consistent with
PHN supports the diagnosis. Additional factors supporting the diagnosis are [36]:
● Age >60 years

● Distribution in trigeminal or brachial plexus dermatomes
● The presence of localized allodynia
● Severe pain or rash with acute herpes zoster episode
We obtain neuroimaging, typically magnetic resonance imaging (MRI) with contrast, for
patients with atypical clinical presentations including those with dermatomal pain not
preceded by an episode of acute herpes zoster and those with neurologic signs or
symptoms suggestive of alternative pathologies, such as radiculopathy. Imaging should
include the spinal level corresponding to the dermatome of the pain; MRI of the brain is
performed for patients with pain in trigeminal or other cranial distributions. (See
'Differential diagnosis' below.)
Testing for varicella-zoster virus (VZV) antibodies in the blood or cerebrospinal fluid is
available and may be useful in atypical cases to confirm past exposure to the virus;
however, positive tests do not specify PHN as the source of pain. (See "Diagnosis of
varicella-zoster virus infection".)
Differential diagnosis — The diagnosis is based on the clinical presentation and is

straightforward in most cases. However, the diagnosis of PHN can be more challenging
when a patient was not diagnosed with (or does not recall) a preceding acute herpes zoster
episode [36]. In addition, the identification of a preceding acute herpes zoster episode may
be challenging in some patients with PHN whose symptoms began as dermatomally
restricted neuropathic pain without rash, a condition called "zoster sine herpete" [37].
Other causes of focal, persistent neuropathic pain include:
● Trigeminal neuropathy – Patients with trigeminal neuropathy (ie, anesthesia

dolorosa) report pain and reduced sensation in the distribution of the trigeminal
nerve. Trigeminal neuropathy may be attributed to PHN, but patients without a
history of a preceding rash typical for acute herpes zoster warrant neuroimaging to
evaluate for secondary causes such as neoplasm. (See "Overview of craniofacial pain",
section on 'Painful trigeminal neuropathy'.)
● Other forms of craniofacial pain – Craniofacial pain syndromes involving nerve

distributions other than the trigeminal nerve are described by their distinct
characteristics such as headache or cranial neuropathies that may distinguish them
from PHN. These syndromes are described separately. (See "Overview of craniofacial
pain".)
● Acute radiculopathy – Patients with spinal radiculopathies, often from nerve root
compression, may report dermatomal pain but typically also have weakness in the
muscles innervated by the affected nerve. Radiculopathies are more common in
lumbosacral and cervical regions, unlike PHN, which is more common in thoracic
regions. Nerve conduction studies and electromyography as well as spinal imaging
may help identify patients with radiculopathies. (See "Clinical features and diagnosis
of cervical radiculopathy" and "Acute lumbosacral radiculopathy: Pathophysiology,
clinical features, and diagnosis".)
● Diabetic amyotrophy and idiopathic lumbosacral radiculoplexus neuropathy –

The onset of pain with diabetic or idiopathic amyotrophy may be acute and focal but
typically extends beyond a dermatome. Patients may also report weakness,
autonomic symptoms such as orthostatic hypotension or urinary dysfunction, and
weight loss. While the pain with PHN is typically lateralized and dermatomally
restricted, diabetic and idiopathic amyotrophy frequently progresses to become more
widespread and involve the contralateral side. (See "Diabetic amyotrophy and
idiopathic lumbosacral radiculoplexus neuropathy".)
● Recurrent acute herpes zoster – Neuropathic pain may be prolonged in patients

who develop a recurrent episode of acute herpes zoster. The recurrent acute attack
may be identified by a recurring rash along with the neuritis. Recurrent acute herpes
zoster is likelier to occur in immunocompromised patients. (See "Epidemiology,
clinical manifestations, and diagnosis of herpes zoster", section on 'Recurrent herpes
zoster'.)
TREATMENT
Multiple medications have shown benefit in reducing PHN symptoms. However, PHN can
be difficult to treat, and some patients require multimodal therapy to manage symptoms.
The choice among treatments for PHN should be individualized according to the severity
and location of pain, comorbid conditions, medication side effect profile, treatment cost
and availability, and patient values and preferences ( algorithm 1). Because the pain of
PHN may be chronic, long-term therapy is often required [38]. However, the long-term
benefits of most therapies are uncertain, and side effects are common [39].
Initial therapies — Both gabapentinoids (ie, gabapentin and pregabalin) and tricyclic

antidepressants (TCAs) have been found to be effective and generally well tolerated for
PHN in clinical trials and meta-analyses [40-44]. Gabapentinoids may have a lower risk of
discontinuation due to adverse effects than TCAs, but these agents have not been
compared directly for PHN. We use patient variables including medication side effect
profile, comorbid conditions, and symptom severity to help select initial therapy. As
examples, gabapentin or pregabalin may be preferred for patients to help co-treat a
seizure disorder or to avoid the risk of cognitive impairment associated with TCAs.
Amitriptyline or other TCAs may be preferred for patients to help co-treat depression.
Gabapentinoids for most patients with moderate or severe pain — For most patients
with moderate to severe pain, we suggest a gabapentinoid (gabapentin or pregabalin) as
initial therapy [45]. Gabapentin and pregabalin are structural analogs of gamma-
aminobutyric acid (GABA) and have been approved by the US Food and Drug
Administration (FDA) for PHN. Both are generally well tolerated and neither alters the
pharmacokinetics of other medications because neither binds to plasma proteins [46,47].
We typically start with gabapentin because of lower cost and more favorable tolerability
[43]. However, pregabalin is also a reasonable initial choice for PHN based on efficacy
because there are no direct comparisons with gabapentin.
● Gabapentin − Gabapentin is typically started at a low dose to minimize the risk of

discontinuation from adverse effects. The daily dose is titrated to effect, for most
patients typically from 1800 up to 3600 mg. Our suggested initial titration of the
immediate release formulation of gabapentin for PHN is:
• 300 mg on day 1
• 300 mg twice daily on day 2
• 300 mg three times daily on day 3
• Thereafter, increase as needed by 300 mg every three days up to 600 mg three
times daily
Lower doses may be used or the titration may be slowed for patients who report relief
or adverse effects at intermediate doses during the initial titration.
For patients who report minimal or no relief after one month at a total daily dose of
1800 mg, we switch to a TCA. (See 'Tricyclic antidepressants if gabapentinoids
ineffective or not tolerated' below.)
For patients who report partial but inadequate pain relief at a total daily dose of 1800
mg, gabapentin may be further increased as needed and tolerated by up to 600 mg
each week to a maximum of 3600 mg given in three divided doses.
The extended-release formulation of gabapentin is titrated according to the same

schedule using the total daily dosage to determine the once-daily dosing. Adjustment
for kidney impairment is required for both immediate- and extended-release

formulations, and use of the extended-release formulation is not recommended in

patients with severe kidney impairment (eg, creatinine clearance <30 mL/minute).
There is moderate-quality evidence supporting the efficacy of gabapentin for PHN,

but some trials have failed to show a benefit with the extended-release formulation of
gabapentin, and benefits beyond 12 weeks are uncertain [43,48]. In a meta-analysis
including eight trials of more than 2200 patients with moderate to severe pain due to
PHN, patients receiving gabapentin at a daily dose of 1200 mg or higher daily were
more likely to report benefit (at least 50 percent reduction in pain intensity or "very
much improved" pain) than those receiving placebo (32 versus 17 percent) [49].
Gabapentin is generally well tolerated. In a pooled analysis of adverse effects

including 37 trials for multiple types of neuropathic pain, patients were more likely to
discontinue gabapentin than placebo due to adverse effects (11 versus 8 percent)
[49]. The most common adverse effects reported were somnolence or drowsiness (14
versus 5 percent), dizziness (19 versus 7 percent), peripheral edema (7 versus 2
percent), and ataxia or gait disturbance (14 versus 3 percent). The rate of serious
adverse effects was 3 percent for both groups.
● Pregabalin − The immediate-release formulation of pregabalin is given two or three

times daily. Our titration regimen based on effect and tolerability is:
• 75 mg twice daily for one week, then

• 150 mg twice daily for one to three weeks, then
• 300 mg twice daily
An extended-release preparation is also available for once-daily dosing. The titration

schedule is the same used for the immediate-release formulation; however, the
starting dose is 165 mg daily and the maximum dose is 660 mg daily.
When stopping the drug, pregabalin should be tapered over a week to reduce the risk
of withdrawal symptoms [50].
Adjustment for kidney impairment is required for both the immediate- and extended-
release formulations; the extended-release formulation is not recommended for
patients with severe kidney impairment (eg, creatinine clearance <30 mL/minute).
Pregabalin is designated as a schedule V controlled substance in the United States
because it has been reported to cause euphoria.
A systematic review of pregabalin for neuropathic pain identified eight trials including
more than 2300 patients with PHN [51]. In the meta-analysis of 732 patients in four
trials of patients with PHN, a dose response and significant reduction in pain (at least
50 percent) was more likely for patients receiving pregabalin than those receiving
placebo: 150 mg (24 versus 13 percent), 300 mg (32 versus 13 percent), and 600 mg
(41 versus 15 percent). Common side effects associated with pregabalin dosing
included somnolence (300 mg, 16 percent; 600 mg, 25 percent) and dizziness (300
mg, 29 percent; 600 mg, 35 percent). Other side effects are dry mouth, peripheral
edema, and weight gain.
Tricyclic antidepressants if gabapentinoids ineffective or not tolerated — For patients

who do not tolerate or respond to a gabapentinoid, we suggest a TCA. They are frequently
used for depression or other types of neuropathic pain and are also effective for PHN but
have a lower tolerability than gabapentinoids [52,53]. For most patients using a TCA, we
typically start with amitriptyline; however, nortriptyline or desipramine may be preferred
for patients at risk for anticholinergic symptoms and those with adverse effects from
amitriptyline.
● Amitriptyline is started at 10 mg each night. The dose may be uptitrated as needed

and tolerated over four weeks up to a dose of 50 mg each night. For patients who
report minimal or no relief after one month at 50 mg, we switch to an alternative
agent (see 'Alternative therapies' below). For those who report partial but inadequate
relief at a dose of 50 mg, the dose may be further uptitrated every four weeks up to a
maximum daily dose of 150 mg, monitoring for adverse effects.
● Nortriptyline is typically started at 10 mg each night and increased by 10 to 20 mg

each week to effect as tolerated, with a maximum daily dose of 150 mg.
● Desipramine is typically started at 25 mg each night and increased by 25 mg each

week to effect as tolerated, with a maximum daily dose of 150 mg.
TCAs inhibit the reuptake of norepinephrine and serotonin in the central nervous system.
They are thought to increase the inhibition of nociceptive signals from the periphery
[54,55].
Anticholinergic side effects (principally sedation and dry mouth) limit the tolerability of
TCAs ( table 1) [56]. Because of their anticholinergic effects, TCAs should be used
cautiously in older patients, particularly those with cognitive impairment or dementia. We
also avoid TCAs in patients with heart disease, epilepsy, or glaucoma. Adverse effects may
be reduced by using a slow titration; however, delayed onset of efficacy (up to three weeks)
before TCAs begin to reduce pain may lead to premature discontinuation. A treatment trial
of at least one month at a target dose may be needed to assess the efficacy of TCAs. In one
study, symptom relief correlated with serum levels of amitriptyline and active metabolites
[57]. Patients who reported no benefit despite serum levels of 100 ng/mL for at least three
weeks were considered to have failed TCA therapy.

A 2015 systematic review found moderate-quality evidence supporting the efficacy of TCAs
for PHN [43]. Efficacy among TCAs is best established for amitriptyline, which was found
effective in producing at least moderate pain relief in multiple short-term studies, typically
at doses of 65 to 75 mg daily [57,58]. Nortriptyline was better tolerated than amitriptyline
in a small crossover trial of 33 patients with PHN [59]. Approximately two-thirds of patients
reported a good response with either medication, but adverse effects leading to
discontinuation were more common with amitriptyline than nortriptyline (48 versus 30
percent). The small study size limits generalizability of these results. Desipramine appears
to have the fewest side effects of the first-generation TCAs and was effective for PHN in a
small trial at mean dose 165 mg per day [60,61]. Almost half reported good response with
desipramine. However, methodologic criticisms of this trial limit the certainty of these
conclusions [62].
Topical therapy for patients with milder symptoms — For patients with mild to
moderate and localized pain and for those who prefer a topical agent, we suggest
capsaicin. We switch to lidocaine patches for those who do not tolerate capsaicin.
● Capsaicin – Capsaicin is formulated as a cream, gel, lotion, or a high-concentration

patch.
We use capsaicin cream (0.025 to 0.075%) for most patients with PHN and reserve the
high-concentration capsaicin (8%) patch for selected patients with partial response to
capsaicin cream who prefer a longer acting formulation.
• Capsaicin cream may be applied to the affected area up to four times each day.
• High-concentration capsaicin patches are administered as a single 60-minute

application. The application may be repeated after three months. It must be
administered by a health care professional, and patients are monitored for up to
two hours after treatment. To manage local pain from capsaicin application, the
skin is usually pretreated with a local anesthetic such as topical lidocaine, and
some studies also used post-treatment oral analgesics such as oxycodone for up
to five days [63]. Further study is needed to confirm long-term effectiveness and
tolerance of the high-concentration capsaicin patch.
Limited data suggest that topical application of standard-concentration capsaicin is

effective for PHN [41]. In one small trial, 143 patients with PHN assigned to capsaicin
cream (0.075%) four times per day for six weeks were likelier to report significant pain
relief than those assigned to placebo (21 versus 6 percent) [64]. The rate of adverse
skin reactions was similar in patients receiving capsaicin and placebo.

A 2013 systematic review identified four randomized controlled trials that evaluated
1272 subjects with PHN treated with one application of either high-concentration
capsaicin patch or standard-concentration capsaicin. The only common endpoint
reported by all four trials, a ≥30 percent pain intensity reduction at eight weeks
compared with baseline, was significantly greater for high-concentration capsaicin
patch (43 versus 34 percent; relative benefit 1.3, 95% CI 1.1-1.5) [65].
High-concentration capsaicin patches are approved by the FDA for the treatment of
PHN. However, capsaicin can cause burning, stinging, and erythema, making it
difficult to achieve true blinding in clinical studies. In practice, application of capsaicin
is intolerable in up to one-third of patients.
● Lidocaine — Lidocaine patches (5%) may provide short term relief for PHN. Up to 3
patches may be applied over the affected area for up to 12 hours daily.
Data from small trials and open-label studies suggest that topical lidocaine (5
percent) may be beneficial for pain relief in patients with PHN [66]. Lidocaine patches
have been approved by the FDA for PHN. However, a 2014 systematic review of topical
lidocaine for neuropathic pain (including 280 patients with PHN) found only very low
quality evidence of efficacy of topical lidocaine due to small numbers, incomplete
outcome assessments, and modest outcome measures of efficacy [67].
Alternative therapies — For patients who do not tolerate or are unresponsive to initial

therapy, we switch to an alternative agent ( algorithm 1). For patients with a partial but
suboptimal response with initial therapy, we use combination therapy by adding an
alternative agent. We use patient preferences and medical comorbidities to help select
among options.
Antiseizure medications — A trial of one of a (non-gabapentinoid) anticonvulsant agent

may be useful for some patients who do not respond to or cannot tolerate initial
medication options. Treatment decisions should be individualized based on patient
characteristics, medical comorbidities, side effects, and drug interactions. The benefit of
anticonvulsants is based in part on their efficacy in other neuropathic pain conditions such
as trigeminal neuralgia and diabetic neuropathy and also on low-quality and anecdotal
evidence for PHN. Options and typical target daily doses for PHN include:
● Valproic acid 500 to 1000 mg daily

● Carbamazepine 200 to 1200 mg daily
● Oxcarbazepine 600 to 1200 mg daily
● Lamotrigine 100 to 300 mg daily
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The dosing, titration, and monitoring of these agents for PHN is similar to regimens used
in trigeminal neuralgia and typically lower doses than those to achieve anticonvulsant
effects. (See "Trigeminal neuralgia", section on 'Medical treatment'.)
In an eight-week trial of 48 patients with PHN, patients assigned to divalproex sodium

(1000 mg per day) were likelier to report at least moderate improvement in pain than those
assigned to placebo (58 versus 15 percent) [68]. Results of small trials of valproic acid in
other neuropathic pain conditions were mixed [69]. In short-term trials in patients with
trigeminal neuralgia, both carbamazepine and oxcarbazepine reduced pain more than
placebo, but neither drug was tested in patients with PHN [70,71]. Lamotrigine may be
better tolerated than carbamazepine but has not been studied extensively for neuropathic
pain.
Serotonin-norepinephrine reuptake inhibitors — Serotonin-norepinephrine reuptake

inhibitors (SNRIs) may be useful for some patients with PHN based on efficacy data for
painful polyneuropathy [43]. These medications may be useful for patients with comorbid
depression. We use duloxetine or venlafaxine for patients with PHN.
● Duloxetine is typically started at 30 mg daily. Typical daily doses are 60 to 120 mg. The
dose may be increased weekly to effect and as tolerated. Adverse effects including
nausea, dry mouth, dizziness, and insomnia are more common at higher doses.
● Venlafaxine may be started at 75 mg daily and increased every two weeks to effect as
tolerated. Typical daily doses are 150 to 225 mg. Venlafaxine should be used with
caution in patients with glaucoma and in those taking anticoagulants. Common
adverse effects include nausea, dizziness, and somnolence.
The initial titration and administration of SNRIs are presented in greater detail separately.
(See "Serotonin-norepinephrine reuptake inhibitors: Pharmacology, administration, and
side effects".)
The effectiveness of SNRIs such as duloxetine and venlafaxine for patients with PHN is
based on data for those with other types of neuropathic pain. A systematic review of eight
trials and including 4084 patients found that duloxetine was beneficial for patients with
painful diabetic neuropathy [72]. Venlafaxine was found to be effective in a short-term trial
of 244 patients with painful diabetic polyneuropathy [73]. Patients assigned venlafaxine at
150 to 225 mg were likelier to report at least 50 percent pain reduction than those
assigned placebo (50 versus 27 percent). However, a 2015 systematic review of six trials
including 460 patients with neuropathic pain found only low-quality data of modest
efficacy for venlafaxine [74]. The efficacy of SNRIs for diabetic neuropathy is presented in
greater detail separately. (See "Management of diabetic neuropathy", section on
'Administration and efficacy'.)

Adjunctive options — For patients with symptoms refractory to prior therapies, adjunctive

options and other interventional therapies such as botulinum toxin injections may be tried
or added ( algorithm 1). These include oral or transdermal opioid analgesics and
intrathecal glucocorticoid injections. The selection of these agents depends on individual
patient preferences and comorbidities.
Opioids — Opioids may be beneficial for selected patients with intractable pain during
the titration of initial or alternative therapies. They can be administered simultaneously for
short-term relief along with the nonopioid agents. They should be initiated at low doses if
used and titrated to provide relief while awaiting benefit from nonopioid treatments, at
which point opioids should be tapered off.
Opioids are available in short- or long-acting formulations ( table 2 and table 3). We
start with short-acting options for opioid-naïve patients and use the lowest effective dose.
The strategies for initiation and chronic use of opioids for patients with PHN is similar to
that of other patients with noncancer pain and is discussed in greater detail separately.
(See "Use of opioids in the management of chronic non-cancer pain".)
Small trials support the efficacy of opioid analgesics for PHN [75-79]. In one crossover trial
involving 76 patients with PHN, treatment with morphine (mean daily dose 91 mg) or
methadone (mean daily dose 15 mg) or a TCA for eight weeks was more effective than
placebo [77]. There was a trend toward greater pain relief with opioids, but certainty with
these results is limited by small sample size.
The use of opioids for chronic PHN should be avoided. Opioids for chronic noncancer pain
remains controversial due to the risk of physical dependence, tolerance, addiction, and
overdose. Because of these risks, opioids are regarded as third-line treatment options and
typically reserved for short-term, adjunctive use for PHN [38,43,80]. Available trials of
opioids for neuropathic pain including PHN do not address the issues of abuse and
addiction [81]. Pharmacovigilance is essential to using opioids in any population
( table 4). (See "Opioid use disorder: Epidemiology, clinical features, health
consequences, screening, and assessment".)
Neuraxial glucocorticoid infusion — Intrathecal glucocorticoid injections may be

beneficial for patients who continue to have intractable pain despite initial or alternative
therapies. These injections are not useful for pain in the distribution of the trigeminal
nerve.
Intrathecal glucocorticoids for PHN are typically given as a single course of weekly
injections over four weeks [82]. Techniques for intrathecal glucocorticoid infusion are
discussed in greater detail separately. (See "Spinal anesthesia: Technique".)

Intrathecal glucocorticoid injections are associated with an uncertain but probably low risk
of serious adverse events, including aseptic meningitis, transverse myelitis, cauda equina
syndrome, lumbar radiculitis, headache, urinary retention, and arachnoiditis [83,84].
Some [40,82,85] but not all [86] studies have found a benefit with intrathecal
methylprednisolone infusions for patients with PHN. The largest trial evaluated 277
patients with intractable PHN who were assigned to one of three treatment groups:
intrathecal methylprednisolone plus lidocaine once per week for four weeks, intrathecal
lidocaine alone once per week for four weeks, or no treatment [82]. More than 90 percent
of patients in the methylprednisolone group reported excellent or good pain relief both at
four weeks compared with 6 and 4 percent in the lidocaine and no treatment groups,
respectively. These results were sustained at two-year follow-up. There were no serious
adverse events associated with the injection.
Intrathecal administration of methylprednisolone was found more effective than

administration in the epidural space in a small trial of 25 patients with PHN [85].
Therapies for refractory symptoms — We reserve other interventional and surgical

approaches such as botulinum toxin injections, cryotherapy, and neuromodulation for
patients with refractory symptoms who do not respond to other therapies ( algorithm 1).
The benefit of such therapies has been shown in small trials and observational studies;
larger studies are needed to better define their role for patients with PHN.
Botulinum toxin — Botulinum toxin injection for PHN is not extensively studied, but
evidence from observational studies and small trials suggests it is effective [87-90]. One
trial evaluated 30 adults with PHN who had persistent pain for at least three months [87].
Patients assigned to botulinum toxin type A (onabotulinumtoxinA) injections were likelier
to achieve ≥50 percent pain reduction at two weeks compared with those who received
placebo injections (13 of 15 patients [87 percent] versus none of 15). The benefit persisted
for a median of 16 weeks. In a comparative study of 60 patients with PHN, patients who
received onabotulinumtoxinA injection reported a greater pain reduction at seven days
when rated on the visual analog scale compared with those who received lidocaine
injections (4.5 versus 2.6 points) [88]. These findings were sustained at three months.
Improvement in sleep and reduction in opiate use were also reported in the botulinum
toxin group.
Botulinum toxin injections should be performed by a clinician experienced with this

treatment [91-93]. No safety concerns were identified in small studies [87,88]. However,
botulinum toxin may cause localized or systemic adverse effects including bruising,
weakness, pain, or headache and may be contraindicated for some patients. Larger and
longer-term studies would be helpful to further clarify the safety and efficacy on this
treatment in PHN.
Neuromodulation and nerve stimulation — Invasive neuromodulatory strategies such

as spinal cord stimulation and peripheral nerve stimulation are considered experimental.
These techniques target peripheral nerves and are thought to modulate neuronal signaling
or inflammatory processes [94]. Techniques that have shown some benefit for patients
with PHN include:
● Transcutaneous electrical nerve stimulation (TENS) [95]

● Pulsed radiofrequency [96-100]
● Spinal cord stimulation [101,102]
These techniques been reported to be effective in approximately half of patients in case

reports and case series [103]. They should be performed by experienced clinicians and in
centers with expertise.
Cognitive and behavioral therapies — Some patients with PHN achieve only partial
relief even with combination pharmacotherapy. For other patients, the efficacy of
pharmacotherapy is limited by adverse effects. Nonpharmacologic approaches, including
cognitive-behavioral therapy (CBT), may be useful for some patients with refractory PHN
pain or associated impairment in mood, sleep, or other quality-of-life domains [104,105]. In
a small trial of 40 patients with PHN treated with pregabalin, patients who were assigned
to also receive CBT reported a greater improvement in pain intensity and mood symptoms
than those assigned to pregabalin alone [106]. Cognitive and behavioral therapies for the
treatment of chronic pain are discussed in detail separately. (See "Approach to the
management of chronic non-cancer pain in adults", section on 'Psychological therapy'.)
Therapies of uncertain or limited benefit
● NMDA receptor antagonists – Animal data suggest a role for excitatory amino acid
neurotransmitters in the maintenance of chronic pain due to nerve injury [107,108].
Antagonists of the N-methyl-D-aspartate (NMDA) receptor have been shown to relieve
neuropathic pain in humans [109].
The most widely available NMDA receptor antagonists are ketamine and
dextromethorphan. Intravenous ketamine induces modest pain relief in patients with
PHN but at doses that cause sedation, dysphoria, and dissociative episodes [110]. In a
crossover trial, pain relief after six weeks was similar in those taking
dextromethorphan or placebo [111].
● Intravenous lidocaine – Small trials have failed to find sustained benefit of

intravenous lidocaine compared with placebo in patients with PHN [40,112]. Any
temporary changes in pain measured immediately after infusion do not appear to be
sustained by four weeks [40,112-116].

The role of topical lidocaine for PHN is discussed separately. (See 'Topical therapy for
patients with milder symptoms' above.)
● Surgical ablation and other interventional procedures – Cryotherapy is an ablation

technique that involves freezing peripheral nerves. A small, unblinded study of
cryotherapy for facial pain failed to show a significant benefit in patients with PHN
[117]. The authors did not provide inclusion criteria, concomitant therapies, or
information on how the response was assessed. By contrast, a second trial reported
"considerable" relief in 11 of 14 patients with cryotherapy to the intercostal nerves for
PHN [118]. In most cases, however, the duration of relief was less than two weeks as
assessed by questionnaire.
Surgical interventions including central electrical stimulation of the thalamus,

ablation by anterolateral cordotomy, and electrocoagulation of the dorsal root carry
substantial risks of permanent neurologic deficits. A systematic review of surgical
procedures for patients with refractory PHN reported the pain reduction with surgical
ablation procedures was frequently accompanied by serious complications including
neuromuscular weakness [119].
● Simple analgesics – Analgesic medications such as aspirin or other nonsteroidal anti-

inflammatory drugs are of limited value in patients with either acute herpetic
neuralgia or PHN [38,120].
PROGNOSIS
The pain of PHN may persist for months, years, or even life [38]. However, there are few
published data for follow-up beyond one year. Prognostic data on PHN is available from
long-term outcome of observational studies in acute herpes zoster. In one study of 85
patients with PHN who were followed to one year, moderate to severe neuropathic pain
persisted in approximately 55 percent [121]. In a long-term follow-up of a study that
included 158 of 298 original patients from an acute herpes zoster trial, 21 percent of
patients reported long-term pain (mean follow-up 9 years) [122].
In a questionnaire study of 385 adults age ≥65 years with persistent PHN, the mean
duration of symptoms was 3.3 years [123].
PREVENTION
Prevention of PHN involves either treatment of acute zoster or the use of a vaccine to
decrease the incidence of acute zoster and PHN. These issues are discussed separately.

(See "Treatment of herpes zoster" and "Vaccination for the prevention of shingles (herpes
zoster)" and "Prevention and control of varicella-zoster virus in hospitals".)
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and

regions around the world are provided separately. (See "Society guideline links: Varicella-
zoster virus" and "Society guideline links: Neuropathic pain".)
INFORMATION FOR PATIENTS
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the
Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th
grade reading level, and they answer the four or five key questions a patient might have
about a given condition. These articles are best for patients who want a general overview
and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces
are longer, more sophisticated, and more detailed. These articles are written at the 10th to
12th grade reading level and are best for patients who want in-depth information and are
comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to
print or email these topics to your patients. (You can also locate patient education articles
on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
● Basics topic (see "Patient education: Neuropathic pain (The Basics)")
● Beyond the Basics topic (see "Patient education: Shingles (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
● Definition and risk factors – Postherpetic neuralgia (PHN) refers to pain persisting
beyond three months from the initial onset of the rash associated with a prior acute
herpes zoster episode. The major risk factors for PHN are age >60 years and severe
pain and rash with a preceding acute herpes zoster episode. (See 'Introduction' above
and 'Epidemiology and risk factors' above.)
● Clinical features – PHN is most often a continuation of pain that failed to resolve
following an acute episode of herpes zoster but may develop months to years after
resolution of the initial acute event. (See 'Clinical manifestations' above.)

The pain is localized to a dermatome. Thoracic (especially T4 to T6), cervical, and

trigeminal nerves are most commonly affected with PHN. The neuropathic pain
associated with PHN can be burning, pruritic, sharp, or stabbing and constant or
intermittent. Many patients also report allodynia.
● Diagnosis – The diagnosis of PHN is made when localized neuropathic pain persists
beyond three months in the same distribution as a preceding documented episode of
acute herpes zoster. (See 'Evaluation' above.)
● Treatments – PHN can be difficult to treat and some patients require multimodal
therapy for symptomatic management. The choice among treatments for PHN should
be individualized according to severity and location of pain, comorbid conditions,
medication side effect profile, treatment cost and availability, and patient values and
preferences ( algorithm 1). (See 'Treatment' above.)
• Initial therapies – For most patients, we suggest a gabapentinoid (gabapentin or

pregabalin) as initial therapy (Grade 2C). Tricyclic antidepressant medications are a
reasonable alternative to gabapentinoids. Topical treatments (eg, capsaicin) are
another reasonable alternative for patients with milder symptoms and for those
who prefer a topical therapy. (See 'Gabapentinoids for most patients with
moderate or severe pain' above and 'Tricyclic antidepressants if gabapentinoids
ineffective or not tolerated' above and 'Topical therapy for patients with milder
symptoms' above.)
• Alternative therapies – For patients who do not tolerate or are unresponsive to

initial therapies, we add or switch to an alternative agent. Medications with
evidence of efficacy for PHN or other types of neuropathic pain include other
antiseizure medications (eg, valproic acid, carbamazepine) and serotonin-
norepinephrine reuptake inhibitors (eg, duloxetine, venlafaxine). (See 'Alternative
therapies' above.)
• Adjunctive options and therapies for refractory symptoms – For patients with
partial response to initial or alternative therapies, adjunctive options may provide
additional benefit. These include oral or transdermal opioid analgesics and
intrathecal glucocorticoid injections. We reserve other interventional and surgical
approaches such as botulinum toxin injections, cryotherapy, and neuromodulation
for patients with refractory symptoms who do not respond to other therapies. (See
'Adjunctive options' above and 'Therapies for refractory symptoms' above.)
● Prognosis – The pain of PHN may persist for months, years, or even life. (See
'Prognosis' above.)

ACKNOWLEDGMENT
The UpToDate editorial staff acknowledges Zahid H Bajwa, MD, who contributed to earlier
versions of this topic review.
Use of UpToDate is subject to the Terms of Use.
REFERENCES
1. Watson CP, Morshead C, Van der Kooy D, et al. Post-herpetic neuralgia: post-mortem
analysis of a case. Pain 1988; 34:129.
2. Woolf CJ. Recent advances in the pathophysiology of acute pain. Br J Anaesth 1989;
63:139.
3. LaMotte RH, Shain CN, Simone DA, Tsai EF. Neurogenic hyperalgesia: psychophysical
studies of underlying mechanisms. J Neurophysiol 1991; 66:190.
4. Simone DA, Baumann TK, LaMotte RH. Dose-dependent pain and mechanical
hyperalgesia in humans after intradermal injection of capsaicin. Pain 1989; 38:99.
5. Cline MA, Ochoa J, Torebjörk HE. Chronic hyperalgesia and skin warming caused by
sensitized C nociceptors. Brain 1989; 112 ( Pt 3):621.
6. Bennett GJ. Hypotheses on the pathogenesis of herpes zoster-associated pain. Ann

Neurol 1994; 35 Suppl:S38.
7. Gershon AA, Breuer J, Cohen JI, et al. Varicella zoster virus infection. Nat Rev Dis
Primers 2015; 1:15016.
8. Burke BL, Steele RW, Beard OW, et al. Immune responses to varicella-zoster in the
aged. Arch Intern Med 1982; 142:291.
9. Meier JL, Straus SE. Comparative biology of latent varicella-zoster virus and herpes
simplex virus infections. J Infect Dis 1992; 166 Suppl 1:S13.
10. Fitzgerald PJ, Denny-Brown D, Adams RD. Pathologic features of herpes zoster: A note
on 'geniculate herpes'. Arch Neurol Psychiatr 1944; 51:216.
11. Head H, Campbell AW. The pathology of herpes zoster and its bearing on sensory
localization. Brain 1900; 23:353.

12. ZACKS SI, ELLIOTT FA, LANGFITT TW. HERPETIC NEURITIS: A LIGHT AND ELECTRON
MICROSCOPIC STUDY. Neurology 1964; 14:744.
13. Dworkin RH, Portenoy RK. Pain and its persistence in herpes zoster. Pain 1996; 67:241.
14. Dworkin RH, Gnann JW Jr, Oaklander AL, et al. Diagnosis and assessment of pain
associated with herpes zoster and postherpetic neuralgia. J Pain 2008; 9:S37.
15. Arani RB, Soong SJ, Weiss HL, et al. Phase specific analysis of herpes zoster associated
pain data: a new statistical approach. Stat Med 2001; 20:2429.
16. Watson CP, Deck JH, Morshead C, et al. Post-herpetic neuralgia: further post-mortem
studies of cases with and without pain. Pain 1991; 44:105.
17. Üçeyler N, Valet M, Kafke W, et al. Local and systemic cytokine expression in patients
with postherpetic neuralgia. PLoS One 2014; 9:e105269.
18. Cao S, Zhang D, Yuan J, et al. Inflammatory cytokine expression in the skin of patients
with postherpetic neuralgia. J Int Med Res 2020; 48:300060520929582.
19. Gilden DH, Kleinschmidt-DeMasters BK, LaGuardia JJ, et al. Neurologic complications
of the reactivation of varicella-zoster virus. N Engl J Med 2000; 342:635.
20. Acosta EP, Balfour HH Jr. Acyclovir for treatment of postherpetic neuralgia: efficacy
and pharmacokinetics. Antimicrob Agents Chemother 2001; 45:2771.
21. Oxman MN, Levin MJ, Johnson GR, et al. A vaccine to prevent herpes zoster and
postherpetic neuralgia in older adults. N Engl J Med 2005; 352:2271.
22. Helgason S, Petursson G, Gudmundsson S, Sigurdsson JA. Prevalence of postherpetic

neuralgia after a first episode of herpes zoster: prospective study with long term
follow up. BMJ 2000; 321:794.
23. Dworkin RH, Boon RJ, Griffin DR, Phung D. Postherpetic neuralgia: impact of
famciclovir, age, rash severity, and acute pain in herpes zoster patients. J Infect Dis
1998; 178 Suppl 1:S76.
24. Nagasako EM, Johnson RW, Griffin DR, Dworkin RH. Rash severity in herpes zoster:
correlates and relationship to postherpetic neuralgia. J Am Acad Dermatol 2002;
46:834.
25. Whitley RJ, Weiss HL, Soong SJ, Gnann JW. Herpes zoster: risk categories for persistent
pain. J Infect Dis 1999; 179:9.

26. Jung BF, Johnson RW, Griffin DR, Dworkin RH. Risk factors for postherpetic neuralgia
in patients with herpes zoster. Neurology 2004; 62:1545.
27. Forbes HJ, Bhaskaran K, Thomas SL, et al. Quantification of risk factors for
postherpetic neuralgia in herpes zoster patients: A cohort study. Neurology 2016;
87:94.
28. Ragozzino MW, Melton LJ 3rd, Kurland LT, et al. Population-based study of herpes
zoster and its sequelae. Medicine (Baltimore) 1982; 61:310.
29. Balfour HH Jr. Varicella zoster virus infections in immunocompromised hosts. A review
of the natural history and management. Am J Med 1988; 85:68.
30. Drolet M, Brisson M, Schmader K, et al. Predictors of postherpetic neuralgia among

patients with herpes zoster: a prospective study. J Pain 2010; 11:1211.
31. Schott GD. Triggering of delayed-onset postherpetic neuralgia. Lancet 1998; 351:419.
32. Johnson RW, Bouhassira D, Kassianos G, et al. The impact of herpes zoster and post-
herpetic neuralgia on quality-of-life. BMC Med 2010; 8:37.
33. Bowsher D. Pathophysiology of postherpetic neuralgia: towards a rational treatment.

Neurology 1995; 45:S56.
34. Watson CP, Evans RJ, Watt VR, Birkett N. Post-herpetic neuralgia: 208 cases. Pain 1988;
35:289.
35. Drolet M, Brisson M, Schmader KE, et al. The impact of herpes zoster and
postherpetic neuralgia on health-related quality of life: a prospective study. CMAJ
2010; 182:1731.
36. Nalamachu S, Morley-Forster P. Diagnosing and managing postherpetic neuralgia.

Drugs Aging 2012; 29:863.
37. Gilden DH, Wright RR, Schneck SA, et al. Zoster sine herpete, a clinical variant. Ann
Neurol 1994; 35:530.
38. Johnson RW, Rice AS. Clinical practice. Postherpetic neuralgia. N Engl J Med 2014;
371:1526.
39. Liu X, Wei L, Zeng Q, et al. The Treatment of Topical Drugs for Postherpetic Neuralgia:
A Network Meta-Analysis. Pain Physician 2020; 23:541.
40. Hempenstall K, Nurmikko TJ, Johnson RW, et al. Analgesic therapy in postherpetic

neuralgia: a quantitative systematic review. PLoS Med 2005; 2:e164.
41. Edelsberg JS, Lord C, Oster G. Systematic review and meta-analysis of efficacy, safety,
and tolerability data from randomized controlled trials of drugs used to treat
postherpetic neuralgia. Ann Pharmacother 2011; 45:1483.
42. Attal N, Cruccu G, Baron R, et al. EFNS guidelines on the pharmacological treatment of
neuropathic pain: 2010 revision. Eur J Neurol 2010; 17:1113.
43. Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in
adults: a systematic review and meta-analysis. Lancet Neurol 2015; 14:162.
44. Dubinsky RM, Kabbani H, El-Chami Z, et al. Practice parameter: treatment of

postherpetic neuralgia: an evidence-based report of the Quality Standards
Subcommittee of the American Academy of Neurology. Neurology 2004; 63:959.
45. Moore RA, Wiffen PJ, Derry S, McQuay HJ. Gabapentin for chronic neuropathic pain
and fibromyalgia in adults. Cochrane Database Syst Rev 2011; :CD007938.
46. Beydoun A, Uthman BM, Sackellares JC. Gabapentin: pharmacokinetics, efficacy, and
safety. Clin Neuropharmacol 1995; 18:469.
47. Ben-Menachem E. Pregabalin pharmacology and its relevance to clinical practice.

Epilepsia 2004; 45 Suppl 6:13.
48. Moore A, Derry S, Wiffen P. Gabapentin for Chronic Neuropathic Pain. JAMA 2018;
319:818.
49. Wiffen PJ, Derry S, Bell RF, et al. Gabapentin for chronic neuropathic pain in adults.
Cochrane Database Syst Rev 2017; 6:CD007938.
50. Pregabalin (lyrica) for neuropathic pain and epilepsy. Med Lett Drugs Ther 2005;
47:75.
51. Derry S, Bell RF, Straube S, et al. Pregabalin for neuropathic pain in adults. Cochrane
Database Syst Rev 2019; 1:CD007076.
52. Argoff CE. Review of current guidelines on the care of postherpetic neuralgia.
Postgrad Med 2011; 123:134.
53. Chandra K, Shafiq N, Pandhi P, et al. Gabapentin versus nortriptyline in post-herpetic

neuralgia patients: a randomized, double-blind clinical trial--the GONIP Trial. Int J Clin
Pharmacol Ther 2006; 44:358.

54. Dubner R, Bennett GJ. Spinal and trigeminal mechanisms of nociception. Annu Rev
Neurosci 1983; 6:381.
55. Basbaum AI, Fields HL. Endogenous pain control mechanisms: review and hypothesis.
Ann Neurol 1978; 4:451.
56. By the American Geriatrics Society 2015 Beers Criteria Update Expert Panel. American
Geriatrics Society 2015 Updated Beers Criteria for Potentially Inappropriate
Medication Use in Older Adults. J Am Geriatr Soc 2015; 63:2227.
57. Max MB, Schafer SC, Culnane M, et al. Amitriptyline, but not lorazepam, relieves
postherpetic neuralgia. Neurology 1988; 38:1427.
58. Watson CP, Evans RJ, Reed K, et al. Amitriptyline versus placebo in postherpetic
neuralgia. Neurology 1982; 32:671.
59. Watson CP, Vernich L, Chipman M, Reed K. Nortriptyline versus amitriptyline in

postherpetic neuralgia: a randomized trial. Neurology 1998; 51:1166.
60. DasGupta K. Treatment of depression in elderly patients: recent advances. Arch Fam
Med 1998; 7:274.
61. Kishore-Kumar R, Max MB, Schafer SC, et al. Desipramine relieves postherpetic
neuralgia. Clin Pharmacol Ther 1990; 47:305.
62. Hearn L, Moore RA, Derry S, et al. Desipramine for neuropathic pain in adults.
Cochrane Database Syst Rev 2014; :CD011003.
63. Backonja M, Wallace MS, Blonsky ER, et al. NGX-4010, a high-concentration capsaicin
patch, for the treatment of postherpetic neuralgia: a randomised, double-blind study.
Lancet Neurol 2008; 7:1106.
64. Watson CP, Tyler KL, Bickers DR, et al. A randomized vehicle-controlled trial of topical
capsaicin in the treatment of postherpetic neuralgia. Clin Ther 1993; 15:510.
65. Derry S, Rice AS, Cole P, et al. Topical capsaicin (high concentration) for chronic
neuropathic pain in adults. Cochrane Database Syst Rev 2017; 1:CD007393.
66. Wolff RF, Bala MM, Westwood M, et al. 5% lidocaine-medicated plaster vs other
relevant interventions and placebo for post-herpetic neuralgia (PHN): a systematic
review. Acta Neurol Scand 2011; 123:295.
67. Derry S, Wiffen PJ, Moore RA, Quinlan J. Topical lidocaine for neuropathic pain in
adults. Cochrane Database Syst Rev 2014; :CD010958.

68. Kochar DK, Garg P, Bumb RA, et al. Divalproex sodium in the management of post-
herpetic neuralgia: a randomized double-blind placebo-controlled study. QJM 2005;
98:29.
69. Aiyer R, Mehta N, Gungor S, Gulati A. A Systematic Review of NMDA Receptor

Antagonists for Treatment of Neuropathic Pain in Clinical Practice. Clin J Pain 2018;
34:450.
70. Wiffen PJ, Derry S, Moore RA, Kalso EA. Carbamazepine for chronic neuropathic pain
and fibromyalgia in adults. Cochrane Database Syst Rev 2014; :CD005451.
71. Bennetto L, Patel NK, Fuller G. Trigeminal neuralgia and its management. BMJ 2007;
334:201.
72. Hossain SM, Hussain SM, Ekram AR. Duloxetine in Painful Diabetic Neuropathy: A
Systematic Review. Clin J Pain 2016; 32:1005.
73. Rowbotham MC, Goli V, Kunz NR, Lei D. Venlafaxine extended release in the treatment
of painful diabetic neuropathy: a double-blind, placebo-controlled study. Pain 2004;
110:697.
74. Gallagher HC, Gallagher RM, Butler M, et al. Venlafaxine for neuropathic pain in
adults. Cochrane Database Syst Rev 2015; :CD011091.
75. Max MB, Schafer SC, Culnane M, et al. Association of pain relief with drug side effects
in postherpetic neuralgia: a single-dose study of clonidine, codeine, ibuprofen, and
placebo. Clin Pharmacol Ther 1988; 43:363.
76. Rowbotham MC, Reisner-Keller LA, Fields HL. Both intravenous lidocaine and
morphine reduce the pain of postherpetic neuralgia. Neurology 1991; 41:1024.
77. Raja SN, Haythornthwaite JA, Pappagallo M, et al. Opioids versus antidepressants in
postherpetic neuralgia: a randomized, placebo-controlled trial. Neurology 2002;
59:1015.
78. Boureau F, Legallicier P, Kabir-Ahmadi M. Tramadol in post-herpetic neuralgia: a

randomized, double-blind, placebo-controlled trial. Pain 2003; 104:323.
79. Watson CP, Babul N. Efficacy of oxycodone in neuropathic pain: a randomized trial in
postherpetic neuralgia. Neurology 1998; 50:1837.
80. Harden RN, Kaye AD, Kintanar T, Argoff CE. Evidence-based guidance for the
management of postherpetic neuralgia in primary care. Postgrad Med 2013; 125:191.

81. McNicol ED, Midbari A, Eisenberg E. Opioids for neuropathic pain. Cochrane Database
Syst Rev 2013; :CD006146.
82. Kotani N, Kushikata T, Hashimoto H, et al. Intrathecal methylprednisolone for

intractable postherpetic neuralgia. N Engl J Med 2000; 343:1514.
83. Nelson DA. Intraspinal therapy using methylprednisolone acetate. Twenty-three years
of clinical controversy. Spine (Phila Pa 1976) 1993; 18:278.
84. Nelson DA, Landau WM. Intraspinal steroids: history, efficacy, accidentality, and
controversy with review of United States Food and Drug Administration reports. J
Neurol Neurosurg Psychiatry 2001; 70:433.
85. Kikuchi A, Kotani N, Sato T, et al. Comparative therapeutic evaluation of intrathecal

versus epidural methylprednisolone for long-term analgesia in patients with
intractable postherpetic neuralgia. Reg Anesth Pain Med 1999; 24:287.
86. Rijsdijk M, van Wijck AJ, Meulenhoff PC, et al. No beneficial effect of intrathecal
methylprednisolone acetate in postherpetic neuralgia patients. Eur J Pain 2013;
17:714.
87. Apalla Z, Sotiriou E, Lallas A, et al. Botulinum toxin A in postherpetic neuralgia: a

parallel, randomized, double-blind, single-dose, placebo-controlled trial. Clin J Pain
2013; 29:857.
88. Xiao L, Mackey S, Hui H, et al. Subcutaneous injection of botulinum toxin a is

beneficial in postherpetic neuralgia. Pain Med 2010; 11:1827.
89. Hu Y, Zou L, Qi X, et al. Subcutaneous botulinum toxin-A injection for treating

postherpetic neuralgia. Dermatol Ther 2020; 33:e13181.
90. Jain P, Jain M, Jain S. Subcutaneous Injection of Botulinum Toxin in Patients with Post
Herpetic Neuralgia. A Preliminary Study. J Assoc Physicians India 2018; 66:48.
91. Klein AW. Complications, adverse reactions, and insights with the use of botulinum
toxin. Dermatol Surg 2003; 29:549.
92. Naumann M, Jankovic J. Safety of botulinum toxin type A: a systematic review and
meta-analysis. Curr Med Res Opin 2004; 20:981.
93. Rodrigues FB, Duarte GS, Marques RE, et al. Botulinum toxin type A therapy for
cervical dystonia. Cochrane Database Syst Rev 2020; 11:CD003633.
94. Lin CS, Lin YC, Lao HC, Chen CC. Interventional Treatments for Postherpetic Neuralgia:

A Systematic Review. Pain Physician 2019; 22:209.
95. Borghi A, Rimessi A, Minghetti S, et al. Efficacy of magnesium chloride in the

treatment of Hailey-Hailey disease: from serendipity to evidence of its effect on
intracellular Ca(2+) homeostasis. Int J Dermatol 2015; 54:543.
96. Ke M, Yinghui F, Yi J, et al. Efficacy of pulsed radiofrequency in the treatment of

thoracic postherpetic neuralgia from the angulus costae: a randomized, double-
blinded, controlled trial. Pain Physician 2013; 16:15.
97. Saxena AK, Lakshman K, Sharma T, et al. Modulation of serum BDNF levels in
postherpetic neuralgia following pulsed radiofrequency of intercostal nerve and
pregabalin. Pain Manag 2016; 6:217.
98. Pi ZB, Lin H, He GD, et al. Randomized and controlled prospective trials of Ultrasound-
guided spinal nerve posterior ramus pulsed radiofrequency treatment for lower back
post-herpetic neuralgia. Clin Ter 2015; 166:e301.
99. Makharita MY, El Bendary HM, Sonbul ZM, et al. Ultrasound-guided Pulsed
Radiofrequency in the Management of Thoracic Postherpetic Neuralgia: A
Randomized, Double-blinded, Controlled Trial. Clin J Pain 2018; 34:1017.
100. Ding Y, Li H, Hong T, Yao P. Efficacy of Pulsed Radiofrequency to Cervical Nerve Root
for Postherpetic Neuralgia in Upper Extremity. Front Neurosci 2020; 14:377.
101. Yanamoto F, Murakawa K. The effects of temporary spinal cord stimulation (or spinal
nerve root stimulation) on the management of early postherpetic neuralgia from one
to six months of its onset. Neuromodulation 2012; 15:151.
102. Naja ZM, Maaliki H, Al-Tannir MA, et al. Repetitive paravertebral nerve block using a
catheter technique for pain relief in post-herpetic neuralgia. Br J Anaesth 2006;
96:381.
103. Kurklinsky S, Palmer SC, Arroliga MJ, Ghazi SM. Neuromodulation in Postherpetic
Neuralgia: Case Reports and Review of the Literature. Pain Med 2018; 19:1237.
104. Zhu X, Hu P, Fan Z, et al. Effects of Mindfulness-Based Stress Reduction on

Depression, Anxiety, and Pain in Patients With Postherpetic Neuralgia. J Nerv Ment Dis
2019; 207:482.
105. Meize-Grochowski R, Shuster G, Boursaw B, et al. Mindfulness meditation in older

adults with postherpetic neuralgia: a randomized controlled pilot study. Geriatr Nurs
2015; 36:154.

106. Saxena AK, Bhardwaj N, Chilkoti GT, et al. Modulation of mRNA Expression of IL-6 and
mTORC1 and Efficacy and Feasibility of an Integrated Approach Encompassing
Cognitive Behavioral Therapy Along with Pregabalin for Management of Neuropathic
Pain in Postherpetic Neuralgia: A Pilot Study. Pain Med 2021; 22:2276.
107. Wu LJ, Zhuo M. Targeting the NMDA receptor subunit NR2B for the treatment of
neuropathic pain. Neurotherapeutics 2009; 6:693.
108. Chizh BA, Headley PM. NMDA antagonists and neuropathic pain--multiple drug
targets and multiple uses. Curr Pharm Des 2005; 11:2977.
109. Kristensen JD, Svensson B, Gordh T Jr. The NMDA-receptor antagonist CPP abolishes
neurogenic 'wind-up pain' after intrathecal administration in humans. Pain 1992;
51:249.
110. Eide PK, Jørum E, Stubhaug A, et al. Relief of post-herpetic neuralgia with the N-
methyl-D-aspartic acid receptor antagonist ketamine: a double-blind, cross-over
comparison with morphine and placebo. Pain 1994; 58:347.
111. Nelson KA, Park KM, Robinovitz E, et al. High-dose oral dextromethorphan versus
placebo in painful diabetic neuropathy and postherpetic neuralgia. Neurology 1997;
48:1212.
112. Moulin DE, Morley-Forster PK, Pirani Z, et al. Intravenous lidocaine in the
management of chronic peripheral neuropathic pain: a randomized-controlled trial.
Can J Anaesth 2019; 66:820.
113. Baranowski AP, De Courcey J, Bonello E. A trial of intravenous lidocaine on the pain
and allodynia of postherpetic neuralgia. J Pain Symptom Manage 1999; 17:429.
114. Kim YC, Castañeda AM, Lee CS, et al. Efficacy and Safety of Lidocaine Infusion
Treatment for Neuropathic Pain: A Randomized, Double-Blind, and Placebo-Controlled
Study. Reg Anesth Pain Med 2018; 43:415.
115. Liu H, Lu F, Zhou D, et al. The Analgesic and Emotional Response to Intravenous
Lidocaine Infusion in the Treatment of Postherpetic Neuralgia: A Randomized,
Double-Blinded, Placebo-controlled Study. Clin J Pain 2018; 34:1025.
116. Tan X, Ma L, Yuan J, et al. Intravenous infusion of lidocaine enhances the efficacy of
conventional treatment of postherpetic neuralgia. J Pain Res 2019; 12:2537.
117. Barnard D, Lloyd J, Evans J. Cryoanalgesia in the management of chronic facial pain. J
Maxillofac Surg 1981; 9:101.

118. Jones MJ, Murrin KR. Intercostal block with cryotherapy. Ann R Coll Surg Engl 1987;
69:261.
119. Texakalidis P, Tora MS, Boulis NM. Neurosurgeons' Armamentarium for the
Management of Refractory Postherpetic Neuralgia: A Systematic Literature Review.
Stereotact Funct Neurosurg 2019; 97:55.
120. Vo T, Rice AS, Dworkin RH. Non-steroidal anti-inflammatory drugs for neuropathic
pain: how do we explain continued widespread use? Pain 2009; 143:169.
121. Pica F, Gatti A, Divizia M, et al. One-year follow-up of patients with long-lasting post-
herpetic neuralgia. BMC Infect Dis 2014; 14:556.
122. McKendrick MW, Ogan P, Care CC. A 9 year follow up of post herpetic neuralgia and
predisposing factors in elderly patients following herpes zoster. J Infect 2009; 59:416.
123. Oster G, Harding G, Dukes E, et al. Pain, medication use, and health-related quality of
life in older persons with postherpetic neuralgia: results from a population-based
survey. J Pain 2005; 6:356.
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05/09/2023, 08:23 Neuralgia pós-herpética - UpToDate

Revisão da literatura atualizada até: agosto de 2023.

O vírus varicela-zoster (VZV) é o agente causador da varicela, ou "catapora", e do herpes

A patogênese, epidemiologia, características clínicas, diagnóstico e tratamento da NPH são

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Existem três fases de dor associadas ao herpes zoster [ 13-15 ]:

● Acute herpetic neuralgia refers to pain preceding or accompanying the eruption of

A search for responsible neurotransmitters in PHN has been difficult. Substance P is a

EPIDEMIOLOGY AND RISK FACTORS

The major risk factors for PHN are [23-27]:

● Age >60 years

Diagnosis — The diagnosis of PHN is made when localized neuropathic pain persists

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● Age >60 years

Differential diagnosis — The diagnosis is based on the clinical presentation and is

Other causes of focal, persistent neuropathic pain include:

● Trigeminal neuropathy – Patients with trigeminal neuropathy (ie, anesthesia

● Other forms of craniofacial pain – Craniofacial pain syndromes involving nerve

● Diabetic amyotrophy and idiopathic lumbosacral radiculoplexus neuropathy –

● Recurrent acute herpes zoster – Neuropathic pain may be prolonged in patients

Initial therapies — Both gabapentinoids (ie, gabapentin and pregabalin) and tricyclic

● Gabapentin − Gabapentin is typically started at a low dose to minimize the risk of

The extended-release formulation of gabapentin is titrated according to the same

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formulations, and use of the extended-release formulation is not recommended in

There is moderate-quality evidence supporting the efficacy of gabapentin for PHN,

Gabapentin is generally well tolerated. In a pooled analysis of adverse effects

● Pregabalin − The immediate-release formulation of pregabalin is given two or three

• 75 mg twice daily for one week, then

An extended-release preparation is also available for once-daily dosing. The titration

Tricyclic antidepressants if gabapentinoids ineffective or not tolerated — For patients

● Amitriptyline is started at 10 mg each night. The dose may be uptitrated as needed

● Nortriptyline is typically started at 10 mg each night and increased by 10 to 20 mg

● Desipramine is typically started at 25 mg each night and increased by 25 mg each

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● Capsaicin – Capsaicin is formulated as a cream, gel, lotion, or a high-concentration

• High-concentration capsaicin patches are administered as a single 60-minute

Limited data suggest that topical application of standard-concentration capsaicin is

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Alternative therapies — For patients who do not tolerate or are unresponsive to initial

Antiseizure medications — A trial of one of a (non-gabapentinoid) anticonvulsant agent

● Valproic acid 500 to 1000 mg daily

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In an eight-week trial of 48 patients with PHN, patients assigned to divalproex sodium

Serotonin-norepinephrine reuptake inhibitors — Serotonin-norepinephrine reuptake

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Adjunctive options — For patients with symptoms refractory to prior therapies, adjunctive

Neuraxial glucocorticoid infusion — Intrathecal glucocorticoid injections may be

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Intrathecal administration of methylprednisolone was found more effective than

Therapies for refractory symptoms — We reserve other interventional and surgical

Botulinum toxin injections should be performed by a clinician experienced with this

Neuromodulation and nerve stimulation — Invasive neuromodulatory strategies such

● Transcutaneous electrical nerve stimulation (TENS) [95]

These techniques been reported to be effective in approximately half of patients in case

Therapies of uncertain or limited benefit

● Intravenous lidocaine – Small trials have failed to find sustained benefit of

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● Surgical ablation and other interventional procedures – Cryotherapy is an ablation

Surgical interventions including central electrical stimulation of the thalamus,

● Simple analgesics – Analgesic medications such as aspirin or other nonsteroidal anti-

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