Post-herpetic neuralgia - [PDF Document] (2024)

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International Journal of General Medicine 2012:5 861–871

International Journal of General Medicine

Post-herpetic neuralgia

Monica Tontodonati1,*Tamara Ursini1,*Ennio Polilli2

Francesco Vadini3

Francesco Di Masi4

Damiano Volpone5

Giustino Parruti4

1Infectious Disease Clinic, Chieti, 2Microbiology and Virology Unit, Pescara General Hospital, Pescara, 3Psycho-Infectivology Unit, Pescara General Hospital, Pescara, 4Infectious Disease Unit, Pescara General Hospital, Pescara, Italy; 5Local Health District, Pescara, Italy

*These authors contributed equally to this work

Correspondence: Giustino Parruti Via Fonte Romana 8, Pescara 65124, Italy Mobile +39 32 7541 4170 Email [emailprotected]

Background: In spite of the large body of evidence available in the literature, definition

and treatment of Post-Herpetic Neuralgia (PHN) are still lacking a consistent and universally

recognized standardization. Furthermore, many issues concerning diagnosis, prediction and

prevention of PHN need to be clarified in view of recent contributions.

Objectives: To assess whether PHN may be better defined, predicted, treated and prevented

in light of recent data, and whether available alternative or adjunctive therapies may improve

pain relief in treatment recalcitrant PHN.

Methods: Systematic reviews, meta-analyses, randomized controlled trials, cohort studies and

protocols were searched; the search sources included PubMed, Cochrane Library, NICE, and

DARE. More than 130 papers were selected and evaluated.

Results: Diagnosis of PHN is essentially clinical, but it can be improved by resorting to the

many tools available, including some practical and accessible questionnaires. Prediction of

PHN can be now much more accurate, taking into consideration a few well validated clinical

and anamnestic variables. Treatment of PHN is presently based on a well characterized array

of drugs and drug associations, including, among others, tricyclic antidepressants, gabapenti-

noids, opioids and many topical formulations. It is still unsatisfactory, however, in a substantial

proportion of patients, especially those with many comorbidities and intense pain at herpes

zoster (HZ) presentation, so that this frequent complication of HZ still strongly impacts on the

quality of life of affected patients.

Conclusion: Further efforts are needed to improve the management of PHN. Potentially rel-

evant interventions may include early antiviral therapy of acute HZ, prevention of HZ by adult

vaccination, as well as new therapeutic approaches for patients experiencing PHN.

Keywords: pain relief, PHN treatment, PHN predictors, PHN prevention

IntroductionDefinition and clinical presentationHerpes zoster (HZ) is a self-limiting disease, with pain quenching at the end of vesicular

eruption. In a significant proportion of patients, however, pain can persist or relapse

months to years after rash healing, being then referred to as post-herpetic neuralgia

(PHN). Pain in PHN is described as burning, throbbing, lancinating, or electric- shock-

like, and intermittent or continuous. PHN is sometimes associated with allodynia or

hyperesthesia, spreading at the same dermatome(s) as in HZ.

The definition of PHN has been a matter of discussion for a long time, being

defined at different time intervals after rash healing in HZ. PHN has been defined as

pain persisting or resuming 4, 6, 8, 12 weeks, or even 6 months after rash healing.1–12

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At the end of the 1990s, Dworkin and Portenoy1 proposed a

definition that was widely accepted: they set the diagnosis

of PHN at 3 months after rash healing, referring to pain

persisting at earlier time points as zoster-associated pain

(ZAP). More recently, this definition has been revised, with

a further distinction:2,3,6 pain present within 30 days from the

onset of rash is defined as acute herpetic neuralgia; pain pres-

ent between 30 and 120 days is defined as subacute herpetic

neuralgia; pain persisting after 120 days from the onset of HZ

is defined as PHN. Moreover, other authors introduced the

concept that only clinically relevant pain should be defined as

PHN, to avoid overestimation of the problem: they proposed

PHN to be defined as pain $3 on a 10-point scale persisting

120 days after rash healing.4,5,7

Different tools have been assessed to quantify and

qualify pain in PHN. Verbal rating scales are easy to handle

in real clinical settings, but have limited value to stratify

and characterize pain. Visual analog scales (VASs) have

been extensively investigated and used in various settings

of pain clinical management,4,13 allowing a more precise

identification of the single patient’s pain level, and being

easily understood by patients. Furthermore, PHN has been

considered in recent years as a continuum rather than a parti-

tion of herpetic pain and total pain burden measured with a

single comprehensive parameter by Coplan et al,5 who used

an area-under-the-curve (AUC) method to combine measures

of HZ pain intensity and duration. AUC highly correlated

with other pain, quality of life, and activities of daily living

validated questionnaires.7

The AUC method was similarly adopted by other authors

with subtle variations.12,14 A recent Italian prospective study

used verbal rating pain scores instead of worst pain scores.12

Drolet et al14 considered only pain relevantly affecting quality

of life and activities of daily living, that is pain scored $ 3

on a 0–10 scale. All these attempts ushered a potentially

relevant tool to better estimate the impact of HZ and PHN

in real life, and to thoroughly assess the cost-efficacy of

vaccination for HZ.

Diagnosis of PHN is essentially clinical. VAS and

the McGill Pain Questionnaire, as structured diagnostic

tools, are useful and validated to quantify and qualify the

patient reported pain. Thorough investigation of other pos-

sible underlining causes of neuralgia (eg, neoplastic, toxic,

traumatic, and compressive) should be carried out when

appropriate. Further structured tools have been developed in

recent years: the McGill Pain Questionnaire in its short form15

was widely used for pain evaluation in a consistent fraction

of more recent studies.4,16,17 Zoster Brief Pain Inventory

(ZBPI) is the more specific tool designed specifically for

HZ pain:5 it includes discomfort other than pain, such as

itching, occurring in the same area as HZ rash. It measures

the severity of pain (current, least, and worst) in the last

24 hours on a 0–10 scale, together with HZ pain interference

with various activities of daily life. This tool was shown to

have good validity in the context of ZAP and PHN.5,7 The

lack of a consistent definition of PHN, however, may still

hamper a proper management of PHN. In view of the recent

literature, proper definition of PHN should refer to relaps-

ing or long-lasting herpetic pain at least 3 months after HZ.

Quantification of patient-reported pain, furthermore, may be

ill-defined without appropriate tools.

EtiologyThe understanding of the pathophysiological mechanisms

underlying the onset of chronic pain in PHN is still an open

challenge. The initial viral replication causes direct damage

by neuritic inflammation on the rear dorsal root, resulting in

necrosis, fibrosis, and destruction of nerve tissue from periph-

eral afferent fibers to the spinal cord.18,19 Several studies have

documented atrophy of the posterior horn in the spinal cord,

fibrosis of the posterior root ganglia, and loss of cutaneous

innervation, with pathological degeneration of cell bodies and

axons of primary afferent neurons,20 determining hypoesthesia

and pallestesia in association with pain. However, the precise

mechanism(s) at the basis of pain in PHN remain unclear, and

attempts to draw a single unifying theory are inconclusive.

The pathophysiology of PHN may involve both peripheral and

central mechanisms, such as gate control, viewing PHN as a

chronic pain syndrome due to deafferentation,21 or strength-

ening of existing synaptic connections between central pain

pathways and peripheral Aβ fibers.22 However, several stud-

ies have revealed interesting aspects about central nervous

system (CNS) support cells and structures, evaluating the

role of the immune system in the pathogenesis of PHN, as

glia cells (astrocytes and oligodendrocytes) and their recep-

tors produce factors influencing neuronal functioning.23,24

Damage of myelinated fibers would activate Schwann cells

and satellite cells, in turn releasing neuro-excitatory mediators

such as tumor necrosis factor-α.25,26 Other support structures

putatively involved in the pathogenesis of chronic pain are

vasa nervorum and nervi nervorum.27–29 The hypothesis that

the activation of trophic and support structures of peripheral

nerves would play an important pathogenic role in PHN

may have important therapeutic implications.19 Another

hypothesis by Gilden et al30 suggests the potential role of

persistent varicella-zoster virus (VZV) replication and chronic

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Tontodonati et al

International Journal of General Medicine 2012:5

ganglionitis resulting in PHN. A Chinese work published in

2009 analyzed the relationship between pro-inflammatory

cytokines in acute HZ and the development of PHN, show-

ing that patients with PHN had higher interleukin-6 serum

levels.28,31 The role of calcitonin gene-related peptide (CGRP)

in triggering chronic pain conditions has also been recently

explored.32 The differential expression and regulation of

CGRP isoforms may be a detectable signal involved in sen-

sory transduction and modulation, as well as in contributing

to chronic pain mechanisms.32

The different hypotheses so far postulated are not mutu-

ally exclusive, and the pathophysiology of chronic pain in

PHN may well be multifactorial. Therefore, further studies

are needed to allow a more comprehensive view of this severe

and disrupting condition and to develop targeted therapies

for PHN.

EconomicsUntil 2006, few published studies addressed the economic

burden of PHN directly (in general together with HZ or

diabetic neuropathy), mostly including costs of medications,

outpatient visits, hospitalization and length of stay, and loss

of working days. Mean costs for estimated PHN episodes per

year in Italy were as high as EUR 33.7 million.33

MethodsSystematic reviews, meta-analyses, randomized controlled

trials (RCTs), cohort studies and protocols were searched

and the search sources include PubMed, Cochrane Library,

NICE, and DARE. Articles were searched using the fol-

lowing key words: “post herpetic neuralgia”, “post herpetic

neuralgia treatment”, “post herpetic neuralgia predictors”,

“post herpetic neuralgia etiology”, “neuropathic pain”,

“neuropathic pain assessment”, wherever occurring in the

text. Among the many papers retrieved, approximately 120

were selected and quoted.

ResultsPrediction of PHNNo systematic reviews, meta-analyses, or RCTs had evidence

pertaining to the prediction of PHN. However, 14 cohort

studies did.6,8–12,34–41

Predictors of PHN in the acute phase of HZ have been

extensively investigated in order to point out patients who are

at higher risk of developing this painful syndrome and need

to be monitored more carefully during follow-up.

Older age is one factor associated with PHN in almost

all studies, whenever investigated.6,8–12,34–38 Central and

peripheral nervous systems in the elderly may less efficiently

tolerate the damage associated with VZV reactivation and the

consequent burst of immune response (see Table 1).42

Pain at presentation is the second best-established risk

factor for PHN (see Table 1). Trials on antiviral therapy for

HZ suggested the importance of pain intensity at presentation

in predicting PHN;35,39 several cohort studies have confirmed

these data in real life6,9–12,36,38,40 (see Table 1). The pathogen-

esis of this correlation is still unclear: the intensity of acute

pain may reflect central structural and functional processes,

such as excitotoxic damage in the dorsal horn, and damage

to primary afferent nociceptors.43

Severity of rash, assessed as the number of lesions

appearing on the patients’ skin at presentation, suggests a

relationship between the extent of neural damage and PHN

(see Table 1).6,10,35,37–39,41

The presence and duration of symptoms prodromal to HZ

rash (pain, dysesthesia, and allodynia) have been reported

as tightly predictive of PHN in several studies:6,36,40,44 This

association may reflect a more intense involvement of nerve

fibers by viral reactivation in the early phases of HZ, leading

to extended damage and PHN.45

In a few reports, PHN has been reported as more frequent

in ophthalmic and thoracic zoster patients,10 suggesting a

predictive role of HZ localization. Higher levels of VZV

DNA at HZ presentation were also suggested as an inde-

pendent predictor of pain persistence.9 Surgical interven-

tions and mechanical trauma were associated with a higher

risk of HZ, but their possible role in predicting PHN has

been poorly investigated. In a recent prospective survey on

519 HZ patients,12 trauma was associated with a higher risk of

PHN (see Table 1). Furthermore, cigarette smoking has been

scantly evaluated as a possible risk factor for pain intensity

at presentation of PHN. In the same survey,12 smoke was

associated with both higher pain at presentation and higher

risk of PHN.

Psychosocial factors have been proposed to be associ-

ated both with a higher ZAP burden and higher risk of PHN.

Depression, together with the severity of HZ disease at

presentation, was associated with higher pain intensity and

ZAP burden.44 In a small prospective study,46 greater anxiety,

greater depression, lower life satisfaction, and greater disease

conviction were predictors at baseline for chronic zoster pain.

Hence, psychological factors may be useful in evaluating

patients with HZ.

Finally, female sex has been proposed as a predictor

of PHN, not yet reaching, however, a convincing level of

evidence so far.6,10,12

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Prediction, prevention, and treatment of PHN

International Journal of General Medicine 2012:5

Tab

le 1

Pre

dict

ors

of P

HN

in t

rial

s an

d co

hort

stu

dies

quo

ted

to t

his

purp

ose

Stud

yP

atie

nts

Stud

y

desi

gnP

HN

defi

niti

onO

lder

ag

eFe

mal

e

sex

Gre

ater

ac

ute

pain

se

veri

ty

Gre

ater

ra

sh

seve

rity

No

anti

vira

l th

erap

y

for

HZ

Pre

senc

e

of a

pr

odro

me

HZ

OD

epre

s-si

onD

urat

ion

of

prod

rom

eV

ZV

vi

rem

ia a

t pr

esen

tati

on

Oth

ers

Cho

o

et a

l 34

821

H

Z –

PH

N n

dR

etro

spec

tive

Pain

per

sist

ing

1 an

d 2

mon

ths

af

ter

rash

ons

et

XX

Dw

orki

n

et a

l35

419

H

Z –

129

(nd

) PH

N

Fam

cicl

ovir

tri

alPa

in fo

llow

ing

rash

hea

ling,

1

(and

3)

mon

ths

afte

r

HZ

dia

gnos

is

XX

XX

a

whi

tley

et

al39

ndA

cycl

ovir

and

pr

edni

sone

tri

alT

ime

to c

essa

tion

of a

cute

ne

uriti

s an

d Z

AP

(Cox

)X

X

Dec

roix

et

al36

1897

H

Z –

PH

N n

dO

pen-

labe

l va

lacy

clov

ir

stud

y

Tim

e to

ces

satio

n

of Z

AP

(Cox

)X

XX

X

Ops

telte

n

et a

l8

837

H

Z –

54

PHN

Ret

rosp

ectiv

ePa

in 1

mon

th a

fter

H

Z d

iagn

osis

XX

Nag

asak

o

et a

l41

1778

H

Z –

PH

N n

dFo

ur fa

mci

clov

ir

tria

lsPa

in p

rese

nt 3

mon

ths

af

ter

rash

ons

etX

Kur

okaw

a

et a

l37

263

H

Z –

PH

N n

dPr

ospe

ctiv

ePa

in p

ersi

stin

g 3–

6 m

onth

s

afte

r H

Z d

iagn

osis

XX

Dist

urbe

d sle

ep,

hypa

nest

hesia

Scot

t

et a

l9

278

H

Z –

42

(78)

PH

N

Pros

pect

ive

Pain

pre

sent

at

6 w

eeks

(a

nd 3

mon

ths)

afte

r H

Z

diag

nosi

s

XX

X

Jung

et

al6

965

H

Z –

114

PH

NT

wo

fam

cicl

ovir

tr

ials

Pain

per

sist

ing

120

days

af

ter

rash

ons

etX

XX

XX

Kat

z

et a

l40

129

H

Z –

20

PHN

Pros

pect

ive

Pain

120

day

s af

ter

ra

sh o

nset

XX

X

Ops

telte

n

et a

l38

598

H

Z –

46

PHN

Pros

pect

ive

(in

the

PIN

E st

udy)

Pain

$ 3

0 V

AS

3 m

onth

s

afte

r H

Z d

iagn

osis

XX

XT

rust

in h

ealth

ca

re

Vol

pi

et a

l10

219

H

Z –

70

PHN

Pros

pect

ive

Pain

pre

sent

6 m

onth

s af

ter

H

Z d

iagn

osis

XX

XX

X

Parr

uti

et a

l12

519

HZ

– 2

26

(130

) PH

NPr

ospe

ctiv

ePa

in p

ersi

stin

g/re

laps

ing

1 (a

nd 3

) m

onth

s af

ter

HZ

dia

gnos

is

XX

Xb

Tra

uma,

sm

oke

Dro

let

et

al11

249

HZ

– 5

6 PH

NPr

ospe

ctiv

ePa

in $

3/1

0 V

AS

pers

istin

g

3 m

onth

s af

ter

HZ

dia

gnos

isX

XLi

mite

d fu

nctio

nal s

tatu

s

Not

es: a P

atie

nts

rece

ivin

g an

tivir

al t

hera

py (

fam

cicl

ovir

ver

sus

plac

ebo)

had

a s

igni

fican

tly lo

wer

pre

vale

nce

of P

HN

; b the

re w

as a

hig

her

perc

enta

ge o

f pat

ient

s de

velo

ping

PH

N a

mon

g th

ose

who

did

not

rec

eive

(an

y) a

ntiv

iral

the

rapy

.A

bbre

viat

ions

: HZ

, her

pes

zost

er; H

ZO

, her

pes

zost

er o

phth

alm

ic; n

d, n

ot d

ecla

red;

PH

N, p

ost-

herp

etic

neu

ralg

ia; P

INE,

Pre

vent

ion

by E

pidu

ral I

njec

tion

of P

osth

erpe

tic N

eura

lgia

in t

he E

lder

ly; V

AS,

vis

ual a

nalo

g sc

ale;

VZ

V, v

aric

ella

-zo

ster

vir

us; Z

AP,

zos

ter-

asso

ciat

ed p

ain.

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Tontodonati et al

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Prevention of PHNFive systematic reviews, 47–51 three RCTs7,35,52 and one cohort

study12 contained evidence pertaining to the prevention of

PHN; no meta-analyses did.

A potential role in prevention has been proposed for

antivirals, according to the hypothesis that interrupting viral

replication in the acute phase of HZ may reduce damage to

nerve fibers and subsequent onset of PHN. Their role in PHN

prevention, however, is still controversial: a recent Cochrane

review47 raises some doubts about their efficacy. In spite of

that, studies with different designs suggest different conclu-

sions. Vander Straten et al48 suggested that antivirals in the

acute phase of HZ appear to be effective in reducing PHN

severity and duration, but not its incidence. Dworkin et al35

found that patients receiving antiviral therapy (famciclovir

versus placebo) had a significantly lower prevalence of PHN

in a cohort study of 419 HZ patients. Parruti et al12 showed

that HZ patients not prescribed antivirals in the acute phase

have a significantly higher risk of developing PHN, in a pro-

spective cohort of 519 HZ unselected patients in a real-life

clinical setting (see Table 1).

Corticosteroids prescribed in the acute phase of HZ

have been shown to be ineffective in preventing PHN onset

in several trials and in a recent review,49 as well as antide-

pressants.50 As greater acute pain severity predisposes to

higher risk of PHN onset, pain relief in acute HZ has been

investigated as to its possible preventive role. Interventional

techniques, such as topical local anesthetics, subcutaneous

local anesthetics and corticosteroids, percutaneous electrical

nerve stimulation, and sympathetic and epidural blocks, have

been proposed as prevention. They can produce an effective

short-term pain relief in the acute phase, thus reducing the

pain burden in this time frame, but their effect in reducing

PHN remains unclear.51

The latest hypothesis investigated in the field of preven-

tive pain relief in acute HZ is the combination of antivirals

and gabapentin. In a recent study,52 133 consecutive patients

with acute HZ were enrolled in a private dermatology clinic

and treated with valacyclovir and gabapentin at currently

recommended dosages, with a lower incidence of PHN at

6 months.

In 1995, vaccination for varicella with a wild-type VZV

Oka strain was introduced under a Food and Drug Admin-

istration (FDA) recommendation, and at present, universal

coverage vaccination programs are ongoing in the USA and

several other countries. Varicella vaccine at higher dosage

(at least 14 times) than in standard Varicella vaccination

was demonstrated to be protective for the development of

HZ in the Shingles Prevention Study.7 This was a random-

ized double-blind placebo-controlled trial including 38,546

healthy subjects aged over 60 years, randomly assigned

to receive a mock vaccine or an investigational anti-VZV

vaccine, and followed for 3.13 years on average after vac-

cination. The incidence of HZ was significantly reduced,

from 11.1 per 1000 person-years in the placebo arm to 5.4

per 1000 person-years in the vaccine arm.7 The incidence of

PHN, defined as pain $ 30/100 at 90 days from the onset

of rash, was similarly markedly reduced in the vaccine arm,

from 1.38 to 0.46 per 1000 person-years. Moreover, vac-

cinated subjects developing HZ and PHN had significantly

less pain and discomfort.5,7 Therefore, zoster vaccination

reduced overall HZ and PHN incidence by 51.3% and 66.5%,

respectively in this large, pivotal study.7

Since HZ vaccine approval by the FDA for adults

aged . 60 in the United States in 2006, the real cost-

effectiveness of HZ vaccination for the general population

has been widely investigated. Several studies have assessed

the economic burden of HZ and PHN, showing that they are

frequent and costly conditions, also in terms of impact on

quality of life.33,53–57 In Italy, a recent study estimated that

total annual costs for HZ and PHN were EUR 41.2 million,

including both direct and indirect costs.33 Vaccine cost-

effectiveness was determined by decision models in multiple

large countries (Canada, England and Wales, and USA),

suggesting that immunization would increase quality-

adjusted life-years.58–60 In general, studies evaluating vaccine

cost-effectiveness agree on its relevance in the elderly

population.57,61–65 It has been supposed that vaccination could

be equally cost-effective in younger people aged , 50, as

about 19% of HZ cases occur between 50 and 59 years of

age. Further studies are ongoing to assess this point.

Treatment of PHNNineteen systematic reviews,2,50,66–82 63 RCTs (mostly cited in

the systematic reviews),2,50,66–82 one longitudinal study83 and

one meta-analysis84 showed evidence pertaining to this.

Pain relief in PHN with currently available therapies is

often unsatisfactory. A large body of evidence (see Table 2)

indicates that some pharmacologic agents, including opioids,

tricyclic antidepressants (TCAs), antiepileptic drugs, and

lidocaine patches, may result in at least partial pain relief for

a limited proportion of patients with PHN, and that some of

these patients may find the adverse effects of the above medi-

cations outweigh their benefits.66,67 Fully effective treatment

of PHN are still lacking, as its exact pathophysiological

mechanisms are still elusive. Consequently, it is difficult to

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Prediction, prevention, and treatment of PHN

International Journal of General Medicine 2012:5

establish specifically targeted therapies, a task calling for

further research efforts. Indeed, as this condition does not

adequately respond in many cases to any of the conventional

agents tested, many efforts are ongoing even in the field of

alternative therapeutic options. The management of PHN,

however, is and will be complex, requiring a multidisciplinary

approach, including drug therapy and nonpharmacological

adjunctive therapies.

Several systematic reviews indicate that TCAs are effec-

tive in neuropathic pain and PHN,2,66,68 being superior to selec-

tive serotonin reuptake inhibitors (SSRIs).50,69 No studies so

far have assessed the use of serotonin-noradrenalin reuptake

inhibitors for this condition. It is believed that TCAs have

an analgesic action by blocking the re-uptake of serotonin

and norepinephrine, a blockade enhancing the inhibition of

spinal cord neurons involved in pain perception.85 Among

TCAs, the most commonly used compounds are amitrip-

tyline, nortriptyline, and desipramine.86,87 Nortriptyline and

desipramine are generally preferred to amitriptyline because

they have recently been shown to be equally effective with

a lower incidence of anticholinergic side effects such as

sedation, orthostatic hypotension, cognitive decline, and

constipation.66,70,87,88 Other side effects include weight gain,

blurred vision, and QT prolongation. Such side effects may

be of particular concern in the elderly population and in

patients with a history of cardiac arrhythmia or ischemic

heart disease. Although there is no standard guidance for

electrocardiogram (ECG) screening prior to their administra-

tion, TCAs may cause ECG changes (prolonged QT), and

it may be prudent to obtain a baseline ECG in patients with

cardiac disease.71,89,90

Among anticonvulsants, gabapentin and pregabalin

have established eff icacy in PHN, with several trials

(see Table 2) showing the superiority of gabapentin

versus nortriptyline.66,84,91,92 Several RCTs and a few

meta-analyses have established the analgesic efficacy of

gabapentin for the treatment of pain in PHN. RCTs have

shown that a daily dose of 1800–3600 mg, given for 1–2

weeks, is effective in reducing pain and improving sleep,

mood, and patient quality of life.18,72,93 More recent studies

have shown that a dose of 3600 mg daily can reduce pain

by 43%.2 The main reported side effects are drowsiness,

dizziness, ataxia, mild peripheral edema, and a worsen-

ing of cognitive impairment in elderly patients. To reduce

adverse events and increase compliance, gabapentin

should be initially used at lower doses (100–300 mg in a

single dose at bedtime) and then continued at a dose of

100–300 mg three times a day,73 titrating the analgesic

effect and the occurrence of side effects.18,71 However, the

efficacy of gabapentin in some patients with PHN may be

limited by suboptimal drug exposure from unpredictable

and saturable absorption. Recently, a new formulation of

gabapentin (gabapentin enacarbil) has been developed

for absorption by high-capacity transporters expressed

throughout the intestine. It undergoes rapid post-absorp-

tion hydrolysis to gabapentin, providing sustained, dose-

proportional drug exposure.94

Among gabapentinoids, both gabapentin and pregabalin

are likely to provide analgesia by similar mechanisms of

action. Although there are no meta-analyses examining the

analgesic efficacy of pregabalin in PHN, there are a few RCTs

in support. In 2004, the use of pregabalin for the treatment of

diabetic neuropathy and PHN was approved in Europe and

the United States. An RCT in 2004 showed the effectiveness

of this drug in the treatment of PHN.95 Pregabalin was well

tolerated even by elderly patients. The commonly reported

side effects were drowsiness, dizziness, and mild peripheral

edema. The optimal dose to be administered has not yet been

thoroughly assessed. Other recently studied antiepileptic

drugs are sodium divalproate and oxcarbazepine, which

Table 2 Available evidence to support the use of several drugs or drug classes in the treatment of PHN

Drug or drug class Trials (N) Participants Comparator drug(s) Outcome

Gabapentin2,18,66,71–73,84,91–93 16 2798 Placebo/nor-amitryptiline +Gabapentin enacarbil94 1 101 Placebo +Pregabalin95 19 7003 Placebo +Opioids2,18,66,67,71,74,75,98,99 4 272 Placebo/TCA/lidocaine 3+, 1-Antidepressants: TCA2,50,66,68–71,85–90

7 229 Placebo/lorazepam/other classes of antidepressants

5+, 2-

Topical lidocaine2,76–78,83,100,101 6 471 Placebo/pregabalin +Topical capsaicin2,76,79–82,102 9 1600 Placebo/amitryptiline 7+, 2-Topical piroxicam103 1 18 Placebo/lidocaine +

Notes: + indicates positive outcomes; - indicates negative outcomes.Abbreviations: PHN, post-herpetic neuralgia; TCA, tricyclic antidepressant.

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Tontodonati et al

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demonstrated a significant efficacy in reducing pain and

improving patient quality of life.96,97

Although opioid analgesics are accepted as a cornerstone

for the treatment of nociceptive and cancer pain, their role in

the management of chronic neuropathic pain such as PHN has

been debated. The controversy over their efficacy in reliev-

ing neuropathic pain reflects the use of multiple definitions

and pain assessment methodologies in experimental trials

and interindividual differences in opioid responsiveness

(Table 2).67 In addition, many other factors, such as opioid-

related side effects, development of tolerance, exaggerated

fear of addiction, and differences in governmental health

policies, contribute to such a controversy.67 In spite of that,

opioids may be considered as a part of a comprehensive plan

for the treatment of PHN,2,18,71,74 when pain is moderate to

severe, with significant impact on quality of life after proven

inefficacy of first-line agents. Among the investigated for-

mulations, oxycodone, morphine, fentanyl, buprenorphine,

methadone, and weaker opioids such as dihydrocodeine and

tramadol were found to be effective. Treatment should be

started with a short-acting opioid, replaced after 1–2 weeks

with a long-acting formulation (controlled-release morphine,

controlled-release oxycodone, methadone, transdermal

fentanyl) in the event of insufficient effect. Constipation,

nausea, and sedation are common adverse effects associated

with opioid use for chronic neuropathic pain. Tramadol has

a unique pharmacological profile, which makes it one of the

most effective drugs of its class in controlling neuropathic

pain, particularly PHN and diabetic neuropathy.66,98,99 As for

side effects, tramadol may cause nausea, vomiting, dizziness,

constipation, drowsiness and headache; it also increases the

risk of serotonin syndrome in patients using antidepressants

such as SSRIs, TCAs, or inhibitors of mono-amino-oxidase

in combination.75

Local anesthetics may provide analgesia in some neuro-

pathic pain states, where an accumulation of neuronal- specific

sodium channels may contribute to pain, including that of

PHN.76 Topical treatments, including lidocaine patches and

capsaicin cream/patches, have been studied.2 Topical adhe-

sive patches containing 5% lidocaine (700 mg) have been

used for the treatment of PHN with benefit.77 Although there

are few studies on their efficacy, the available clinical trials

in patients with allodynia suggest that lidocaine is effective

in providing pain relief with minimal systemic absorption

and few side effects, the most frequent being mild skin

irritation at the site of application.78,83,100,101 Capsaicin, the

pungent ingredient in hot chili pepper, results in excitation

of nociceptive afferents when applied topically. However,

repeated application of capsaicin results in desensitization

of unmyelinated epidermal nerve fibers and hypoalgesia.79,80

Low-concentration (0.025% or 0.075%) capsaicin creams

have demonstrated efficacy in the topical treatment of

PHN and neuropathic pain conditions.80 Recently, a high-

concentration (8%) synthetic capsaicin dermal patch has

been developed with the aim of providing more rapid and

long-lasting pain relief after a single application. Banckonja

et al102 evidenced that a one-off application of a high concen-

tration (8%) capsaicin patch for 60 minutes was more effec-

tive than a low concentration patch over 12 weeks. Adverse

events reported were local reactions at the application site

(pain, erythema). Therefore, as evidenced by a Cochrane

review, capsaicin, either as a repeated low-dose application

of 0.075% cream or even a single application of a high-dose

8% patch, may provide a good degree of pain relief to some

patients with painful neuropathic conditions.81,82

Other types of topical analgesics that can be applied

for the treatment of PHN are currently under investigation.

A recent trial evaluated the efficacy of piroxicam patches,

resulting in faster and better effects.103

Alternative or adjunctive therapies useful in the treatment of PHNSix systematic reviews,67,104–108 four RCTs,109–112 and one

clinical report113 had evidence relating to this, while no meta

analyses did.

A wide variety of interventional options, such as sym-

pathetic and other nerve blocks, intrathecal injections, and

spinal cord stimulations, have been analyzed as potential

treatments for PHN. Interventional options are part of a com-

prehensive (invasive and noninvasive) strategy for the treat-

ment of PHN. Selective sympathetic nerve blocks have been

one of the most common interventional strategies used.104,105

The incidence of severe complications from sympathetic

nerve blocks is extremely low and, depending on the location

of the nerve block, may consist of local anesthetic toxicity,

pneumothorax, intraspinal/neuraxial injection, or neurologic

injury.67,106 Some data suggest a link between sympathetic

activity and pain in PHN, as patients with PHN demonstrate

increased levels of pain and worsening of their allodynia

after local administration of adrenergic agonists.109 Thus,

administration of sympathetic nerve blocks may theoretically

interrupt the sympathetic-sensory interactions contributing

to pain in PHN.67,105,106 The value of epidural injections for

the treatment of existing PHN has not been evaluated.106

Continuous infusions of analgesic agents (typically an opioid

or local anesthetic) via an externalized intrathecal catheter

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or an internalized intrathecal pump may also be used for the

treatment of PHN, although no controlled trials examining the

analgesic efficacy of these modalities are available.110,111

In extreme cases, spinal cord stimulation may be effective

in the management of severe neuropathic pain.107 The effects

of subcutaneous injections, transcutaneous nerve stimulations,

percutaneous nerve stimulations, and radiofrequency on PHN

has not been established. There is minor anecdotal evidence

for the efficacy of these techniques, and the risk for complica-

tions, such as exacerbation of pain, is unknown. There are no

controlled studies for any of these interventional procedures.106

Reported surgical options for PHN include trigeminal or

spinal peripheral neurectomy, deep brain stimulation, dor-

sal root entry zone lesions (DREZotomy), cordotomy, and

mesencephalotomy. Microsurgical DREZotomy may interrupt

small nociceptive fibers and neurons in the dorsal horn of the

spinal cord. General indications for this procedure include

well localized pain, neuropathic pain including PHN, and

excessive spasticity associated with severe pain. The role of

these invasive surgical treatments in the management of PHN

is uncertain, as there are no controlled studies to date.67

A number of other therapies have been explored, such as

N-methyl-D-aspartate receptor antagonists, topical nonsteroi-

dal anti-inflammatory drugs and TCAs, vincristine iontophore-

sis, botulinum toxin, minocycline, pulsed radiofrequency, and

cryoanalgesia. A recently proposed novel approach consists of

scrambler therapy; that is, a novel approach to pain control that

attempts to relieve pain by providing “non-pain” information

via cutaneous nerves, to block the influx of pain information.112

There is, however, little evidence that justifies evaluation of

the efficacy of these therapeutic options.

Acupuncture is another option to treat PHN. A clinical

report,113 the only one to date retrievable in English on the

possible role of acupuncture in PHN, lacks sufficient meth-

odological consistency to be quoted in terms of efficacy.

A current Cochrane project, however, is due in the near

future on this topic.108

Neuropathic pain reduces quality of life, including mood

and physical and social functioning. Depression and pain-

coping strategies, such as catastrophizing and social support,

predict pain severity in chronic pain states. Therefore, the

importance of psychosocial support and long-term follow-up

for severe cases should not be overlooked, as sometimes it is the

final tool on which to resort for otherwise intractable cases.67

DiscussionAs current evidence shows, treatment for PHN often needs

a combination of drugs to achieve the best individual pain

relief, pain management specialists should play a pivotal role

in caring for this relatively rare but disrupting condition, aided

by infectious disease specialists and general practitioners.

Recent guidelines on evidence-based management of

neuropathic pain and PHN provide distinct recommendations

for first- and second-line treatment, including possible drug

combinations for each step. Guidelines from the European

Federation of Neurological Societies68 recommend TCAs

or gabapentin/pregabalin as first-line treatment in PHN

(level A). Pregabalin and gabapentin got the same level of

evidence, in spite of different safety profiles and convenience.

However, both drugs share a remarkable latency to adequate

pain relief (up to 4–6 weeks). Topical lidocaine (level A;

less consistent results), with its excellent tolerability, may be

considered for a first-line approach in the elderly, especially

if there are concerns regarding the CNS side effects of oral

medications and pain is sufficiently localized. In such cases,

a trial of 2–4 weeks is justified. Strong opioids (level A) are

recommended as a second choice. Opioids and tramadol are

considered as second-line drugs because of their important

side effects; they can provide, however, immediate pain relief.

Capsaicin formulations are promising (level A), but the long-

term effects of repeated applications are not well described,

particularly on sensation.68,102 Other antiepileptic drugs (val-

proate) may be associated in patients with inadequate pain

relief or intolerance to previously indicated medications.96,97

A short antiviral course may be efficacious in reducing

PHN intensity and duration when a persistent or relapsing

ganglionitis may be postulated as the cause of PHN. Alternative

therapies such as acupuncture may still be considered.

Conclusion and future directionsTreatment of PHN is still unsatisfactory in a remarkable

proportion of patients, with a considerable economic burden

and impact on quality of life. Treatment should be guided by

individual pain relief, start as a monotherapy, and progress to

include other drugs, possibly with different mechanisms of

action. Special care should be addressed to elderly patients on

other medications, as side effects and drug-drug interactions

may be more common. In patients with inadequate response

or intolerance to current treatments, even a small degree of

adjunctive pain relief with newer or alternative therapies

may be worth considering. Population-based programs for

vaccination of elderly (and possibly younger adults) for HZ

appear at present the best preventive approach. Timely antiviral

treatment of HZ may likely be another tool for prevention,

especially for those patients with multiple predictors of PHN

at the onset of HZ.

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Tontodonati et al

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Further readingNiv D, Maltsman-Tseikhin A. Postherpetic neuralgia: the

never-ending challenge. Pain Pract. 2005;5(4):327–340.

O’Connor AB, Dworkin RH. Treatment of neuro-

pathic pain: an overview of recent guidelines. Am J Med.

2009;122:S22–S32.

AcknowledgmentThis work was supported by the “Fondazione Camillo de Lellis

per l’Innovazione e la Ricerca in Medicina,” Pescara, Italy.

DisclosureThe authors report no conflicts of interest in this work.

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International Journal of General Medicine 2012:5

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Prediction, prevention, and treatment of PHN