© 2012 Tontodonati et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.
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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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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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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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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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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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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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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