Postherpetic Neuralgia

Treatment of Postherpetic Neuralgia

JMAJ 47(11): 529536, 2004

Akira OZAWA
Professor and Chairman, Dermatology, Course of Specialized Clinical Science,
Tokai University School of Medicine

Abstract: Herpes zoster, a commonly seen condition in daily medical practice, is

reported to occur in 1020% of the population at some time during the lifespan.
Chronic, intractable postherpetic neuralgia, a sequela of herpes zoster, presents a
clinical challenge. In recent years, effective antiviral agents that can be used in the
outpatient setting have been developed for the treatment of herpes zoster and have
achieved good clinical efcacy. However, in the absence of any clear, decisive
treatment for postherpetic neuralgia, a variety of therapies have been elaborated
for use in clinical practice. This paper outlines the treatment of postherpetic
neuralgia and introduces therapeutic iontophoresis, which we have been using
with success in the clinical setting. The prevention and prediction of postherpetic
neuralgia is also discussed.
Key words:

Herpes zoster; Postherpetic neuralgia (PHN); Antiviral agents;

Iontophoresis therapy

of individuals affected is as high as 20 mill

ion.
Herpes zoster, a commonly occurring co Although herpes zoster is not lifethreatening,
ndition, is frequently encountered in the
dermatology clinic and various other clinics. I
t is
reported that the annual number of patie
nts
is 140180 per 100,000 population and
that
1020% of the population suffers from this d
isease at some time during the lifespan. In Jap
an,
approximately 500,000 people are affected
by
herpes zoster each year, and the total num
ber

Introduction

it poses the clinical problems of severe neur about 60 years of age and above. The incide
alnce
gia as a manifestation of the disease
of PHN is about 5% among patients
and
with
chronic
persistent
postherpetic
neural
herpes zoster in their 60s, reaching about 1
gia
0%
(PHN), which follows the successful treatme
among those in their 80s. In Japan, people a
nt
ged
of eruptions. PHN naturally does not occur i
65 years or older already number 23 mill
n
ion,
1)
every patient with herpes zoster, although i
accounting for 18% of the total populati
ts
on.
incidence increases with age, particularly
at
This article is a revised English version of a paper originally published in
the Journal of the Japan Medical Association (Vol. 129, No. 8, 2003, pages 12591264).
The Japanese text is a transcript of a lecture originally aired on December 2, 2002, by the Nihon Sho
rtwave
Broadcasting Co., Ltd., in its regular program Special Course in Medicine.

JMAJ, November 2004Vol. 47, No. 11

A. OZAWA

Table 1

Treatments of Postherpetic Neuralgia in Japan

Therapeutic modality

Dosage

Efcacy, adverse effects, characteristics, and others

Drug Therapy
Systemic therapy
Nonsteroidal
anti-inammatory drugs

Usual oral dose. The dose is increased or decreased Because the effectiveness of prolonged treatment is
depending on symptoms. Suppositories are
poor, care must be taken so as not to continue oral
widely used.
treatment for too long. Care must also be taken
because these drugs cause various side effects when
doses orally.

Antidepressants

Tricyclic

Clomipramine (25

Others

Others including amitriptyline (30 150mg/day)

imipramine, and nortriptyline (10 30mg/day)
Carbamazepine (an antiepileptic agent)

75mg/day)

Extract of inammatory rabbit

skin inoculated with vaccinia
virus

Neurotropin (__units/day divided into one

morning and one evening dose)

Interferon

Chinese medicines
(combined with nerve blocks)

Herbal extracts, Keisi-ka-zyutsubuto, 5g, processed

Japanese aconite daughter root powder, 1 5 g

50 10 units/kg/day

Effective in 10 out of 12 cases, with side effects in 4

Little efcacy, with side effects that pose problems

Patients more than 6 months after onset of herpes
zoster are amenable. Care must be taken not to
continue therapy if there has been no response for
4 weeks.
The incidence of PHN and the duration of neuralgia
were reduced.
70

80% improvement (in 1 case)

Toki-sigyaku-ka-gosyuyu-shokyoto

Effective in 5 out of 12 cases

Antiarrhythmic drugs

Mexiletine hydrochloride

Alleviation in 10 out of 11 cases

Others

Antiviral agents (vidarabine, acyclovir, and others have been reported to be effective in preventing
the development of PHN, but there is a tendency to rule out their efcacy for PHN itself), vitamin B12,
antiparkinson drugs (L-DOPA), immunoglobulin (intravenous infusion at high doses).

Topical therapy
Nonsteroidal
Aspirin
anti-inammatory
drugs

Others

20ml of a solution prepared by dissolving 50g of

aspirin in 1,000 ml of chloroform is applied
topically 2 3 times weekly.

Alleviation in 5 out of 10 patients receiving 5

treatments

60

2% aspirin ointment, ODT after application of 15 g

Alleviation in 5 cases. The effect lasted for 3

hours.

Indomethacin and others

Although this preparation is used widely because it

is easy to apply, its efcacy is variable.

529

Capsaicin

Local anesthetics

Effective in 12 out of 14 patients who had been

treated for 4 weeks. Application causes a burning
sensation.

Capsaicin cataplasms. It is applied twice a day.

Symptomatic improvement achieved in 8 out of 10

cases. Treatment caused a burning sensation.

Xylocaine jelly

Others

530

0.025% capsaicin cream, 5 times daily

10% lidocaine cream

(to be applied 3 5 times daily)

Alleviation in 5 of 10 patients receiving 5

treatments

Lidocaine tape (containing 60% lidocaine)

Effective for 12 hours

60

Nitrates (Isosorbide dinitrate is problematic because it causes headache.), topical anesthetics

(Xylocaine jelly and others), and others

JMAJ, November 2004Vol. 47, No. 11

TREATMENT O F P O S T H E R P E T I C NEURALGIA (PHN

Table 1

Treatments of Postherpetic Neuralgia in Japan (continued)

Therapeutic modality

Dosage

Efcacy, adverse effects, characteristics, and others

Physical Therapy
Nerve blocks

The sympathetic, stellate, and somatic ganglions

are blocked with local anesthetics 10 30 times,
and if necessary, more than 100 times. As a rule,
nerve blocks are administered at frequencies from
daily to twice a week. In some cases, nerve blocks
are administered by continuous infusion. Nerve
blocks are administered in combination with other
therapies such as epidural blocks and acupuncture
in some cases.

Epidural blocks

Local anesthetic agents are used alone or in

It showed little effect in some studies, but produced
combination with steroids. A course consists of
improvement in more than 80% of patients treated
10 blocks given twice a week or it is administered
in other studies. The longer PHN has lasted,
by continuous infusion.
the less effective it is.

Subarachnoid blocks

Injection of phenol or alcohol

Not adequately effective. The procedure is

complicated. It may cause complications.

Injection of 0.1

Effective in 11 out of 14 cases. Blood pressure was

decreased in 2. Respiratory depression

0.2 ml of 10% tetracaine solution

Effective in 40 65% of PHN cases. With PHN

lasting for more than 1 month, the efcacy decreases
as the duration increases. In PHN lasting more than
1 year, it is almost ineffective. The younger
the patient and the earlier the treatment, the more
effective it is. It requires some skill.

Intravenous infusion

Infusion of 0.5% procaine

Topical instillation

Injection into the painful site. Dibucaine; dibucaine

and benzocain; camphor and sodium salicylate;
triamcinolone and procaine; and others

Acupuncture

Anesthesia by acupuncture or with needles left

Anesthesia by acupuncture seems to be more
inserted. Daily to once every three days for a total
effective. Efcacy rate: 36%. Effective in 96% if
of about ten times
administered within 2 weeks after the onset.
Skill is required. It is less painful for the patient.

Iontophoresis

A pad soaked with a solution of lidocaine and

Pain was alleviated by
40% in 2/3 of the patients
methyl predni-solone is applied to the skin.
who received it 3.8 times on average. The procedure
A weak electric current is applied through the pad is not painful. The efcacy is independent of
so that the drugs penetrate into the skin.
the duration of PHN. It is effective even if other
The electric current is applied for about 30 minutes. forms of therapy are ineffective and in patients
The treatment is administered at intervals of 2 6 having underlying diseases. The procedure is simple.
weeks for a total of up to 5 times.

Cryotherapy

Dry ice

Effective, but not in all cases

The effect is transient.

After local anesthesia, a piece of dry ice is pressed

Effective in 77% of the patients who received it
onto the site.
1 14 times (mean: 5.7 times). It causes frost-bite

which gives rise to vesicles and pain.

Liquid
nitrogen

Apply liquid nitrogen with a cotton ball once or

Effective in 70
twice a week or once a day for 2 weeks, and then
once or twice a week

80% of patients treated 4

20 times.

Transepidermal nerve stimulation An active electrode attached directly to the skin is Effective in 78%. Transcutaneous nerve stimulation
(TENS)
used to apply low frequency electric current
can be performed by the patients themselves and is
(low frequency therapy). An implanted electrode is
useful as a home therapy for long-standing neuralgia.
used to stimulate the spinal cord or the brain.
Near infrared irradiation

Infrared light at a wavelength of 700 1,700 nm

(mainly 970 nm) is irradiated for 30 minutes
(temperature at the surface of the skin: 39C).

Effective immediately after irradiation in 39 out of

64 patients, and effective in 12, 24 hours later,
without side effects

Laser therapy

A GA-AI-As semiconductor laser is irradiated for Effective in 50

about 10 minutes once a week for a total of 10 50
times. An Nd-YAG laser, a low reactive laser, and
others are also used.

Others

Moxibustion (pain disappeared when it was repeated 8 times), surgery (interruption of the posterior root
or sympathetic trunk, and others), skin excision (effective in some studies, but seldom satisfactory),
radiofrequency thermocoagulation (may be effective in patients not responsive to other therapies),
electroconvulsive therapy (pain reduced by an electric current of 110 115 V, applied for 5 seconds to
the anterior temporal area under general anesthesia, 1 2 times weekly to a total of 6-12 treatments),
and others

90%

(Source: Reference 5: Dermatology Practice 10, Bunkodo, 2000; pp.110114)

JMAJ, November 2004Vol. 47, No. 11

A. OZAWA

Thus, there is concern that the prevalenc

e of
herpes zoster and PHN will increase further.
In recent years, effective antiviral ag
ents
developed for the treatment of herpes zos
ter
have been used in outpatient clinics with fav
or2)
able clinical results. However, no deci
sive
treatment for PHN exists, necessitating vario
us
clinical elaborations for its treatment (Table
1).
Various attempts to treat PHN are outlin
ed
below.

What Is PHN?
Postherpetic neuralgia is dened by
the
International Association for the Study of Pai
n
as chronic pain following resolution of ac
ute

531

herpes zoster that is accompanied with

skin
degeneration in the affected dermatome.
Another view advocates that neuralgia
following herpes zoster should be collecti
vely
considered postherpetic pain (PHP), in wh
ich
PHN is only one constituent. This view rega
rds
PHN as deafferentation pain due to n
erve
3)
degeneration. According to this theory, tr
ansition to PHN is presumed to occur about o
ne
month after the onset of herpes zoster an
d to
persist thereafter. However, in many case
s of
herpes zoster, neuralgia as a form of PHP
may
be present for 23 months after the
successful
treatment of eruptions, and therefore,
it is
difcult to form a clear distinction bet
ween
PHP and PHN.
Under these circumstances, PHN c
ases

present an issue in evaluating the cli

nical
efcacy of a particular treatment. Consultati
on
were carried out in Japan in 129 accred
among anesthesiologists and dermatologists ited
in
facilities of anesthesiology and 259 accredi
Japan has resulted in the recommendation th ted
at,
facilities of dermatology by the respective a
when examining the efcacy of treatment ca4)
for
demic societies. On the basis of these surv
PHN, patients be examined at least 3 mon eys,
ths
the current status and expected therap
4)
after the onset of herpes zoster.
eutic
efcacy of various anti-pain procedures
for
Treatment of PHN
PHN were investigated and a report issued.
1. Current status and expected efcacy o According to the report, therapies noted f
or
f
their therapeutic efcacy and frequent clini
anti-pain procedures
cal
Surveys of anti-pain procedures used for
use include NSAIDs, psychotropics, and ner
PHN
ve
block therapy. Therapies from which
high
532
JMAJ, November 2004Vol. 47, No. 11
efcacy was expected despite limited ac
tual
use included narcotic analgesics, ster
oids,
laser therapy, iontophoresis, psychother
apy,
and rehabilitation training.
However, no clear treatment has been est
ablished for PHN, although various procedu
res
have been elaborated and employed.
2. Treatment policies for PHN
The basis of treatment for PHN cons
ists
of medical intervention and detailed instr
uctions given to individual patients and t
heir
5)
families. Medical treatment alone often
may
be insufcient.
(1) Instructions for daily life
i) Patients should not be made anxious
or
given preconceived ideas about pain
and
PHN at the onset of herpes zoster.
ii) Patients should be instructed to re
turn
to normal daily activities after erupti
ons

family members.
(2) Medical treatment
restrictions on daily life activities.
i) Since no decisive treatment currently exi
iii) Instructions in the creation of a pain- sts,
the status of pain should be assessed obj
free
environment should be given to patien ectively and treatment chosen according
ts
and their families. Suggestions should to
be
the individual patient.
based on the patients lifestyle, circu ii) A combination of several treatments
may
mbe necessary in some cases depending
stances, personality, and relationships wi
on
th
have been cured. In principle, there are

no

symptoms.
iii) The treatment chosen should be evaluat
ed
frequently to avoid its continued use mer
ely
because the patient complains of pain.
(3) Choice of medical treatment
Treatment should be chosen for each patie
nt
according to his or her symptoms and ph
ase
of illness. The goal of treatment should be
to
restore the patients ability to carry out d
aily
activities such as eating, sleeping, and so
on.
Antiviral agents are unlikely to have therap
eutic efcacy for PHN.
i) Up to 3 months after the cure of eruptio
ns
Although neuralgia as a form of P
HP
remains in many patients, the degree of
its
severity gradually decreases. Therefore
, if
there is no serious impediment to daily li
ving, symptomatic treatment with NSAI
Ds
and vitamin B preparations should c
onstitute the core treatment. When ther
e is

severe pain, aggressive anti-pain pr

ocedures including physical therapies such
as
nerve block should be employed.
ii) Up to 6 months after the cure of erupti
ons
Drug treatment using NSAIDs, vitamin
B
preparations, or antidepressant drugs,
and
physical therapy including nerve b
lock
therapy, laser therapy, acupuncture,
and
iontophoresis therapy should be tried
as
monotherapy or combined therapy.
iii) More than 6 months after the cure of er
uptions
Combined therapy including drug tre
atment and physical therapy should
be
employed, while exercising caution
with
regard to the possible adverse effect
s of
prolonged use.
(4) Treatment of elderly patients
Elderly patients account for a considera
ble
proportion of all patients with PHN. Particul
ar
attention to the following points is importan
t in
the treatment of this population.
i) Is it truly PHN?
It is possible that any pain in patients
who

have had herpes zoster may be wro

ngly
attributed to PHN. Fracture pain, ost
eo-

TREATMENT OF P O S T HE R P E T I C NEURALGIA (PHN

)

arthritis, secondary muscle ache deri

ved
from pain-limited motion, and pain fr
om
other diseases such as cardiac disease
may
be reported as PHN by the patient.
ii) Psychological dependence
Patients with PHN tend to be isolated fro
m
social life, preoccupied with pain and
the
fear of pain, and psychologically depende
nt
on others. It therefore is necessary
for
patients and their families to better und
erstand the patients response to pain and
to
reconsider the living environment.
iii) Assessment of pain
The assessment of pain in elderly patie
nts
can be difcult, often leading to difculti
es
in understanding symptoms. The physici
an
should strive for objective assessment of
the
patients pain, taking into account his/
her
speech and actions in the consultation ro
om
or reports from family members regardi
ng
the patients daily life.
iv) Dependence on treatment
Elderly patients characteristically exhi
bit
intense anxiety in regard to the cessation
or
alteration of treatment. The physician
in
charge should always try to assess
the
patients pain objectively and make cert
ain
that the patient understands the need
to
continue, change, or terminate treatmen
t.

(5) Iontophoresis therapy for PHN

1,000 patients with PHN (mean duration
Iontophoresis therapy is a method of topic of
al
PHN, 30.6 months) showed 40100%
drug delivery by which ionized drug in a sol improveument in neuralgia after an average of 3.8
tion is introduced into the body painlessly v ses5)
ia
sions of therapy.
the skin.
This form of therapy is painless, and its e
We have carried out iontophoresis thera fpy
cacy is not affected by the duration of P
using lidocaine and methylprednisolone in t HN.
he
The treatment was effective in patients
Department of Dermatology, Tokai Universit with
y
School of Medicine (Fig. 1), with favora
ble
JMAJ, November 2004Vol. 47, No. 11
533
clinical results. Over two-thirds of more th
an

A. OZAWA

Step 1

1.0 mA, 10 minutes

10 min.

Return electrode
(1% sodium nitrate)

1.0 mA

Step 2

Site to be treated
(Mixture of lidocaine and epinephrine)

1.0 mA, 10 minutes

10 min.

Site to be treated
(Methylprednisolone solution)
The pad for the return electrode is used
without exchange.

1.0 mA

Fig. 1 Iontophoresis for postherpetic neuralgia

(Source: Reference 5: Dermatology Practice 10, Bunkodo, 2000; pp.110114.
For Information about the instrument, refer to BS Medical, Tel. +81-3-3299-6425.)

pain persisting for more than one year, th

ose
who did not respond to other treatments, a
nd
those who had underlying diseases such
as

malignant tumor, hypertension, or diab

etes
mellitus. Follow-up of patients for 15 y
ears
after the end of therapy conrmed a contin
uing

6)
1. Prevention of herpes zoster
therapeutic effect.
Therefore, iontophoresis therapy for PHN i Varicella vaccine is promising, and th
ose
s
a clinically useful therapeutic option. M who are of an age susceptible to herpes zos
ter,
any
other therapies have been reported to be l i.e., 5055 years of age, should be inocul
ated
ess
effective in patients with neuralgia persist with varicella vaccine to obtain booster im
muing
7)
for at least one year, indicating the usefuln nity. Clinical trials of this procedure h
ave
ess
of iontophoresis therapy for the treatment been carried out in the US as well as Ja
pan,
of
with benets reported.
PHN.

2. Prevention of PHN in herpes zoster

Prevention of the occurrence of PHN is
an
Unfortunately, there is currently no absolu
important issue to be considered when a
te
paprophylaxis for PHN. However, since P tient has already contracted herpes zoster.
HN
(1) Antiviral drug therapy in the early ph
occurs as a sequela to herpes zoster, the ase of
preherpes zoster
vention of herpes zoster is useful.
Herpes zoster should be mitigated throu
gh
8)
early-phase antiviral drug therapy.
Antiviral
534
JMAJ, November 2004Vol. 47, No. 11
agents with excellent clinical efcacy have
been

developed, including Arasena A ointment

as

topical therapy, Zovirax and Barutorex

as

oral preparations, and Arasena A

and

Is Prevention of PHN Possible?

TREATMENT OF P O S T HE R P E T I C NEURALGIA (PHN

Table 2 Immunogenetic Analysis of VZV

Herpes zoster
PHN

Disease resistance: HLA-B*5101

Disease resistance: HLA-B*4001
Disease resistance: HLA haplotype
(A*3303-B*4403-DRB1*1302)

Zovirax
as intravenous preparations.
The
main point of treatment is to use these antiv
iral
agents in the early stage after onset. One re
port

has documented a 50% decrease in the

incidence of PHN after antiviral drug treat
ment
for herpes zoster.

In dosage regimens of antiviral drug thera return to their usual everyday life after e
ruppy,
renal function is an important issue. D tions have subsided. Rehabilitation train
ing
ose
adjustment is necessary for elderly patients should also be considered in some cases,
paror
those who have renal disease. Dosage regim ticularly those with limb lesions.
ens
of intravenous formulations are described Prediction of Onset of Herpes Zoster
in
and PHN
detail in the manufacturers instructions for
If PHN derives from nerve degenerat
use
of the drug, and the treatment of pati ion
ents
resulting from invasion of varicella-zoster
should follow these instructions. When impaire virus
d
( VZ V ) , the bodys immune response (sensi
renal function is present, the dose is d tiveterity) to VZV may be involved in disease on
mined according to serum creatinine clearan set.
ce.
If there were immunogenetic differences
In actual practice, serum creatinine cleara in
nce
patients affected by varicella, zoster, and P
can be estimated from the serum creati HN,
nine
and if such differences were claried, the o
level and the patients body weight and nset
age
of disease might be predicted.
2)
according to a simple formula.
In this regard, we examined the HLA a
It should be noted that the combined use ntiof
gen gene region on the short arm of chro
topical and oral antiviral drugs or topical a mond
some 6 for genetic control of the im
intravenous drip administration generally mune
9)
is
response to VZV.
Results conrmed
not covered by health insurance in some ar the
eas
involvement of HLA antigens in disease
of Japan (e.g., Kanagawa Prefecture).
sus(2) Proper topical therapy for skin lesions ceptibility and genes controlling resista
Dermatologists should select an appropria nce
te
(Table 2). Therefore, if these diseases can
topical preparation for eruptions, with ref be
erpredicted, prevention of their onset
ence to the particular disease stage, may
and
become possible by various means, inclu
2)
provide instructions as to its use.
ding
(3) Aggressive treatment of neuralgia
vaccination.
Neuralgia should be treated as needed,
in
Conclusion
cooperation with an anesthesiologist.
(4) Instructions for daily life
Antiviral agents for herpes zoster have be
For patients with herpes zoster, instructio
en
ns
for daily life that emphasize the importance developed and are in widespread use in clini
cal
of
rest, recreation, and nutrition are necess practice, although the efcacy of these antiv
iral
ary.
In addition, patients should be instructed agents for PHN has been denied. Howe
ver,
to

methods of dealing with patients and the usa into account both the prediction and prev
ge
enand place of antiviral agents in the actual cli tion of the onset of herpes zoster and PHN.
nical setting should be considered further, taki
ng
JMAJ, November 2004Vol. 47, No. 11

535

A. OZAWA

5) Sasao, Y. and Ozawa, A.: Postherpetic neu

ralREFERENCES
gia. Dermatology Practice 10: Dif
cult1) Iizuka, M. and Ozawa, A.: Diagnosis
and
to-Treat Skin Diseases (ed. Hashimoto, K
treatment of postherpetic neuralgia. Monthl . et
y
al.) Bunkodo, Tokyo, 2000; pp. 110114.
Book Derma 1999; 28: 3840. (in Japanese) (in
2) Mabuchi, T. and Ozawa, A.: Appropriate do
Japanese)
s6) Ozawa, A. et al.: Follow-up of clinical
age regimen of antiviral drug therapy a efcacy
nd
of iontophoresis therapy for postherp
instructions for active daily living after cure oetic
f
neuralgia (PHN). J Dermatol 1999; 26: 1
eruptions. Rinsho To Yakubutsu Chiryo 2001 10.
;
7) Levin, M.J. et al.: Use of a live atten
20: 10461050. (in Japanese)
uated
3) Miyazaki, T.: What is postherpetic neuralgi
varicella vaccine to boost varicellaa?
specic
Q & A in Diagnosis and Treatment of Herpe
immune responses in seropositive people
s
55
(ed. Niimura, M.) Research Institute of Cliniyears of age and older: duration of boo
cal Therapeutics and Medicine, Tokyo, 199 ster
3;
effect. J Infect Dis 1998; 178, Suppl 1: S 1
pp. 196197. (in Japanese)
09
4) Miyazaki, T.: Report of a questionnaire surv
S 112.
ey
8) Ozawa, A.: Treatment of herpes z
on the concept of herpes zoster-related
oster.
pain.
Nippon Ishikai Zasshi 1997; 117: 1749
Pain Control of Herpes Zoster (ed. Miyazaki 1753.
,
(in Japanese)
T. et al.) Torre Lazur McCann, Tokyo, 1999 9) Ozawa, A. et al.: HLA A 33 and B 4
;
4 and
pp. 510. (in Japanese)
susceptibility to postherpetic neuralgia (PHN
).
Tissue Antigens 1999; 53: 263268.

536

JMAJ, November 2004Vol. 47, No. 11