Journal of Antimicrobial Chemotherapy (2011) 47, Topic T1, 18

JA
C
Herpes zosterpredicting and minimizing the impact of post-herpetic
neuralgia
Robert W. Johnson*

Pain Management Clinic, Department of Anaesthesia, Bristol Royal Inrmary, Marlborough Street,
Bristol BS2 8HW, UK

Herpes zoster results from reactivation of latent varicella-zoster virus in the dorsal root ganglia
and is frequently associated with severe pain. Most patients suffer acute pain during the rash
phase, and in many, prodromal pain or discomfort also precedes the rash. The pain of herpes
zoster gradually resolves with time, but may persist after the acute disease as post-herpetic
neuralgia for weeks, months or even years. Post-herpetic neuralgia, the most common compli-
cation of herpes zoster, often results in signicant morbidity and healthcare resource usage.
Early treatment with oral antivirals has been shown to accelerate the resolution of post-
herpetic neuralgia, with therapeutic effects particularly evident in the over-50 age group, where
pain generally persists for longer. Progressively increasing life expectancy of the population
translates to increasing numbers of cases of herpes zoster. The socio-economic gains asso-
ciated with active management, including use of oral antivirals where indicated, to speed
resolution of pain and post-herpetic neuralgia, readily justify additional cost.

Herpes zosterthe disease
In common with other herpesviruses, the varicella-zoster
virus ( V Z V ) establishes latency in dorsal root ganglia fol-
lowing primary infection (varicella, or chickenpox), usually
during childhood. Herpes zoster (shingles) results from the
reactivation of VZV and is thus in large part an infection of
the sensory nervous system, with an acute phase character-
ized by pain and skin rash. The interval between primary
infection and reactivation is usually several decades, in
contrast to the far shorter latency periods typical of herpes
simplex virus infection. Second attacks of herpes zoster
occur in only 614% of individuals.1,2 Although immune
senescence through ageing is the commonest cause of
reduced cell-mediated immunity, permitting viral reactiva-
tion,3,4 immune compromise resulting from diseases such as
lymphomas, from immunosuppressant drugs used in dis-
ease management or to prevent rejection of transplanted
tissue and from HIV infection, contributes to the spectrum
of patients developing herpes zoster.
Any dermatome may be affected in herpes zoster and
become the site of the characteristic unilateral rash. Pain
during the continuum of herpes zoster is collectively known
as zoster-associated pain, which encompasses that pre-
ceding and during the rash, as well as that persisting after
the acute disease. The most common long-term complica-
tion is ongoing pain [post-herpetic neuralgia (PHN)], a
condition that often results in signicant morbidity,
especially in elderly individuals. There is no universally
accepted denition of PHN, but that suggested by Dworkin
& Portenoy5presence of signicant pain or abnormal
sensation 3 months after rash healingis now commonly
used both clinically and in research study design. Pain may
be discontinuous, allowing pain-free intervals.
Overall, approximately three per 1000 of the population
per year develop herpes zoster.1,6 In the over-80 age group,
the gure rises to 10 per 1000. In absolute terms, using the
UK as an example, 170 000 people develop herpes zoster
during one year.2 About 22% of patients with herpes zoster
still have spontaneous and/or abnormally evoked pain
3 months after rash appearance. At 1 year, about 510%
still have PHN and by this stage further spontaneous resolu-
tion is limited.7
Pathology of post-herpetic neuralgia
The perception of pain in the intact nervous system requires
stimulation of the receptors of nociceptive primary afferent
neurones by noxious mechanical, thermal or chemical
stimuli, their transduction to electrical impulses and trans-

*Tel: 44-117-928-2766; Fax: 44-117-928-4964; E-mail: robert.johnson@ubht.swest.nhs.uk

1
201
1 The British Society for Antimicrobial Chemotherapy
 R. W. Johnson
mission of these impulses via the dorsal horn of the spinal
cord. Within the substantia gelatinosa of the dorsal horn
gating occurs whereby afferent input from the periphery,
via large diameter mechanoceptor bres (non-pain sensory
neurones), and activity in descending inhibitory pathways
within the spinal cord, modulate the extent to which pain
impulses ascend to the brain stem and cerebral cortex, thus
producing the conscious sensation of pain. The pathologi-
cal changes that may occur following herpes zoster can
affect any part or parts of the pain pathway from the
periphery to the spinal cord. No single pathological feature
is responsible for every case of PHN but rather, a number
of pathological abnormalities, existing in differing propor-
Figure 1. (a) Normal situation and (b) A bre sprouting into
supercial laminae of dorsal horn following damage to C bres
(adapted from Woolf et al.8).
Figure 2. Clinical features of neuropathic pain.
2
tions, bring about the combination of phenomena that
comprise PHN.
PHN may best be described in terms of irritable nocicep-
tors and central sensitization. The more supercial laminae
of the substantia gelatinosa receive small diameter pain (C),
fibres from the periphery and the deeper layers receive
larger diameter, mechanoceptor bres (A). It has been
shown that after nerve injury, C-bre terminals may atrophy
and A-bre terminals sprout into the supercial dorsal
horn.8 When this happens, normally non-noxious stimula-
tion of mechanoceptors (e.g. light touch) within the skin
will activate areas of the dorsal horn that produce pain
impulses which will advance along the pain pathway to
consciousness (Figure 1).8 Central sensitization, whereby
afferent impulses are amplied rather than undergoing
physiological gating, results from complex changes in sodium
and calcium channel activity associated with the N-methyl-
D -aspartate (NMDA) receptors within the primary afferent
unit and may lead to the generation of both spontaneous
and evoked pain.9 Furthermore, Watson & Deck 10 have
shown atrophy of the dorsal horn in affected segments in
post-mortem studies of spinal cords from patients who had
developed PHN. To summarize, a combination in varying
proportions of primary afferent nociceptor (pain) C-bre
damage, sprouting of the A mechanoceptor (light touch)
bres within the dorsal horn rendering them effectively
into abnormal nociceptors (pain-sensing neurones) (Figure
1), and brosis within the dorsal root ganglion with atrophy
of the dorsal horn within the spinal cord, may account for
the pain of PHN.
PHN may manifest as one or more of spontaneous aching
or burning, paroxysmal shooting pains, allodynia (pain
evoked by application of a mild normally non-noxious
stimulusthis may be static or dynamic) and hyperalgesia
(severe pain evoked by application of a normally mildly
painful stimulus) (Figure 2).
 Predicting and preventing post-herpetic neuralgia
Motor decit is frequently present in patients with PHN
but may well pass unnoticed if a thoracic dermatome is
involved. A number of patients with herpes zoster affecting
a mid- or lower-thoracic dermatome describe a swelling
on one side of the abdomen: careful examination shows
paresis of a myotome of the abdominal wall. Although part
of the motor decit may be peripheral, from bystander
damage to motor efferent bres from adjacent, damaged
sensory bres, there is almost certainly anterior horn cell
damage from what is essentially a viral myelitis.
Established post-herpetic neuralgia:
epidemiology, treatment and costs
Epidemiological data for the UK suggest that the incidence
of PHN will account for about 200 000 cases at any one
time.2 Although options for improved management of
PHN are increasing, many patients will suffer moderate to
severe pain for many years and in some cases for life. At the
present time, the most effective treatments, apart from
good psychosocial management and advice on physical
measures such as avoidance of tight or articial bre cloth-
ing and the use of ice packs, are: careful use of certain tri-
cyclic antidepressant drugs, notably amitriptyline,11 for
their central pain-modulating effects; the anticonvulsant
drug gabapentin;12 and, in some cases, well-managed use of
opioid drugs such as oxycodone or morphine.13,14
Although the precise molecular mechanism of action
of gabapentin is not fully understood, current evidence
supports the hypothesis that it may modulate neuronal
hyperexcitability via a high-afnity interaction with the
2 auxiliary subunit of voltage-dependent calcium chan-
nels.1518 The mechanism of action of tricyclic antidepres-
sants (e.g. amtriptyline, nortriptyline) in producing analgesia
is usually independent of any antidepressant effect. These
agents probably enhance central endogenous pain-inhibit-
ing mechanisms within the descending pathways of the
spinal cord by inhibition of noradrenaline and serotonin re-
uptake at synapses. Where depression accompanies pain,
an antidepressant effect may contribute to pain relief. The
side effect of drowsiness may be markedly benecial where
pain results in sleep disorderthese drugs should be given
about 1 h before bedtime.
A practical method of applying topical local anaesthetic
has recently been licensed in the U S A (Lidoderm, Endo
Pharmaceuticals, Chadds Ford, PA , USA ). 19,20 Earlier
preparations of local anaesthetic drugs for topical use were
messy and difcult to use for more than short periods.
Lidoderm shows promise of being effective and practical in
at least some patients with PHN. Capsaicin [N-vanillyl-8-
methyl-6-(E)-noneamide] is a pungent derivative of hot
chilli peppers. Application of capsaicin to sensory nerve
tissue rst stimulates then inhibits, by causing depletion of
the neurotransmitter substance P, activity in nociceptive C
bres. Topical applications of concentrations varying from
3
0.025 to 0.075% have been studied in a number of painful
conditions, including osteoarthritis of the knee and PHN.
Because capsaicin results in a variable degree of burning
sensation after application, blinded controlled studies are
difcult to perform and outcomes have varied. There is
little doubt that some patients gain benet provided they
comply with instructions for its use.21
Costs in terms of patient distress and suffering, plus the
impact of PHN on carers and healthcare provision, are con-
siderable. Both Nathwani et al.22 and Davies et al.23 have
estimated the UK healthcare costs of PHN in terms of
primary care and hospital department management. A
cost-effectiveness analysis of aciclovir treatment of zoster
in Scotland, using data generated from 1988 to 1992,
derived an implied value of US$2125 (range US$5318500
for worst and best single efcacy trial results) for preven-
tion of one case of PHN. 22 The lifetime cost per patient
attending a pain clinic in the UK in 1994 was 770.23 Clearly,
safe measures to reduce acute symptoms and the risk of
developing PHN from a once-in-a-lifetime event are desir-
able and cost-effective for both patients and healthcare
providers.
Predicting and preventing post-herpetic
neuralgia
There is an increasing understanding of predictive factors
for those most at risk of PHN. Importantly, most of these
factors can easily be detected when the patient rst pre-
sents with the acute attack of zoster. Preventive measures
should be applied at this time in any patient with adverse
predictive factors. Positive predictors are advanced age,2426
presence of signicant or prolonged prodromal pain,2426
moderate to severe acute pain25,26 and severe skin rash.27
The risk of PHN becomes highly signicant in otherwise
healthy individuals over the age of 50.26 Those living alone
and showing increased anxiety and depression and/or
increased illness behaviour also appear to be at high risk of
PHN persisting.24
Progressively declining cell-mediated VZV immunity
with advancing age is thought to be the main contributor to
zoster occurring predominantly in older adults.28 Exactly
why or how more severe prodromal and acute pain or
severe rash predispose to more prolonged pain after herpes
zoster has not been established, although it is logical to
suggest that more extensive VZV reactivation in sensory
ganglia, leading to a greater viral load in sensory nerves and
skin, would in turn cause more tissue damage during the
acute phase of zoster, which would then increase the prob-
ability of triggering the train of events resulting in PHN.
Antiviral drugs licensed as oral therapy for acute herpes
zoster are aciclovir, valaciclovir and famciclovir. Valaci-
clovir is the prodrug of aciclovir, while famciclovir is the
prodrug of another nucleoside analogue, penciclovir. The
active moieties, aciclovir and penciclovir, are initially and

selectively phosphorylated by VZV-specic thymidine
kinase in infected cells; following further phosphorylation
by cellular kinases, aciclovir and penciclovir triphosphates
inhibit the activity of viral D N A polymerase and terminate
VZV replication.
Valaciclovir was developed to achieve higher blood
levels of aciclovir, so as to improve penetration of aciclovir
into VZV-infected sensory nerve cells and ultimately clini-
cal outcome, particularly as regards chronic pain and PHN.
Famciclovir allowed investigation of the novel chemical
entity, penciclovir, for efcacy and safety in a range of
herpesvirus infections. Common to both valaciclovir and
famciclovir in studies of herpes zoster was the need for
more convenient oral dosing and measurable impact on the
complications of zoster, particularly PHN. Although aci-
clovir and penciclovir are both nucleoside analogues, their
intracellular mode of action differs. Aciclovir has lower
substrate afnity for the VZV thymidine kinase than does
penciclovir (Km 830 versus 250 M), but this is offset by the
markedly higher inhibitory constant for VZV D N A poly-
merase of aciclovir triphosphate compared with that of
29
penciclovir triphosphate (Ki 0.01 versus 1.6 M). Such
differences, along with the longer intracellular half-life in
VZV-infected cells of penciclovir triphosphate of c. 9 h
(versus 0.8 h for aciclovir triphosphate)30 do not appear to
translate into meaningful differences in clinical outcome.
Placebo-controlled trials of oral aciclovir (800 mg ve
times daily) given for 7 days in herpes zoster were con-
ducted in the late 1980s. Despite differences in design,
follow-up and methods of recording and analysing pain and
PHN, a meta-analysis of these studies has recently been
completed and describes the impact of aciclovir on zoster-
associated pain and PHN using methods common to the
analysis of recent studies of valaciclovir and famciclovir in
herpes zoster.25 Valaciclovir (1000 mg three times daily)
has been compared with aciclovir in patients 50 years
old31 and with placebo in younger adults.32 Studies of
famciclovir in herpes zoster were in patients aged 18
years; one compared 250750 mg three times daily regimens
with aciclovir,33 while the other was a placebo-controlled
comparison of 500 and 750 mg three times daily.34 All these
trial protocols required treatment initiation within 72 h of
onset of zoster rash.
Table. Proportions of patients (aged 50 years) with persisting pain in controlled trials of antiviral therapies for herpes
Aciclovir (800 mg 5 times daily,
710 days) vs placebo25 ( % )
Pain (PHN) at
3 months 25 vs 54a
6 months 15 vs 35a
a
P 0.05 from 95% condence interval for the relative risk for the difference between treatments.
b
Glaxo Wellcome (R. J. Crooks), personal communication.
c
P 0.08.
R. W. Johnson
Oral aciclovir (800 mg ve times daily) signicantly
increased the rate of resolution of zoster-associated pain by
79% (P 0.001) and PHN, dened as pain persisting from
30 days after rash onset, by 81% (P 0.001) compared with
placebo.25 Valaciclovir (1000 mg three times daily) signi-
cantly accelerated the resolution of zoster-associated pain
by 34% compared with aciclovir (P 0.001) and PHN,
dened as pain persisting after rash healing, by 32% (P
0.002).31 Famciclovir (250 or 500 mg three times daily) was
essentially comparable in efcacy to aciclovir (P values
were not provided for the intent-to-treat analysis of zoster-
associated pain) and may have provided minor advantages
in selected subgroups.33 No analysis of impact on PHN is
described for this study. In the placebo-controlled trial,
famciclovir (500 mg three times daily) signicantly acceler-
ated the resolution of PHN, dened as pain persisting after
rash healing, by 70% (P 0.02).34 The impact of famci-
clovir treatment was more marked in patients aged 50
years.34 No analysis of zoster-associated pain was pre-
sented for this study. Study designs, dosages, endpoints and
statistical analysis methods in these trials of valaciclovir
and famciclovir in herpes zoster are not consistent and pre-
clude a more robust comparison of the newer prodrugs. A
preliminary report of a direct comparison of valaciclovir
(1000 mg) and high-dose famciclovir (500 mg), each given
three times daily for 7 days, suggests no substantial differ-
ences on a range of measures of pain in herpes zoster.35
Thus, antiviral therapies for herpes zoster are remark-
ably safe, have few side-effects and signicantly reduce the
acute symptoms as well as reducing subsequent scar-
ring.25,31,33,34,36 Valaciclovir (1000 mg) and famciclovir (250
or 500 mg according to local prescribing information) are
prescribed in three times daily regimens, which should be
easier for patients compared with the ve times daily regi-
men required for aciclovir.
Antivirals undoubtedly speed the resolution of pain in
herpes zoster. But the important clinical question is: do
these drugs reduce the numbers of patients developing
PHN? Aciclovir, valaciclovir and famciclovir reduce the
number of patients with signicant pain or abnormal sensa-
tion 3 and 6 months after the acute zoster attack.25,31,34
Benets, as indicated by point prevalence estimates at
various times after acute zoster, are particularly marked in
zoster
Valaciclovir (1000 mg 3 times Famciclovir (500 mg 3 times
daily, 7 days) vs aciclovir31 ( % ) daily, 7 days) vs placebo33,34 ( % )
31 vs 38b 34.9 vs 49.2a
19.9 vs 25.7c 19.5 vs 40.3a
4
 Predicting and preventing post-herpetic neuralgia
patients over the age of 50 years, the age group in which
PHN is most likely to develop (Table). 25,29,30
The costs and consequences of treating acute herpes
zoster were modelled using data generated in the com-
parative study of valaciclovir and aciclovir and applying
branded drug costs that were relevant at the time of the
modelling.37,38 Average direct costs (drug acquisition of
antivirals and analgesics, plus consultation, treatment and
hospitalizations costs for management of long-term com-
plications) and indirect costs (productivity) were lower
with valaciclovir by 17 and 25%, respectively. In anticipa-
tion of the pending availability of generic aciclovir in the
USA , this cost-consequence analysis included a cost-effec-
tiveness analysis. Even if the price of aciclovir is reduced to
zero, while the cost of branded valaciclovir is maintained,
in a person 50 years old the additional direct medical
costs of managing a case of zoster with valaciclovir would
be US$5.30 for each additional day of zoster-associated
pain avoided.38
Systemic steroids given during the acute phase of zoster
have recently been shown by two large, controlled studies
to afford no protection against PHN. 3941 One randomized,
controlled study showed earlier return to normal life
activities and reduced analgesic requirement in patients
receiving steroids.41 Another study conducted in the UK
did not specically look for this but showed a greater
frequency of adverse events in the steroid groups, despite
exclusion of patients from the study who had any relative
contraindication to steroid administration.39 It should be
emphasized that neither study showed any reduction in the
prevalence of PHN in patients receiving steroids.39,41
Encouragement to return early to pre-zoster activity levels
is, however, considered important.
The mode of transport of VZV particles from their site
of initial reactivation to the periphery and centrally to the
spinal cord is by neural transmission and this is one factor
in the process of the acute disease that may be inuenced
by local anaesthetic sensory and/or sympathetic blockade,
suggested by some to prevent PHN. 42,43 Sympathetic nerve
blocks in herpes zoster remain controversial. Early studies
were unsatisfactory and no valid conclusions may be
drawn. Studies from Japan are suggestive that prolonged
(several weeks) epidural blockade on an inpatient basis may
alleviate acute pain and shorten the duration of ongoing
pain.44,45 This treatment is extremely costly and is not with-
out risk.
Guidelines
Guidelines for management of herpes zoster have been
published by the International Herpes Management
Forum (IHMF ) (Figure 3), and by the British Society for
the Study of Infection.46,47 There is broad agreement
between the guidelines except where dose regimens differ
between the U S A and U K . However, neither guideline
states the extent of evidence to justify the guidance given.
5
It is current recommended practice to state the evidence
or opinion upon which each guideline is based, with the
degree of condence which may be attached to that evi-
dence:48,49
(a) Requires at least one randomized, controlled trial as
part of a body of specic recommendation.
(b) Requires the availability of well-conducted clinical
studies but no randomized clinical trials on the topic of
recommendation.
(c) Requires evidence obtained from expert committee
reports of opinions or clinical experiences of respected
authorities. This indicates absence of directly applic-
able clinical studies of good quality.
Revised guidelines are to be produced by the Varicella-
zoster Virus Research Foundation (VZVRF) and the
IHM F according to current standards for guideline produc-
tion.48,49
Varicella-zoster virus, vaccination and predicted
future changes
Varicella is more commonly a disease of young adults in
countries with hotter climates.50 In the U K , young adult
immigrants from such countries who work in the healthcare
sector have not usually experienced the primary infection
and are therefore susceptible to VZV infection from
elderly patients with herpes zoster.51 As travel between
countries becomes more common, there is increasing oppor-
tunity for mixing of geographically distinct VZV geno-
types.52 It is unknown whether these viral genotypes
(strains) differ in their biological properties and, in particu-
lar, whether they result in more- or less-severe zoster when
they reactivate.
Childhood vaccination against varicella is now available
in a number of countries.53,54 In some, for example the U K ,
it is reserved for groups at high risk from severe varicella
infection. In others, notably the USA , it is made available
to all children, partly, at least, for convenience and reduced
need for home care during the illness. If varicella vaccina-
tion were to become universal, a number of scenarios arise
that could inuence the natural history of herpes zoster.
The vaccine is a live attenuated Oka strain virus, which, like
wild-type V Z V, becomes latent and is subsequently
capable of reactivation, albeit less frequently or perhaps
with reduced disease severity.55,56 With universal vaccina-
tion, presumably some few generations later, herpes zoster
would cease to exist.7 But in the meantime, what happens
to those individuals who have had the primary (wild-type)
infection but cease to be in close contact with children of
subsequent generations with chickenpox? It is likely that
such contact with a wild-type virus has the effect of boost-
ing immunity and thus delays the opportunity for latent
VZV to reactivate to the extent necessary to cause zoster.57
Without this continual boosting effect, zoster might occur
at an earlier age when the risk of PHN should be less and
 R. W. Johnson

Figure 3. I HMF guidelines for the management of herpes zoster.46

a
Aciclovir has been shown to reduce the ocular complications of herpes zoster when given up to 7 days after rash onset.

additionally serve to self boost the individuals immunity
to prevent future zoster attacks in older age.
The Oka strain varicella vaccine has been shown to
enhance VZV-specic cell-mediated immunity in older
adults.58,59 Over 200 VZV-seropositive individuals (mean
age 67 years) were immunized with Oka vaccine and cell-
mediated immunity assessed from responder cell counts
per 105 peripheral blood mononuclear cells (PBMCs).
The PBMC response nearly doubled, from 1.4 to 2.5, pre-
vaccination to 6 months post-vaccination, and persisted
with a half-life of 4.5 years. Such a level of cell-mediated
immunity achieved 6 months after vaccination is similar to
that observed in otherwise healthy individuals of about
40 years of age, in whom herpes zoster is relatively rare.60
The Oka strain vaccine was well tolerated in this study and
is now under examination for use in adults as a means of

6
 Predicting and preventing post-herpetic neuralgia
boosting immunity to result in a milder disease from any
VZV reactivation that may occur, or provide adequate pro-
tection to prevent herpes zoster for the remaining years of
the individuals life.60
Conclusions
PHN is remarkably intractable and results in signicant
suffering and healthcare resource usage. Safe measures
that help prevent PHN are laudable from all aspects and
should be widely known in the form of national guidelines
and local treatment algorithms. At present, the only safe
and practical preventive treatment shown to have any ben-
ecial effect is early use of oral antiviral drugs. Shortening
the course of PHN, and thus reducing its prevalence, as
demonstrated in trials of antiviral drugs, more than justies
the use of such drugs to treat acute herpes zoster. In the
U K , a course of antiviral treatment for herpes zoster is
approximately 100 and second attacks of the condition are
unusual: this cost would seem reasonable to reduce the
personal suffering, carer distress and inconvenience, and
healthcare costs of the management of PHN. There may be
signicant advances in both prevention and management
of PHN in the future and the epidemiology of herpes zoster
may alter.
References
1. Hope-Simpson, R. E. (1965). The nature of herpes zoster: a long-
term study and a new hypothesis. Proceedings of the Royal Society
of Medicine 58, 920.
2. Bowsher, D. (1999). The lifetime occurrence of herpes zoster and
prevalence of post-herpetic neuralgia: a retrospective study in an
elderly population. European Journal of Pain 3, 33542.
3. Miller, A. E. (1980). Selective decline in cellular immune response
to varicella-zoster in the elderly. Neurology 30, 5827.
4. Weksler, M. E. (1994). Immune senescence. Annals of Neuro-
logy 35, Suppl., S357.
5. Dworkin, R. H. & Portenoy, R. K. (1994). Proposed classication
of herpes zoster pain. Lancet 343, 1648.
6. Ragozzino, M. W., Melton, L. J. 3rd, Kurland, L. T, Chu, C. P. &
Perry, H. O. (1982). Population-based study of herpes zoster and its
sequelae. Medicine (Baltimore) 61, 3106.
7. Johnson, R. W. (1995). The future of predictors, prevention, and
therapy in postherpetic neuralgia. Neurology 45, Suppl. 8, S702.
8. Woolf, C. J., Shortland, P. & Coggeshall, R. E. (1992). Peripheral
nerve injury triggers central sprouting of myelinated afferents.
Nature 355, 758.
9. Coderre, T. J., Katz, J., Vaccinario, A. L. & Melzack, R. (1993).
Contributions of central neuroplasticity to pathological pain: review
of clinical and experimental evidence. Pain 52, 25985.
10. Watson, C. P. N. & Deck, J. H. (1993). The neuropathology of
herpes zoster with particular reference to postherpetic neuralgia and
its pathogenesis. In Herpes Zoster and Postherpetic Neuralgia,
(Watson, C. P. N., Ed.), Elsevier, Amsterdam.
11. Max, M. B. (1995). Thirteen consecutive well-designed ran-
7
domized trials show that antidepressants reduce pain in diabetic
neuropathy and postherpetic neuralgia. Pain Forum 4, 24853.
12. Rowbotham, M., Harden, N., Stacey, B., Bernstein, P. &
Magnus-Miller, L. (1998). Gabapentin for the treatment of post-
herpetic neuralgia: a randomized controlled trial. Journal of the
American Medical Association 280, 183742.
13. Watson, C. P. & Babul, N. (1998). Efcacy of oxycodone
in neuropathic pain: a randomized trial in postherpetic neuralgia.
Neurology 50, 183741.
14. Rowbotham, M. C., Reisner-Keller, L. A. & Fields, H. L. (1991).
Both intravenous lidocaine and morphine reduce the pain of post-
herpetic neuralgia. Neurology 41, 10248.
15. Stefani, A., Spadoni, F. & Bernardi, G. (1998). Gabapentin
inhibits calcium currents in isolated rat brain neurons. Neuro-
pharmacology 37, 8391.
16. Calabresi, P., Centonze, D., Mara, G. A., Pisani, A. & Bernadi,
G. (1999). An in vitro electrophysiological study on the effects of
phenytoin, lamotrigine and gabapentin on striatal neurons. British
Journal of Pharmacology 126, 68996.
17. Taylor, C. P., Gee, N. S., Su, T. Z., Kocsis, J. D., Welty, D. F.,
Brown, J. P. et al. (1998). A summary of mechanistic hypotheses of
gabapentin pharmacology. Epilepsy Research 29, 23349.
18. Gee, N. S., Brown, J. P., Dissanayake, V. U., Offord, J.,
Thurlow, R. & Woodruff, G. N. (1996). The novel anticonvulsant
drug, gabapentin, (Neurontin), binds to the 2 subunit of a calcium
channel. Journal of Biological Chemistry 271, 576876.
19. Rowbotham, M. C., Davies, P. S., Verkempinck, C. & Galer, B.
S. (1996). Lidocaine patch: double-blind controlled study of a new
treatment method for post-herpetic neuralgia. Pain 65, 3944.
20. Galer, B. S., Rowbotham, M. C., Perander, J. & Friedman, E.
(1999). Topical lidocaine patch relieves postherpetic neuralgia more
effectively than a vehicle topical patch: results of an enriched enrol-
ment study. Pain 80, 5338.
21. Watson, C. P., Evans, R. J. & Watt, V. R. (1988). Post-herpetic
neuralgia and topical capsaicin. Pain 33, 33340.
22. Nathwani, D., MacDonald, T. & Davey, P. (1995). Cost-effec-
tiveness of aciclovir for varicella infections in immunocompetent
patients: a British perspective. Infectious Diseases in Clinical Prac-
tice 4, 13845.
23. Davies, L., Cossins, L., Bowsher, D. & Drummond, M. (1994).
The cost of treatment for postherpetic neuralgia in the UK. Pharmaco-
Economics 6, 1428.
24. Dworkin, R. H., Hartstein, G., Rosner, H. L., Walther, R. R.,
Sweeney, E. W. & Brand, L. (1992). A high-risk method for studying
psychosocial antecedents of chronic pain: the prospective investiga-
tion of herpes zoster. Journal of Abnormal Psychology 101, 2005.
25. Wood, M. J., Kay, R., Dworkin, R. H., Soong, S. J. & Whitley,
R. J. (1996). Oral acyclovir therapy accelerates pain resolution in
patients with herpes zoster: a meta-analysis of placebo-controlled
trials. Clinical Infectious Diseases 22, 3417.
26. Whitley, R. J., Shukla, S. & Crooks, R. J. (1998). The identica-
tion of risk factors associated with persistent pain following herpes
zoster. Journal of Infectious Diseases 178, Suppl. 1, S715.
27. Dworkin, R. H., Boon, R. J., Grifn D. R. & Phung, D. (1997).
Postherpetic neuralgia: impact of famciclovir treatment, age, lesion
severity and pain severity in acute herpes zoster patients. In Pro-
ceedings of the Third International Conference on the Varicella
Zoster Virus, Palm Beach, Florida. Abstract no. 20. Varicella Zoster
Virus Research Foundation.
 R. W. Johnson
28. Burke, B. L., Steele, R. W., Beard, O. W., Wood, J. S., Cain,
T. D. & Marmer D. J. (1982). Immune responses to varicella-zoster
virus antigen in the aged. Archives of Internal Medicine 142, 2913.
29. Grifths, P. D. (1994). Spectrum of activity of antiherpesvirus
drugs. Antiviral Chemistry and Chemotherapy 5, Suppl. 1, 1722.
30. Grifths, P. D. (1999). Strengths and limitations of therapies for
genital herpes pre-clinical aspects. In Optimizing the Management
of Genital Herpes. Round Table Series 69, RSM Press, London.
31. Beutner, K. R., Friedman, D. J., Forszpaniak, C., Andersen, P.
L. & Wood, M. J. (1995). Valaciclovir compared with acyclovir for
improved therapy for herpes zoster in immunocompetent adults.
Antimicrobial Agents and Chemotherapy 39, 154653.
32. Perry, C. M. & Faulds, D. (1996). Valaciclovir. A review of its
antiviral activity, pharmacokinetic properties and therapeutic ef-
cacy in herpesvirus infections. Drugs 52, 75472.
33. Degreef, H. & The Famciclovir Herpes Zoster Clinical Study
Group. (1994). Famciclovir, a new oral antiherpes drug: results of the
rst controlled clinical study demonstrating its efcacy and safety in
the treatment of uncomplicated herpes zoster in immunocompetent
patients. International Journal of Antimicrobial Agents 4, 2416.
34. Tyring, S., Barbarash, R. A., Nahlik, J. E., Cunningham, A.,
Marley, J., Heng, M. et al. (1995). Famciclovir for the treatment of
acute herpes zoster: effects on acute disease and postherpetic
neuralgia. A randomized, double-blind, placebo-controlled trial.
Annals of Internal Medicine 123, 8996.
35. Ormrod, D. & Goa, K. (2000). Valaciclovir: A review of its use in
the management of herpes zoster. Drugs 59, 131740.
36. Dworkin, R. H., Boon, R. J., Grifn, D. R. & Phung, D. (1998).
Postherpetic neuralgia: impact of famciclovir, age, rash severity, and
acute pain in herpes zoster patients. Journal of Infectious Diseases
178, Suppl. 1, S7680.
37. Paul, J. E., Mauskopf, J. A. & Bell, L. (1995). Cost-consequence
models for varicella zoster virus infections. Pharmacotherapy 15,
49S58S.
38. Grant, D. M., Mauskopf, J. A., Bell, L. & Austin, R. (1997). Com-
parison of valaciclovir and acyclovir for the treatment of herpes
zoster in immunocompetent patients over 50 years of age: a cost-
consequence model. Pharmacotherapy 17, 33341.
39. Wood, M. J., Johnson, R. W., McKendrick M. W., Taylor, J.,
Mandal, B. K. & Crooks, J. (1994). A randomized trial of acyclovir for
7 days or 21 days with and without prednisolone for treatment of acute
herpes zoster. New England Journal of Medicine 330, 896900.
40. Whitley, R. J., Weiss, H., Gnann, J., Tyring, S., Wolf, J., Pollard,
R. et al. (1995). The efcacy of steroids and acyclovir therapy of
herpes zoster in the elderly. Antiviral Research 26, A303.
41. Whitley, R. J., Weiss, H., Gnann, J. W. Jr, Tyring, S., Mertz, G. J.,
Pappas, P. G. et al. (1996). Acyclovir with and without prednisone for
the treatment of herpes zoster. A randomized, placebo-controlled
trial. Annals of Internal Medicine 125, 37683.
42. Pasqualucci, A., Pasqualucci, V., Galla, F., De Angelis, V.,
Marzocchi, V., Colussi, R. et al. (2000). Prevention of post-herpetic
neuralgia: acyclovir and prednisolone versus epidural local anaes-
thetic and methylprednisolone. Acta Anaesthesiologica Scandinavica
44, 9108.
43. Lavoie, P. A., Khazen, T. & Filion, P. R. (1988). Mechanisms of
the inhibition of fast axonal transport by local anaesthetics. Neuro-
pharmacology 28, 17581.
44. Manabe, H., Dan, K. & Higa, K. (1995). Continuous epidural
infusion of local anaesthetics and shorter duration of acute zoster-
associated pain. Clinical Journal of Pain 11, 2208.
45. Higa, K., Hori, K., Harasawa, I., Hirata, K. & Dan, K. (1998). High
thoracic epidural block relieves acute herpetic pain involving the
trigeminal and cervical regions: comparison with effects of stellate
ganglion block. Regional Anaesthesia and Pain Medicine 23, 259.
46. IHMF Management Strategies Workshop. (1996). Manage-
ment Strategies in Herpes: Reducing the Burden of Zoster-Asso-
ciated Pain Update, (Wood, M. J. & Kroon, S., Eds), PAREXEL
MMS Europe Ltd, Worthing, UK.
47. Johnson, R. W. & Mandal, B. K. (1995). Guidelines for the
management of shingles. Report of a working group of the British
Society for the Study of Infection (BSSI). Journal of Infection 30,
193200.
48. Shaneyfelt, T. M., Mayo-Smith, M. F. & Rothwangl, J. (1999).
Are guidelines following guidelines? The methodological quality of
clinical practice guidelines in the peer-reviewed medical literature.
Journal of the American Medical Association 281, 19005.
49. Shekelle, P. G., Woolf, S. H., Eccles, M. & Grimshaw, J. (1999).
Clinical guidelines: developing guidelines. British Medical Journal
318, 5936.
50. Lee, B. W. (1998). Review of varicella zoster seroepidemiology
in India and Southeast Asia. Tropical Medicine and International
Health 3, 88690.
51. Hastie, I. R. (1980). Varicella-zoster virus affecting immigrant
nurses. Lancet ii, 1545.
52. Hawrami, K., Hart, I. J., Pereira, F., Argent, S., Bannister, B.,
Bovill, B. et al. (1997). Molecular epidemiology of varicella-zoster
virus in East London, England, between 1971 and 1995. Journal of
Clinical Microbiology 35, 28079.
53. Holmes, S. J. (1996). Review of recommendations of the Advis-
ory Committee on Immunization Practices, Centers for Disease
Control and Prevention, on varicella vaccine. Journal of Infectious
Diseases 174, Suppl. 3, S3424.
54. Asano, Y., Suga, S., Yoshikawa, T., Kobayashi, I., Yazaki, T.,
Shibata, M. et al. (1994). Experience and reason: twenty-year follow-
up of protective immunity of the Oka strain live varicella vaccine.
Pediatrics 94, 5246.
55. Takahashi, M. (1984). Development and characterization of a
live varicella vaccine (Oka strain). Biken Journal 27, 316.
56. Hardy, I., Gershon, A. A., Steinberg, S. P. & LaRussa, P. (1991).
The incidence of zoster after immunization with live attenuated
varicella vaccine. A study in children with leukemia. Varicella Vaccine
Collaboration Group. New England Journal of Medicine 325,
154550.
57. Arvin, A. M. (1992). Cell-mediated immunity to varicella-zoster
virus. Journal of Infectious Diseases 166, Suppl. 1, S3541.
58. Levin, M. J., Murray, M., Rotbart, H. A., Zerbe, G. O., White, C. J.
& Hayward, A. R. (1992). Immune responses of elderly individuals to
a live attenuated varicella vaccine. Journal of Infectious Diseases
166, 2539.
59. Levin, M. J., Murray, M., Zerbe, G. O., White, C. J. & Hayward,
A. R. (1994). Immune responses of elderly persons 4 years after
receiving a live attenuated varicella vaccine. Journal of Infectious
Diseases 170, 5226.
60. Oxman, M. N. (1995). Immunization to reduce the frequency
and severity of herpes zoster and its complications. Neurology 45,
Suppl. 8, S416.