Journal of Clinical Virology Richard J. Whitley *, Antonio Volpi

Journal of Clinical Virology 48 (2010) S1, S20–S28
Contents lists available at ScienceDirect
Journal of Clinical Virology
j o u r n a l h o m e p a g e : www.elsevier.com/locate/jcv
Management of herpes zoster and post-herpetic neuralgia now and in the future
Richard J. Whitleya, *, Antonio Volpib , Mike McKendrickc , Albert van Wijckd , Anne Louise Oaklandere
a University
of Alabama at Birmingham, CHB 303, 1600-Seventh Avenue South, Birmingham, AL 35233, USA
of Public Health, University of Rome Tor Vergata, Via Montpellier 1, 00133 Roma, Italy
Yorkshire Regional Department of Infection and Tropical Medicine, Royal Hallamshire Hospital, Sheffield S10 2JF, UK
d Pain Clinic, Department of Anaesthesiology, University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht, The Netherlands
e Harvard Medical School, Nerve Injury Unit, Massachusetts General Hospital, 275 Charles Street, Boston, MA 02214, USA
b Department
c South
article info
summary
Keywords:
Zoster
VZV
Antivirals
Management
Herpes zoster (HZ; shingles) – a reactivation of the latent varicella zoster virus (VZV) – can cause
significant morbidity. Its major complication is pain, particularly post-herpetic neuralgia (PHN).
We will review the current management strategies available for the treatment of both acute HZ
and PHN, including antiviral drugs, analgesic agents, anticonvulsants, tricyclic antidepressants and
topical therapies. New molecules in development that show improved activity against VZV are
also covered, and new drug targets are outlined. The role of translational neuroscience in moving
towards a goal of finding disease-modifying treatments will be examined.
© 2010 Elsevier B.V. All rights reserved.
Abbreviations
1. Introduction
HZ:
PHN:
VZV:
GP:
5-FU:
TTP:
HUS:
FDA:
ZAP:
RR:
DPD:
BVaraU:
BCNA:
SVV:
BVDU:
HPMPA:
PMEA:
TK:
TCA:
ECG:
DRG:
PRF:
NE:
APN:
NEP:
CNS:
The objectives of treating herpes zoster (HZ) are to control
acute pain, accelerate rash healing, minimize complications and
reduce the risk of post-herpetic neuralgia (PHN) and other lateappearing sequelae. An additional objective, particularly important
for immunosuppressed patients, is to reduce the risk of cutaneous
and visceral dissemination of the varicella zoster virus (VZV).1
herpes zoster
post-herpetic neuralgia
varicella zoster virus
general practitioner
5-fluorouracil
thrombotic thrombocytopoenic purpura
haemolytic-uraemic syndrome
Food and Drug Administration
zoster-associated pain
risk ratio
dihydropyrimidine dehydrogenase
bromovinyl arabinosyl uracil
bicyclic nucleoside analogue
simian varicella virus
bromovinyldeoxyuridine
9-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]adenine
phosphonomethoxy-ethyl-adenine
thymidine kinase
tricyclic antidepressant
electrocardiogram
dorsal root ganglion
pulsed radio frequency
norepinephrine
aminopeptidase N
neutral endopeptidase
central nervous system
* Corresponding author. University of Alabama at Birmingham,
CHB 303, 1600-Seventh Avenue South, Birmingham, AL 35233, USA.
Tel.: +1 205 934 5316; fax: +1 205 934 8559.
E-mail address: rwhitley@peds.uab.edu (R.J. Whitley).
1590-8658 /$ – see front matter © 2010 Elsevier B.V. All rights reserved.
2. Current management of acute HZ
The diagnosis of HZ is generally evident at clinical presentation.
However, there are situations where diagnosis is difficult, or the
patient or physician had not recognized the symptoms and signs
early enough. Several studies indicate potential hurdles in diagnosis.
One seminal study tested the hypothesis that vaccination against
VZV would decrease the incidence and/or severity of HZ and PHN
among adults aged >60 years, including the burden of illness. This
study involved >38,000 volunteers and demonstrated that 5–6% of
the clinical diagnoses by academic physicians were not laboratory
confirmed,2 suggesting that even knowledgeable infectious diseases
clinicians are occasionally wrong in their diagnosis. Similarly, a
prospective study of HZ diagnoses by general practitioners (GPs)
found 17% of diagnoses to be incorrect.3 Furthermore, in a recent
study of psychosocial correlates of HZ,4 which used pain as an
indicator of disease onset, 92% of 533 individuals with HZ had
pain at presentation. However, only 46% sought medical attention
within 72 hours of pain onset and 54% within 72 hours of rash
appearance. Initial assessment was late, at a median time of
72 hours after the onset of rash. Importantly, >80% of the subjects
reported prodromal pain, which in the majority of cases lasted
2 or 3 days.
R.J. Whitley et al. / Journal of Clinical Virology 48 (2010) S20–S28
S21
Table 1
Antivirals currently available for the treatment of HZ.
Drug
Dosage a
Comments, adverse events and contraindications
Reference
Oral acyclovir
800 mg five times daily for
7–10 days
• Adverse events similar to placebo
Prescribing information5
Intravenous acyclovir
10 mg/kg three times daily
Adults and children over 40 kg:
800 mg four times daily for
5 days
• Indicated in immunocompromised patients
• Adverse events include crystalluria associated with rapid infusion in patients
with renal impairment
• Rarely, CNS disturbances in elderly with renal dysfunction
Prescribing information5
Valacyclovir
1000 mg three times daily for
7 days
• Acute hypersensitivity reactions including anaphylaxis, angioedema,
dyspnoea, pruritus, rash and urticaria
• Contraindications: Hypersensitivity to valacyclovir (e.g., anaphylaxis),
acyclovir or any component of the formulation
• Pregnancy category B: Should be used during pregnancy only if the potential
benefit justifies the potential risk to the foetus
• In two clinical studies, adverse events included nausea, headache, vomiting,
dizziness and abdominal pain
• TTP/HUS reported in AIDS and transplant patients during clinical trials
Prescribing information6
Famciclovir
500 mg every 8 hours for 7 days
• Contraindicated in patients with known hypersensitivity to famciclovir, its
components and penciclovir cream
• Pregnancy category B: Should be used during pregnancy only if the benefit
to the patient clearly exceeds the potential risk to the foetus
• In clinical studies, adverse events included headache, paresthesia, nausea
and vomiting
Prescribing information7
Brivudin
125 mg once daily for 7 days
• Adverse events included nausea (incidence and type of potential adverse
drug experiences were consistent with those known to occur with other
nucleoside antiviral agents belonging to the same class)
• Contraindicated in:
– Patients undergoing cancer chemotherapy, especially if treated with 5-FU,
including its topical preparations, its prodrugs (e.g., capecitabine,
floxuridine, tegafur) and combination products containing these active
substances or other 5-fluoropyrimidines
– Immunocompromised patients such as those undergoing cancer
chemotherapy, immunosuppressive therapy or therapy with flucytosine in
severe systemic mycosis
– Pregnant women or nursing mothers
Product characteristics8
Abbreviations: 5-FU, 5-fluorouracil; HUS, haemolytic-uraemic syndrome; TTP, thrombotic thrombocytopoenic purpura.
a Dosage of antivirals may differ between countries. Please refer to local prescribing information.
2.1. Current antiviral therapies
Three oral nucleoside analogues – acyclovir, valacyclovir (prodrug
of acyclovir) and famciclovir (prodrug of penciclovir) – are
approved worldwide for the treatment of HZ, including in
immunocompromised patients. An additional antiviral drug,
brivudin, is widely available in some countries but is limited to an
indication for immunocompetent patients because of a potentially
fatal interaction with 5-fluorouracil (5-FU) (see Table 1).
All of the antiviral drugs significantly decrease the incidence of
new lesion formation and accelerate healing and the resolution of
acute pain. In addition, antiviral therapy shortens the duration of
viral shedding,1 which hypothetically may limit neuron damage,
thereby reducing the incidence, severity and duration of pain.
An essential component of antiviral treatment is its effects on
the resolution of pain. There are three forms of pain defined as
follows. First, pain at presentation is acute pain and the extent of
its resolution can be quantified over the first 30 days. Second, and
the most debilitating form of pain, is PHN. Several definitions of
PHN have been used over the past 30 years, and all have different
implications for clinical studies. PHN is defined by the US Food and
Drug Administration (FDA) as ‘Pain that has not resolved 30 days
after disease onset’.9 An alternative definition is pain that persists
after skin healing. The third form of pain is that of zoster-associated
pain (ZAP), whereby pain is viewed as a continuum from the time
of acute zoster until its complete resolution, if it occurs.
To date, there is no consensus on the definition of PHN. Early
studies used a wide range of definitions, including ‘any pain that
follows disappearance of the rash of herpes zoster’, whereas other
studies used the definition of ‘pain present for more than 1 or
2 months after rash onset’.10 However, recent models of pain
resolution and statistical analysis suggest that the most appropriate
definition of PHN is pain that persists 90 days or more after the
onset of HZ rash.11
In early acyclovir studies, PHN was defined as ‘persistence 30 days
after disease onset or the healing of skin’. Thus, the early acyclovir
trials and a large meta-analysis involving 691 patients suggested
that acyclovir (800 mg five times daily for 7–10 days) was more
effective than placebo in reducing pain.12 Benefits were particularly
noticeable for patients aged >50 years. Overall, the incidence and
duration of PHN among patients receiving acyclovir were half those
reported by placebo recipients, and fewer acyclovir-treated patients
had PHN at 3 and 6 months.12 However, this has not been proven
in a sufficiently powered prospective study.
According to ZAP analyses from various clinical studies, valacyclovir (a prodrug of acyclovir) is more efficacious than acyclovir. One
study comparing two different regimens of valacyclovir (1000 mg
three times daily for 7 days, or 1000 mg three times daily for
14 days) with acyclovir (800 mg five times daily for 7 days)
showed that the time to ZAP resolution was significantly longer
with acyclovir therapy (median time to ZAP resolution: acyclovir,
51 days; 7-day valacyclovir, 38 days [p = 0.002]; 14-day valacyclovir,
44 days [p = 0.03]).13 Valacyclovir therapy also had a faster time
to ZAP resolution that had persisted for >30 days compared with
acyclovir (HR 1.24; CI 1.04–1.48; p = 0.01 for the 7-day valacyclovir
R.J. Whitley et al. / Journal of Clinical Virology 48 (2010) S20–S28
group; HR 1.17; CI 0.98–1.39; p = 0.09 for the 14-day valacyclovir
group). In this study, pain was recorded in 85% of the patients in
the acyclovir group, and in 79% and 80% of the patients receiving
valacyclovir for 7 and 14 days, respectively.13
Famciclovir is also an effective and well-tolerated therapy of
HZ. A study of 419 patients with HZ given either famciclovir
500 mg/day or 750 mg/day for 7 days, or placebo, showed that
famciclovir treatment accelerated lesion healing and decreased
the median duration of PHN resolution.14 The efficacy-evaluable
analyses revealed that time to full crusting was 1.3- to 1.5-fold
faster in the 500 mg famciclovir (p = 0.02) and 750 mg famciclovir
(p = 0.02) groups compared with the placebo group. PHN was also
significantly reduced in the famciclovir groups (500 mg famciclovir:
HR 1.7 and 95% CI 1.1–2.7; 750 mg famciclovir: HR 1.9 and CI 1.2–2.9;
p = 0.02 and 0.01, respectively).
Famciclovir has the advantage of reduced frequency of dosing15,16
but it is important to note that the recommended dose of
famciclovir varies between countries. A study of 545 patients with
HZ randomized to receive 7 days of either famciclovir 250, 500
or 750 mg three times daily or acyclovir 800 mg five times daily,
initiated within 72 hours of the onset of the zoster rash, showed
that famciclovir was as effective as acyclovir at all doses for the
healing of cutaneous lesions.17 Time to resolution of acute pain was
similar in all arms, but time to ZAP resolution was significantly
shorter in those treated with famciclovir within 48 hours of
rash onset compared with acyclovir (famciclovir 250, 500 and
750 mg vs. acyclovir, p = 0.006, 0.003 and 0.042, respectively).17
Median time to ZAP resolution after skin healing was faster in
the famciclovir arms than in the acyclovir arm (resolution was
1.4 [p = 0.086], 1.8 [p = 0.003] and 1.4 [p = 0.05] times faster in
the 250 mg, 500 mg and 750 mg famciclovir groups, respectively,
compared with acyclovir).17
A direct head-to-head comparison of famciclovir and valacyclovir
in immunocompetent patients aged >50 years showed that the two
drugs were therapeutically equivalent, for both healing rate and
pain resolution.18
The fourth commercially available anti-VZV drug used to treat
HZ is the synthetic pyrimidine analogue, brivudin. Brivudin is
licensed in some European countries, South Africa and Israel for
the early treatment of HZ in immunocompetent adults.19 Brivudin
is 200–1,000 times more effective in inhibiting viral replication
in vitro than acyclovir or penciclovir,20 and it accumulates rapidly
inside virus-infected cells.21
Brivudin (125 mg once daily for 7 days) was more effective
than acyclovir (800 mg five times daily for 7 days) in a study
of 1,227 immunocompetent patients with HZ.22 The time to ZAP
resolution was similar between the two groups (risk ratio [RR]
0.996; p = 0.001), but the brivudin group had a faster time to
last formation of new vesicles compared with acyclovir (RR 1.13;
p = 0.014). However, the intent-to-treat analysis of lesion healing
indicated that brivudin is as effective as acyclovir according to
time to first crust (brivudin RR 0.93; 95% CI 0.83–1.05; acyclovir
RR 0.93, CI 0.83–1.05), time to full crusting (brivudin RR 1.03; 95%
CI 0.92–1.16; acyclovir RR 1.03, CI 0.92–1.16) and time to loss of
crusting (brivudin RR 0.95; 95% CI 0.85–1.07; acyclovir RR 0.93, CI
0.85–1.07). A large multicentre study of 2,027 patients with acute
HZ aged ≥50 years demonstrated that brivudin had a similar efficacy
on pain and rash and a similar tolerability profile to famciclovir
(250 mg three times daily for 7 days).23
Drug interactions have been reported between brivudin and 5-FU
and other 5-fluoropyrimidines. The main metabolite of brivudin,
bromovinyl uracil, inhibits dihydropyrimidine dehydrogenase
(DPD), which regulates the metabolism of pyrimidine derivatives;
hence, brivudin therapy can cause the accumulation and enhanced
toxicity of these drugs. A congener analogue, bromovinyl arabinosyl
uracil (BVaraU), when administered to patients receiving 5-FU,
resulted in several deaths in Japan.24 Consequently, brivudin should
not be administered concomitantly with 5-FU or its derivatives,
capecitabine, floxuridine or flucytosine. As a further precaution,
DPD activity should be monitored before starting any treatment
with 5-fluoropyrimidine drugs in patients who have recently
received brivudin.25
2.2. The rationale for existing antiviral treatment schedules
Current evidence from clinical trials is based on the initiation of
therapy within 72 hours of rash outbreak.26 There are no wellcontrolled clinical trials that have compared early-onset therapy
with later therapy (>72 hours). Bean et al.27 found that the time
to viral shedding was reduced by acyclovir therapy compared with
placebo in patients who had a zoster rash for <72 hours (Figure 1).
It is surprising that, in a HZ vaccine trial,2 only two thirds of the
patients who developed HZ received appropriate antiviral treatment
within 72 hours, despite being informed at study onset about
the symptoms and signs of HZ. These drugs may afford greater
benefit if they are used within the first 72 hours of rash onset.
Early diagnosis and treatment of HZ result in accelerated cutaneous
healing and reduced median duration of pain according to the
ZAP analyses. It seems likely that one of the major causes of
decreased efficacy of antiviral therapy is the delay between onset of
symptoms and initiation of treatment. Treatment with more active
and lipophilic agents may be beneficial in reducing viral replication
and consequent neural damage as quickly as possible, and hence
may reduce both acute and chronic manifestations of HZ. The need
for more education of the public and healthcare providers on HZ is
also evident.
100
90
80
% with positive cultures
S22
70
Acyclovir
Placebo
60
50
40
30
20
10
0
0
1
2
3
4
5
Study days
6
7
8
Fig. 1. Time to cessation of viral shedding.27 Reprinted from Bean B, et al., Acyclovir
therapy for acute herpes zoster. Lancet 1982;320(8290):118–21. © 1982, with
permission from Elsevier.
Longer courses of antiviral therapy administered either orally
or intravenously do not confer additional benefit in reducing the
duration of PHN.10,28,29
For individuals with zoster ophthalmicus, early antiviral treatment reduces the incidence of ocular complications. In placebocontrolled studies, oral acyclovir, valacyclovir and famciclovir,
initiated within 72 hours of rash onset, reduced the incidence of
ocular complications in patients with ophthalmic zoster compared
with placebo or historical untreated controls (reviewed in Johnson
et al., 2001).30 A retrospective comparison of ocular outcomes
in 202 antiviral-treated and 121 non-treated ophthalmic zoster
patients in Minnesota, USA, showed that patients treated with
antivirals had a lower risk of severe visual loss or other adverse
R.J. Whitley et al. / Journal of Clinical Virology 48 (2010) S20–S28
S23
Fig. 2. Molecular structures of Cf1743 (left) and FV100 (right).39,40
outcome at 5 or 10 years than non-treated patients (2.1% vs. 8.9%,
respectively, p = 0.009).31 Furthermore, the development of serious
inflammatory complications among treated patients appeared to be
associated with a delay in antiviral treatment, which emphasizes
the importance of early treatment. The concomitant treatment
with corticosteroids under the supervision of an ophthalmologist
is discussed here.
Current International Herpes Management Forum (IHMF® )
guidelines30 recommend that all patients with zoster ophthalmicus
presenting within 1 week of rash onset should be offered oral
antiviral therapy with one of the following to reduce the incidence
of ocular complications: (a) acyclovir 800 mg five times daily for
10 days; (b) valacyclovir 1000 mg three times daily for 7 days; or
(c) famciclovir 500 mg three times daily for 7 days.
2.3. The role of corticosteroids
When administered systemically within 72 hours of rash onset,
corticosteroids have a clinically significant benefit on acute pain
but no demonstrable effect on PHN.28,32 A double-blind study of
400 acute zoster patients, comparing oral acyclovir (800 mg five
times daily) with and without prednisolone, found that more of
the rash area had healed on Days 7 and 14 (p = 0.02) in those
receiving steroids.28 Pain reduction was greater during the acute
phase of the disease in those treated with steroids than in those
without steroids. However, there were no significant differences
between any of the groups in the time to first or complete
cessation of pain. Notably, no placebo controls were included in
this study.28
There is evidence that the use of steroids in combination with
acyclovir can improve quality-of-life outcomes in healthy patients
aged >50 years with localized HZ.32 More than 200 patients with
acute HZ were stratified into four arms to receive acyclovir or
placebo plus prednisone or placebo during the acute phase of
their illness. Times to total crusting and healing were accelerated
in patients receiving acyclovir plus prednisone compared with
patients receiving two placebos; patients receiving acyclovir plus
prednisone had a shorter time to cessation of acute neuritis, time to
return to uninterrupted sleep, time to return to usual daily activity
and time to cessation of analgesic therapy. However, there was no
difference in pain resolution during the 6 months after rash onset
between the combination therapy group and the other groups.
Individuals at risk for complication of steroid therapy were excluded
from this trial (e.g., those with hypertension, osteoporosis and/or
diabetes, among others).32
If there is any evidence of uveitis or corneal inflammation,
topical ophthalmic steroids are prescribed by ophthalmologists in
combination with an oral drug for zoster ophthalmicus. Systemic
steroids are routinely considered in patients with HZ who have
added symptoms from the compression of enlarged, inflamed nerve
roots, such as in VII nerve palsy.
2.4. New molecules in development
Four new drugs are being considered for the treatment of HZ:
CMX001; a nucleoside analogue valomaciclovir (H2G); a helicaseprimase inhibitor; and two bicyclic nucleoside analogues (BCNAs).
CMX001 (hexadecyloxypropyl-cidofovir) is a lipid ester of
cidofovir with enhanced oral bioavailability conferred by the lipid
moiety. The enhanced bioavailability of the ester also reduces
nephrotoxicity by reducing exposure to cidofovir.33 Once inside the
cell, the molecule is cleaved by phospholipase to liberate cidofovir.
In cell culture assays, CMX001 is significantly more active than
cidofovir against all double-stranded DNA viruses, including VZV
and other herpesviruses.34 Because it is a derivative of and is
metabolized to cidofovir, there is a persistent concern for its toxicity,
and in particular its carcinogenicity.35 Importantly, in Phase IB and
early Phase II studies, nephrotoxicity has not been a concern. It
is envisioned that CMX001 will have a primary role in the organ
transplant setting.
Valomaciclovir is the diester prodrug (valine and stearic
acid) of the acyclic guanosine derivative, H2G. It is a potent,
broad-spectrum anti-herpes agent, especially active against VZV
infection, and is phosphorylated by virus-infected cells to H2G
triphosphate to yield a potent inhibitor of viral DNA synthesis.
The pre-clinical pharmacology and toxicology, initial human clinical
pharmacology and pharmacokinetics, and Phase II proof-of-efficacy
of valomaciclovir have now been completed.36
Helicase-primase inhibitors prevent viral DNA replication by
inhibiting VZV-specific enzymes. The helicase-primase inhibitor
ASP2151 is more potent against VZV than acyclovir in tests against
several strains of the virus, including clinical isolates.37,38
The aryl BCNAs are extremely potent and selective against
VZV. The lead molecule, Cf1743 (Figure 2),39 shows activity at
around 0.1 nM in vitro, making it 10,000 times more potent
than acyclovir. The BCNAs are also highly selective: whereas
other nucleoside analogues have activity against simian varicella
virus (SVV), the BCNAs are inactive against SVV. Moreover, SVV
has a genome sequence that is 75% homologous to VZV and
shares many common features, including latency, recurrence and
varicella-like disease. All previous compounds that inhibit VZV also
inhibited SVV, the ratio of EC50 values (SVV:VZV) being 0.2:7 among
the diverse families of antivirals, including bromovinyldeoxyuridine (BVDU), BVaraU, acyclovir, ganciclovir, penciclovir, 9-(S)[3-hydroxy-2-(phosphonomethoxy)propyl]adenine (HPMPA) and
phosphonomethoxy-ethyl-adenine (PMEA).41 Therefore, the BCNAs
are the first compounds shown to inhibit VZV while being inert to
SVV. This result cannot be explained by lack of phosphorylation
S24
R.J. Whitley et al. / Journal of Clinical Virology 48 (2010) S20–S28
Table 2
Prevalence of PHN at 6 months in selected clinical trials.
Study
Proportion of patients
with pain (%)
Reference
Acyclovir (800 mg five times daily) vs. placebo for 7 days
14 vs. 13
McKendrick et al., 198945
Acyclovir (800 mg five times daily for 7 days) vs. placebo
15 vs. ≥50 a
Morton and Thomson, 198944
Valacyclovir (1000 mg three times daily for 7 or 14 days) vs. acyclovir (800 mg five times daily for 7 days)
19.3 vs. 25.7 a
Beutner et al., 199513
Valacyclovir (1000 mg three times daily for 7 days) vs. valacyclovir (1000 mg three times daily for 14 days)
Famciclovir (500 or 750 mg three times daily) vs. placebo for 7 days
19.9 vs.
18.6 a
Approximately 20 vs.
Valacyclovir (1000 mg three times daily) vs. famciclovir (500 mg three times daily) for 7 days
19 vs.
19 a
9.6 a,b
Brivudin (125 mg once daily) vs. famciclovir (250 mg three times daily) for 7 days
11.3 vs.
Brivudin (125 mg once daily) vs. acyclovir (800 mg five times daily) for 7 days
32.7 vs. 43.5 a,b
a
p < 0.05.
b
Beutner et al., 199513
40 a
Tyring et al., 199517
Tyring et al., 200014
Wassilew et al., 200523
Wassilew et al., 200322
3-month follow-up.
because the BCNAs are competitive inhibitors; also, alternative
substrates for the SVV include thymidine kinase (TK), therefore
BCNA nucleotides must arise in SVV-infected cells.
BCNAs are non-toxic in vitro and have no toxicity up to very high
doses (2000 mg/kg) in vivo. They are highly lipophilic and rapidly
permeate cells. Whereas the parent compounds have poor water
solubility and low oral bioavailability, these problems are both
solved by esterification, resulting in the valyl prodrug FV100. FV100
is currently under development, having successfully completed
Phase I clinical trials in the USA; Phase II studies in HZ are
ongoing.40
3. PHN and other complications
HZ is associated with significant neurological complications, the
most prevalent being pain (see Gershon et al., this supplement,42
and Opstelten et al., this supplement43 ).
3.1. The limitations of antiviral therapies in PHN
While antiviral drugs are clinically effective in the treatment of
acute HZ, the data about their benefit in reducing the duration or
incidence of PHN are conflicting. The incidence of PHN in selected
clinical trials is summarized in Table 2. A meta-analysis of all
placebo-controlled trials with acyclovir for HZ established that
there is a significant reduction in ZAP in patients who received
acyclovir.9,46 Similar results were obtained with valacyclovir (ZAP
analysis), which is also more effective than acyclovir at reducing
the duration of PHN11 ; the average duration of pain was 38 days
with valacyclovir and 51 days with acyclovir. Similar reductions
in pain were also noted at 6 months after healing of the rash;
only 19% of patients taking valacyclovir reported pain compared
with 26% of patients taking acyclovir.11 However, a recent Cochrane
report47 concluded that acyclovir has no effect on PHN, although
the study design determined which studies were included in the
review – and many were excluded. The Cochrane report noted that
pain severity, in addition to pain duration, should be used as an
efficacy measure in future randomized trials of antivirals for the
prevention of PHN.47
Famciclovir has also proven effective in acute HZ, promoting
cutaneous healing and reducing the duration of acute pain. The
median duration of pain was half as many days in patients
who received famciclovir compared with those receiving placebo,
resulting in a 3.5-month reduction in the average duration of pain.17
When famciclovir and valacyclovir were compared in a head-tohead study, the drugs were equally effective at resolving ZAP.18
Complications of HZ other than PHN are poorly studied, and
reliable epidemiological information is scarce. An observational,
retrospective analysis of 1,401 HZ cases recorded by dermatologists
and GPs in Italy showed that the most frequently occurring zosterrelated complications, excluding PHN, were ocular complications
(5.7%) and facial palsy (0.6%), with the risk increasing with
age.4,42 Individuals aged >65 years had almost four times the
risk of complications as those aged <35 years. Interestingly,
much lower rates of zoster complications were observed in the
recent Shingles Prevention Study.2 The most frequent zoster-related
complications, excluding pain, were neurological (1.4%) and ocular
(0.7%) in non-vaccinated individuals, and cutaneous (0.7%) and
neurological (0.5%) in vaccine recipients.2 Ocular complications
were markedly lower in this North American population than
in Italian clinical practice, which could be attributed to the
prompt use of antiviral drugs for the majority of patients.48,49
However, it could also reflect regional variations, differences in
study selection criteria or some other unidentified cause, such
as concurrent use of biological therapies (e.g., the monoclonal
antibodies infliximab and adalimumab or the fusion protein
etanercept used to treat autoimmune diseases such as rheumatoid
arthritis), which appear to have an effect on the incidence, severity
and type of HZ. A disproportionately high incidence of atypical
and severe presentations occurs in patients receiving biological
therapies.50,51
3.2. Other treatments for PHN
Opioid analgesics are frequently prescribed for the treatment of
acute and persistent pain. Both short- or long-acting agents, such
as controlled-release morphine and oxycodone, may be used.52 The
side effects of opioid analgesics include drowsiness and cognitive
slowing, nausea, constipation and pruritus. General concerns about
the potential for abuse are less relevant for geriatric populations,
particularly in older patients with no previous history of substance
abuse. In a blinded, within-patient, crossover trial comparing
opioids, tricyclics and placebo for established PHN, opioids had the
highest patient preference.53
Tricyclic antidepressants (TCAs) and the anticonvulsants gabapentin and pregabalin have been the most frequently studied drug
classes for the management of neuropathic pain, including PHN.54
TCAs provide moderate to excellent pain relief and have been used
extensively for the treatment of PHN.55,56 They are widely available
in generic form and can have added benefits for mood and sleep.
In a retrospective study to assess the effects of acyclovir treatment
of acute HZ on subsequent PHN, the effect of amitriptyline was
also examined; early treatment was almost twice as likely to be
successful as late treatment.57 Amitriptyline is the most widely
prescribed TCA for PHN, but others, such as nortriptyline and
desipramine, can also be used effectively and may have fewer side
effects.58 Side effects associated with amitriptyline are common and
include cardiovascular problems such as orthostatic hypotension,
Change from baseline in
numeric pain rating scale score (%)
R.J. Whitley et al. / Journal of Clinical Virology 48 (2010) S20–S28
S25
Control (0.04% capsaicin patch)
8% capsaicin patch
0
–10
–20
–30
–40
a
b
c
c
a
c
c
c
b
c
1
2
3
4
5
6
7
8
9
10
a
c
11
12
Time (weeks)
Number at risk
8% capsaicin 206 203 202 202 202 199 198 197 196 190 187 187 185
Control 196 189 189 189 190 186 186 185 184 180 177 177 172
8% capsaicin patch vs. control:
a
b
c
p < 0.05, p < 0.01, p < 0.001.
Fig. 3. Rapid and sustained pain relief with the 8% capsaicin patch.68 Reprinted from Backonja M, et al., NGX-4010, a high concentration capsaicin patch, for the treatment
of postherpetic neuralgia: a randomised double-blind study. Lancet Neurol 2008;7(12):1106–12. © 2008, with permission from Elsevier.
arrhythmias and electrocardiogram (ECG) abnormalities. These side
effects may be an issue when prescribing to elderly patients; hence,
either nortriptyline or desipramine is the preferred treatment.
Gabapentin, a second-generation anticonvulsant, significantly
reduces the severity of PHN.59,60 Patients receiving gabapentin
have lower daily pain scores and fewer disturbances in mood
and sleep compared with those receiving placebo.59,60 Although
there is no standard dosing regimen, recent studies indicate that
treatment can be initiated at 900 mg/day and, if pain relief is
not satisfactory, the dose may be titrated to 1800 mg/day as side
effects permit (often about 7–10 days).61 Higher doses (up to
3600 mg/day) may be required in some patients. Gabapentin has
a good safety profile, especially among older patients. Designed
as a more potent successor to gabapentin, the anticonvulsant
pregabalin, like gabapentin, is associated with analgesic, anxiolytic
and antiepileptic activity.62 Analgesic effects are mediated through
the a2 -d-l subunit. Oral bioavailability is ≥90%, and peak blood level
is achieved in 1.3 hours with no plasma protein binding. Pregabalin
is devoid of drug interactions. Because it is excreted unchanged
by the kidneys, it is contraindicated in severe renal impairment
(CLCR ≤30).63 Four studies using 150–600 mg/day in divided doses
showed efficacy in reducing pain and sleep interference in PHN.64
It is generally well tolerated but may cause side effects similar to
those of gabapentin. Pregabalin offers a more rapid clinical effect
than gabapentin.
Topical analgesics are commonly used for the relief of PHN,
despite very limited evidence of efficacy. Topical agents for the
treatment of PHN include: acetylsalicylic acid 500 mg in 95% alcohol
5 mL; lidocaine 5% patch or gel; geranium oil65 ; and capsaicin.66
Capsaicin cream 0.025%, applied three or four times daily, is
commonly prescribed (but rarely tolerated). It reduces pain by
activating the TRPV1 receptor and depleting substance P,66 leading
to subsequent desensitization and dying back of nociceptive axon
endings. Side effects include intolerable burning pain, and one
meta-analysis showed the efficacy of this therapy to be limited.67
An 8% formulation patch of capsaicin following topical local
anaesthesia was recently compared with the usual 0.04% capsaicin
patch in a randomized controlled trial of 402 patients with PHN.68
One 60-minute application of the 8% capsaicin patch provided
rapid and sustained pain relief, with 42% of patients experiencing
>30% pain relief compared with 32% of patients in the 0.04%
capsaicin patch group (Figure 3). Actual benefit and tolerability of
the capsaicin patch in clinical practice remain to be determined, as
does the long-term effect on axonal damage.
A topical 5% lidocaine patch can also provide PHN relief for
approximately 12 hours after application, with no or mild side
effects.69 Both oral gabapentin and the lidocaine patch, as well as
pregabalin, are approved by the FDA for the treatment of PHN and
may be considered as first-line treatments.
Alternative therapies for the relief of PHN, and methods of lesscertain efficacy, include:
• Invasive techniques, such as nerve blocks, intrathecal administration of local anaesthetics and excision of the affected skin
• Neuromodulation techniques
• Toxins such as BOTOX-A®
• Combinations of drugs
• Pain management programmes.
Nerve blocks are often used by anaesthesiologists in pain clinics
for the treatment of HZ, but there are no controlled clinical
studies demonstrating their efficacy. The rationale for sympathetic
blockade is particularly problematic as the sympathetic ganglia
are spared from acute HZ involvement. Nerve-block interventions
can target several sites, such as the dorsal root ganglion (DRG),
peripheral nerves, sympathetic chain and epidural blocks.
A recent study of epidural steroid injection failed to show
that this approach provided any benefit in preventing long-term
PHN. A single epidural injection of steroids and local anaesthetics
during the acute phase of HZ modestly reduced pain for 1 month
(ZAP analysis),70 but the benefit was lost by 3 months posttreatment. Treating PHN with a single injection near a single DRG
is not always advisable as it can be difficult to tell precisely
which dermatome is affected. Prognostic nerve blocks may need
to be performed to identify the correct ganglion, and there are
no data to support the efficacy of this invasive treatment. The
intrathecal administration of local anaesthetics, corticosteroids
and neuroactive peptides is another potential therapy. In a trial
comparing lidocaine with lidocaine and methylprednisolone,71 the
combination of lidocaine and methylprednisolone administered
in weekly injections over 4 weeks decreased the intensity and
area of pain and reduced the use of the non-steroidal antiinflammatory drug diclofenac compared with either lidocaine alone
or no treatment. One year after treatment, 82% of patients in the
lidocaine and methylprednisolone group reported good or excellent
pain relief compared with only 5% in the lidocaine-only group.
Despite the promising results from this trial, intrathecal steroid
injections have not become widely used for the management
of PHN, mainly owing to concerns over safety and the lack of
confirmation or verification in clinical practice.
Neuromodulation refers to a group of techniques that stimulate
various parts of the nervous system to relieve pain. Limited
data support the use of implanted spinal cord stimulators for
PHN. A single study reports that pulsed radio frequency (PRF)
ablation of the DRG provided significant pain relief compared with
conventional pain treatments in patients with intractable PHN.72
R.J. Whitley et al. / Journal of Clinical Virology 48 (2010) S20–S28
Number of epidermal fibres/mm
S26
Density of epidermal nerve endings in
HZ-affected skin
100
90
80
70
60
50
40
30
20
10
0
No pain group
PHN pain group
Fig. 4. Loss of neurites in skin previously affected by shingles as depicted in vertical sections from skin biopsies immunolabelled against PGP9.5, a standard pan-axonal
marker.76 A patient with PHN (B) has far fewer remaining nerve endings than a demographically matched patient without PHN (A) after shingles. Because HZ kills the entire
neuron, the loss of nerve endings in the skin is likely to predict a loss of sensory input into the CNS. Modified from Oaklander AL, Romans K, Horasek S, Stocks A, Hauer P,
Meyer RA. Unilateral postherpetic neuralgia is associated with bilateral sensory neuron damage. Ann Neurol 1998 Nov;44(5):789–95. © 1998 Annals of Neurology.
There is limited evidence concerning efficacy of stimulation.73
Medically unresponsive PHN affecting the face or hand is a
reasonable target for motor cortex stimulation, a minimally invasive
option in which electrodes are placed outside the brain. A metaanalysis of 11 studies using non-invasive brain stimulation and
22 studies using invasive brain stimulation74 showed that brain
stimulation of the motor cortex can have a significant effect on
chronic pain, with responder rates of 73% in the invasive stimulation
studies and 45% in the non-invasive stimulation studies. Such
treatments are rarely indicated.
3.3. New drug targets for PHN
Many targets for drugs in the pain pathway have been identified,
indicating the complexity of pain pathways and the inability to
identify one key target. Among the candidates being assessed are:
• TRPV1 receptor, which has been targeted by many drugs,
including capsaicin
• NMDA receptor; drugs targeting this receptor have not been found
to be effective in the treatment of PHN
• Cannabinoids have been tested in studies, but they are unlikely
to be used in the clinic because of their legal status in the USA
• Calcium channels are targeted by pregabalin and gabapentin, but
there are other subunits of the channel that could represent
therapeutic targets
• Sodium channels are the targets for many antiepileptic drugs,
some of which have been tested in PHN with only minimal
efficacy
• The norepinephrine (NE) transporter is a new target, and
drugs that interact with this molecule are still at Phase I of
development
• Drugs that target the aminopeptidase N (APN) and neutral
endopeptidase (NEP) are still in early phases of research
• Neurotrophic factors and growth factors are potentially interesting targets because it is thought that the loss of nerve fibres plays
an important role in the pathogenesis of PHN.
3.4. Managing PHN in the future: Translational neuroscience
The goal for managing PHN in the future will be to move away from
palliative care towards disease-modifying treatments. Identifying
patients at highest risk of developing PHN might permit the
development of new translational therapies to be used early in the
disease. Surrogate markers obtained from skin biopsy data might
enable early identification of HZ patients at high risk for PHN, e.g.,
vibration threshold measurements using graduated tuning forks75
or laser Doppler measurements of skin blood flow.
An important advance in the understanding of the pathogenesis
of PHN was the documentation of the loss of neurites in the skin
during HZ (Figure 4). It is known that there is a step-function
relationship between axonal degeneration and the presence of
PHN pain, and a threshold of 650 neurites/mm2 dichotomizes HZ
patients with or without PHN.77 This implies that the absence of
pain after HZ may require the preservation of a minimum density
of primary nociceptive neurons. Because virtually all axons that
end in the epidermis are nociceptors,78 the loss of nociceptive
input from the skin into the central nervous system (CNS) may
contribute towards maintaining ongoing pain. Similar mechanisms
contribute to phantom limb pain after amputation. The plasticity
of the nervous system is becoming better understood, particularly
the way in which near-normal function can be maintained in some
degenerative conditions (including Parkinson’s disease, optic nerve
crush, spinal cord injury and stroke) despite the degeneration
of many neurons.79 After injury, post-synaptic neurons adapt to
enlarge capacity by increasing their gain – a strategy that can
ultimately lead to unprovoked firing of central neurons when
peripheral input is reduced to near zero. If this also applies in
PHN, the implication is that even small reductions in neuronal
death might preserve the minimal necessary residual number of
neurons and thereby decrease the likelihood of PHN. A better
understanding of this pathophysiology will inform the development
of therapeutic and preventative strategies for PHN and other chronic
pain syndromes.
Other observations of the CNS and nerve injury may provide
insight into chronic pain syndromes. For example, unilateral nerve
injury from HZ can cause profound, long-lasting, nerve-branchspecific loss of distal innervation on the unaffected opposite side
of the body (contralaterally), as well as in the territory affected
by the rash. This suggests that CNS changes may have important
effects on pain pathogenesis even in the absence of direct spinal
cord inflammation or injury.76
Animal research shows that minor nerve injuries can have
disproportionately large effects on dorsal-horn neurons and glia,
perhaps providing a biological correlate for the disproportionate
pain of post-traumatic neuralgias that follow seemingly minor
nerve injuries.80 It is well documented that reduced nociceptive
afferent input causes hyperactivity of central pain neurons,81–86 and
limited autopsy data comparing patients with or without PHN after
HZ identified degeneration in the spinal-cord dorsal horn as the
crucial difference between these outcomes.87
4. Summary
The objectives of treating HZ are to control acute pain, accelerate
rash healing, minimize systemic complications and reduce the risk
of PHN and other complications. Existing therapies, particularly
antiviral agents, shorten the duration of HZ and promote rash
healing, but they are not completely effective at preventing PHN,
perhaps partly because of delays in diagnosis and administration.
New treatments with different mechanisms of action are under
development for the prevention and management of PHN. Existing
therapies for established PHN are palliative and mainly include
R.J. Whitley et al. / Journal of Clinical Virology 48 (2010) S20–S28
opioids, TCAs and anticonvulsants. The goal for PHN management
in the future must be to move away from palliative care and
towards disease-modifying treatments. Recent developments in the
understanding of the neuropathogenesis of pain in general, and of
PHN in particular, have identified potential points of intervention
for the future management of chronic pain syndromes, including
PHN.
Conflict of interest
The GVF is a not-for-profit organization. The GVF Zoster Workshop
was sponsored by educational grants from Novartis, Menarini,
Sanofi-Pasteur and Merck.
Acknowledgements
We would like to thank Facilitate Ltd, Brighton, UK, for editorial
assistance with the manuscript.
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