Treating Herpes Zoster and Postherpetic Neuralgia

®
VOL
XXIXXIII
• NO 1
• JUNE
2013 2015
VOL
• NO
4 • MAY
Treating Herpes Zoster
and Postherpetic Neuralgia
Vol.ÊXXI,ÊIssueÊ1Ê
P
Editorial
Boardneuralgia (PHN)
ostherpetic
is the most frequent chronic
Editor-in-Chief
complication of herpes zoster
JaneÊC.ÊBallantyne,ÊMD,ÊFRCA
(shingles).1 Herpes zoster (HZ)
Anesthesiology,ÊPainÊMedicine
USA
represents a reactivation of the varicellaAdvisoryÊBoard
zoster virus (VZV), a ubiquitous,
highly
neurotropic, exclusively human
MichaelÊJ.ÊCousins,ÊMD,ÊDSC
α-herpesvirus.
Primary infection causes
PainÊMedicine,ÊPalliativeÊMedicine
Australia
varicella
(chickenpox), after which VZV
becomes latent in sensory ganglia along
the entire neuraxis. With the decline in
VZV-specific cell-mediated immunity
in elderly and immunocompromised
individuals, VZV reactivates to cause
HZ, characterized by a painful maculopapular or vesicular rash in all or part of
the skin territory innervated by a single
dorsal root ganglion.2 The most common
site of HZ is thoracic, comprising about
half of all cases, followed by trigeminal (usually the ophthalmic branch),
cervical, and lumbar distributions. HZ
generally resolves within a few weeks,
Maija Haanpää, MD, PhD
Department of Neurosurgery,
Helsinki University Hospital
Mutual Insurance Company Etera,
Helsinki, Finland
Email: maija.haanpaa@etera.fi
Andrew S.C. Rice, MB BS, MD,
FRCA, FFPMRCA
Pain Research, Department of Surgery
and Cancer,
Faculty of Medicine
Imperial College London
Chelsea and Westminster Hospital Campus
London, United Kingdom
Email: a.rice@imperial.ac.uk
Michael C. Rowbotham, MD
California Pacific Medical Center
Research Institute
Department of Anesthesia,
UCSF School of Medicine
San Francisco, Calif., USA
Email: rowbotm@cpmcri.org
PAIN: CLINICAL UPDATES • MAY 2015
JuneÊ2013
but a minority of patients experience
months and 15% had pain at 2 years in
pain (PHN) persisting
for
months,
years,
a Dutch study.6 In the landmark zoster
PsychosocialÊAspectsÊofÊChronicÊPelvicÊPain
or even a lifetime.
vaccine study, which included almost
40,000 people aged 60 years or older
(of whom fewer than 1000 developed
Epidemiology
of
HZ
and
PHN
Pain is unwanted, is unfortunately common, and remains essential for survival (i.e.,
HZ) and where PHN was defined as
evading to
danger)
andsystematic
facilitating medical diagnoses. This complex amalgamation of
According
a recent
pain intensity of 3/10 or more, 30% of
sensation,
emotions,ofand
review,
the incidence
HZthoughts
is 3–5 manifests itself as pain behavior. Pain is a moti1patients who developed HZ had PHN and for emergency department visits and is
vating
for physician 3consultations
cases
per factor
1000 person-years.
The
at 1 month, 12% at 3 months, and 5%
age-specific incidence rates of HZ were
at 6 months in the placebo group.7 Acsimilar across countries, with a steep
cording to a meta-analysis, incidence
rise after 50 years of age. The incidence
rates of PHN varied from 3.9 cases per
was 6–8 cases/1000 person-years at
100,000 person-years to 42.0 cases per
60 years of age and 8–12 cases/1000
100,000 person-years across all ages.8
person-years at 80 years of
age. The incidence of HZ has
increased in the past several
decades across seven countries.3 A study in the United
States could not explain the
increase by changes in age
or by the prevalence of immunocompromised people.4
Two-thirds of HZ cases occur
in those 50 years or older, and
the lifetime risk is 30%.2
Estimates of the incidence of PHN vary widely
depending on the population and the definition of PHN used.
Definitions include the duration of
persistent pain (30, 90, or 180 days) and
the severity of pain, either clinically
meaningful pain (i.e., pain intensity of
at least 3/10) or any pain.3 In a population-based study using medical records
in the United States, 18% of patients
reported pain for at least 30 days and
10% for at least 90 days.4 Similarly,
20% of patients had pain for at least 30
days and 14% for at least 90 days in a
study from the United Kingdom,5 and
20% of zoster patients had pain at 3
PHN risk increases with age. In
a study from the United States, the
incidence of PHN (defined as pain at 3
months) in zoster patients was 18% in
persons older than 50 years and 33%
in those older than 80 years. Overall,
80% of all PHN occurs among persons
aged 50 years and older.2 Analysis of
data from the United Kingdom General
Practice Research Database showed
that the incidence of PHN (as defined
by pain at 3 months) rose from 8% at
50–54 years of age to 21% at 80–84
years of age.5
1
Advancing age and the severity
of acute HZ pain are the strongest risk
factors for PHN. Other predictors of
PHN are the severity of the rash, the
presence of prodromal pain, and the
occurrence of sensory abnormalities
such as hypoesthesia or allodynia.9,10
Ophthalmic location of rash, psychosocial distress in the acute phase, and
problems with usual activities before
developing HZ (the last reflecting
poorer health) are also reported as risk
factors.11
Course of the Disease
HZ viral replication first manifests as
ganglionitis and then spreads along the
corresponding peripheral nerve and
the skin. Hemorrhage and inflammation in the affected dorsal root
ganglion and associated nerve may
be seen, and in patients with PHN,
fibrosis and cell loss have been documented post mortem in the dorsal root
ganglion.12 Pain and unilateral rash
are typical symptoms, often accompanied by paresthesias and itching. Most
patients experience pain during HZ.
Pain precedes rash in three-quarters
of cases, lasting usually for some days
before the eruption of the rash. As
described above, only a minority of
patients continue to have pain long
after the healing of the rash.
HZ can also give rise to non-pain
complications, which can be ophthalmic (e.g., keratitis or uveitis), neurological (e.g., cranial and peripheral
nerve palsies), circulatory (vasculitis
and stroke), dermatological (e.g., bacterial superinfection), or visceral (e.g.,
pneumonia).13
Those who continue to suffer from
prolonged pain after HZ may describe
one or more of three broad types of
pain: (1) a constant deep aching or
burning pain; (2) an intermittent paroxysmal pain with a lancinating quality;
and (3) an intermittent pain evoked by
normally innocuous sensory stimuli
(allodynia), typically mechanical but in
some patients thermal as well. Allodynia is present in at least 70% of patients
and is usually considered to be the
most distressing and debilitating PHN
2
component.13 Itching and dysesthesias
may accompany the pain, and in some
patients these symptoms can be even
more annoying than the pain itself.
A longitudinal study of zoster
patients using quantitative sensory testing (QST) and skin biopsies showed that
those who developed PHN (defined as
pain at 6 months) had significantly more
impaired sensory function and more
severe allodynia in the acute phase compared to those who experienced pain
resolution.14 Sensory recovery proceeded at the same rate in both groups
during the first 6 months. Epidermal
nerve fiber density was decreased by
about 40% in the affected skin but not
in contralateral “mirror image” skin,
with no improvement during the first
6 months.15 In a long-term follow-up of
7 years, epidermal nerve fiber density
remained low in spite of good clinical
recovery, which strongly supports the
concept that recovery of sensory function and anatomical reinnervation of
the skin are not prerequisites for pain
resolution.16
HZ and PHN also cause a substantial economic burden to society in the
form of increased health care use and
need for medication, lost working days
in those at working age, and the need
for assistance or even loss of independence in frail, elderly, people with multiple comorbidities. In a study from the
United Kingdom, the average total cost
of a PHN case was estimated to be £340
in 2006. The cost included outpatient
visits and prescribed medication, but
at that time pregabalin and lidocaine
patches were not available there, which
would increase the current cost.20
Burden of the Disease
Antiviral Agents
Pain is the most important outcome of
HZ. It interferes with general activity,
sleep, and mood, and patients with
more severe pain are more likely to report symptoms of anxiety and depression.17, 18 Health-related quality of life
instruments measure four key health
domains: physical, psychological, social, and functional. Both HZ and PHN
have effects on patients’ lives across
all four health domains. Reduced quality of life is a particular problem in
patients whose pain persists as PHN,
and there is a correlation between increasing pain severity and the extent
of PHN’s negative impact on quality of
life.13 A study comparing patients with
PHN to patients with chronic low back
pain showed similar pain intensity,
physical function, cognitive function,
and mood in both groups, but pain
severity depended on different things
(PHN typically increased with touch,
air movement, and stress, whereas
low back pain increased with activity
and exercise).19
Although HZ is a self-limiting and
benign disease in most patients, those
who have a high risk of developing complications should be treated
actively. Systemic antiviral therapy
is strongly recommended as first-line
treatment for all immunocompetent
patients with HZ who fulfill any of the
following criteria (ideally within 72
hours of the onset of rash): (1) are at
least 50 years of age; (2) have moderate or severe pain; (3) have a moderate
or severe rash; or (4) have non-truncal
involvement.21
Acyclovir, famciclovir, and valacyclovir have been approved by the U.S.
Food and Drug Administration for the
treatment of HZ. All of them inhibit
viral replication in the infected cells,
resulting in accelerated healing of rash
and decreased severity and duration of
acute pain. Oral acyclovir does not reduce the incidence of PHN significantly, but there is insufficient evidence to
determine the effect of other antiviral
treatments preventing PHN.22
Pharmacotherapy of Acute
Herpes Zoster
The treatment of HZ aims to limit the
duration and severity of the attack,
relieve symptoms, and prevent complications. All patients should receive
a medical and psychosocial history
evaluation and targeted physical
examination to confirm the diagnosis,
document comorbid illnesses, and
provide a basis for treatment.
PAIN: CLINICAL UPDATES • MAY 2015
Treatment of Acute ZosterAssociated Pain
Active treatment of acute HZ pain is
recommended. In the absence of an
extensive dataset of direct evidence
from high-quality randomized controlled trials, it is reasonable to adhere
to generic principles of acute pain
management; patients with mild to
moderate pain should take acetaminophen (paracetamol) or NSAIDs, alone
or in combination with codeine or
tramadol. Those with severe pain may
need a strong opioid. In a randomized
controlled study, the number-neededto-treat for clinically meaningful pain
relief (>30% pain reduction) was 2.9
for controlled-release oxycodone and
9.6 for gabapentin during the 4-week
study.23 In another study, a single dose
(900 mg) of gabapentin decreased pain
severity and both severity and area of
allodynia in patients with acute zoster.24
For opioids, individual titration, routine
laxative use, and close follow-up are
needed to ensure the best compromise
between efficacy and side effects.
Low-dose amitriptyline (25 mg
once daily for 3 months) has been
recommended because it significantly
reduced the prevalence of PHN at 6
months in a placebo-controlled trial.25
However, this small study requires
repetition on a larger scale.
Corticosteroids in combination with
acyclovir reduced pain and improved
short-term quality of life compared
with placebo in patients with HZ, but
they had no appreciable effect on the
incidence or duration of PHN.26 Corticosteroids are associated with a considerable number of adverse effects and
hence should be used only in patients
with severe symptoms at presentation
or in whom no major contraindications
to corticosteroids exist, and only in combination with antiviral treatment.
Although epidural local anesthetic
injection, with or without a steroid,
has been common practice for many
decades in patients with severe acute or
subacute zoster pain, there are few prospective controlled trials. A large study
that examined the effect of a single
epidural injection of local anesthetic
and a steroid demonstrated reduced
PAIN: CLINICAL UPDATES • MAY 2015
zoster-associated pain at 1 month but no
significant reduction in the likelihood
of PHN.6 A randomized nonblinded
study reported effective pain relief and
prevention of PHN (defined as presence
of any pain) at 1, 6, and 12 months with
repeated paravertebral blockades of a local anesthetic and steroid.27 All patients
(aged 50 years or over) were treated
with oral acyclovir, and the paravertebral blockade group received four
repeated treatments within one week,
whereas the standard group received
simple analgesics for their pain. According to this study, repeated paravertebral
blockades are effective for acute pain
and prevention of PHN. However, this
procedure is obviously not suitable for
patients suffering from cranial zoster.
Treatment of Postherpetic
Neuralgia
The efficacy of current treatments is
still far from satisfactory. PHN is a classical model to test the efficacy of potential new drugs for neuropathic pain. A
global database of all registered PHN
trials and results (if any are available)
has been reported28 and was updated in
mid-2014.29,30 The database is available
as part the Repository of Registered
Analgesic Clinical Trials (RReACT)
through the ACTTION website (http://
www.acttion.org/). Of 112 unique registered trials, 66 were reported as completed. Only 20 completed trials had
results available in the peer-reviewed
literature, and another 17 had results
available via the “gray” literature or
posted on a trials registry. In addition to
the lack of results from a large proportion of completed trials, some important
clinical issues have not been tested in a
clinical trial. For example, none of the
available serotonin and norepinephrine
reuptake inhibitors (SNRIs) have been
studied for PHN.
Numerous meta-analyses and
treatment guidelines have been published. A PHN-specific meta-analysis
was published in 2005,31 but recommendations provided here are largely based
on analyses from 2014 and 2015.1,32
Tricyclic antidepressants (TCAs),
gabapentinoids, opioids, and topical capsaicin have strong evidence
Editorial Board
Editor-in-Chief
Jane C. Ballantyne, MD, FRCA
Anesthesiology, Pain Medicine
USA
Advisory Board
Michael J. Cousins, MD, DSC
Pain Medicine, Palliative Medicine
Australia
Maria Adele Giamberardino, MD
Internal Medicine, Physiology
Italy
Robert N. Jamison, PhD
Psychology, Pain Assessment
USA
Patricia A. McGrath, PhD
Psychology, Pediatric Pain
Canada
M.R. Rajagopal, MD
Pain Medicine, Palliative Medicine
India
Maree T. Smith, PhD
Pharmacology
Australia
Claudia Sommer, MD
Neurology
Germany
Harriët M. Wittink, PhD, PT
Physical Therapy
The Netherlands
Publishing
Daniel J. Levin, Publications Director
Elizabeth Endres, Consulting Editor
Timely topics in pain research and treatment
have been selected for publication, but the
information provided and opinions expressed
have not involved any verification of the findings, conclusions, and opinions by IASP. Thus,
opinions expressed in Pain: Clinical Updates do
not necessarily reflect those of IASP or of the
Officers or Councilors. No responsibility is assumed by IASP for any injury and/or damage
to persons or property as a matter of product
liability, negligence, or from any use of any
methods, products, instruction, or ideas contained in the material herein.
Because of the rapid advances in the
medical sciences, the publisher recommends
independent verification of diagnoses and
drug dosages.
© Copyright 2014 International Association
for the Study of Pain. All rights reserved.
For permission to reprint or translate
this article, contact:
International Association
for the Study of Pain
1510 H Street NW, Suite 600,
Washington, D.C. 20005-1020, USA
Tel: +1-202-524-5300
Fax: +1-202-524-5301
Email: iaspdesk@iasp-pain.org
www.iasp-pain.org
3
Table I
Studies on evidence of TCAs, gabapentinoids, opioids, and topical capsaicin for postherpetic neuralgia
showing positive (P) or negative (N) outcomes
Drug, Maximal Daily Dose
Outcome
Number
Randomized
Duration
Watson et al. 1982
Amitriptyline, average 73 mg
P
24
3 weeks
Max et al. 1988
Amitriptyline, average 65 mg
P
62
6 weeks
Graff-Radford et al. 2000
Amitriptyline, 200 mg
NA
24/49
8 weeks
Kishore-Kumar et al. 1990
Desipramine, 250 mg
P
26
6 weeks
Raja et al. 2002
Nortriptyline or desipramine, 160 mg
P
76
8 weeks
Dworkin et al. 2003
Pregabalin, 600 mg
P
173
8 weeks
Sabatowski et al. 2004
Pregabalin, (150), 300 mg
P
157/238
8 weeks
van Seventer et al. 2006
Pregabalin, (150), 300, 600 mg
P
281/370
13 weeks
Stacey et al. 2008
Pregabalin, 300, 600 mg
P
270
4 weeks
Rowbotham et al. 1998
Gabapentin, 3600 mg
P
229
8 weeks
Rice and Maton 2001
Gabapentin, 1800, 2400 mg
P
334
7 weeks
Wallace et al. 2010
Gabapentin ER, 1800 mg
N
407
10 weeks
Sang et al. 2012
Gabapentin ER, 1800 mg
P
452
10 weeks
Irving et al. 2009
Gabapentine ER, 1800 mg
P twice daily;
N once daily
158
4 weeks
NCT00619476
ClinTrials.gov
Gabapentin enacarbil, 1200, 2400,
3600 mg
P
376
13 weeks
Tramadol, 400 mg
P
127
6 weeks
Watson and Babul 1998
Oxycodone, 60 mg
P
50
4 weeks
Raja et al. 2002
Morphine, 240 mg, or methadone
P
76
8 weeks
Backonja et al. 2008
Capsaicin, 8%, single application
P
402
12 weeks
Backonja et al. 2010
Capsaicin, 8%, single application
P
38
4 weeks
Irving et al. 2011
Capsaicin, 8%, single application
P
418
12 weeks
Webster et al. 2010
Capsaicin, 8%, single application
P
299
12 weeks
Webster et al. 2010
Capsaicin, 8%, single application
N
155
12 weeks
Bernstein et al. 1989
Capsaicin, 0.075%
P
32
6 weeks
Watson et al. 1993
Capsaicin, 0.075%
P
143
6 weeks
Study
TCAs
PREGABALIN
GABAPENTIN
GABAPENTIN ER or ENACARBIL
TRAMADOL
Boureau et al. 2003
OPIOIDS
CAPSAICIN 8%
CAPSAICIN CREAM
Source: Data from supplementary material of Finnerup et al.
Abbreviations: ER, extended release; NA, not applicable; TCAs, tricyclic antidepressants.
32
for efficacy in PHN (Table 1). Topical
lidocaine gel (5% in a nonstandard
formulation) for PHN showed efficacy
in a double-blind, three-session study,33
as did topical lidocaine patch (5%) in a
4
double-blind, four-session study.34 In
an open-label, non-inferiority study, 5%
lidocaine patch showed better efficacy
compared with pregabalin in patients
with PHN.35
First-Line Agents According
to the NeuPSIG Guidelines
The lack of evidence for different
efficacies for most drugs in distinct neuropathic pain disorders caused NeuPSIG
PAIN: CLINICAL UPDATES • MAY 2015
to prepare recommendations for neuropathic pain in general instead of for
various etiologies.32 First-line agents for
neuropathic pain are TCAs, SNRIs, and
gabapentinoids on the basis of evidence
of their efficacy and safety. However,
there are no published reports of randomized controlled clinical trials of any
of the SNRIs in PHN patients. Table 2
presents the mechanisms of action and
dosing for these drugs.
TCAs are inexpensive drugs. The
presence of depression is not required
for their analgesic effect, and pain
relief occurs with lower doses than
are required for an effect on mood.36
The most common side effects of
TCAs include sedation, anticholinergic
effects (e.g., dry mouth, constipation,
and urinary retention), and orthostatic hypotension. In a head-to-head
comparison, amitriptyline and nortriptyline were equally effective, but nortriptyline was better tolerated.37 These
drugs are contraindicated in patients
with cardiac conduction problems or
recent myocardial infarction. Patients
may complain of excessive sedation
or confusion as the most troublesome
side effect, and pre-existing cognitive
impairment may become significantly
worse, which may require a cautionary approach to driving. Accidental or
intentional overdose with a TCA may
be lethal, and is more dangerous compared to SSRI antidepressants.
Gabapentinoids (gabapentin and
pregabalin) have been studied extensively
for PHN (Table 1). Their advantage is
lack of pharmacokinetic interactions,
as they are not bound to plasma proteins and are secreted to urine without
hepatic metabolism. Gabapentin has a
saturable transport mechanism in the
gut, whereas absorption of pregabalin
is more linear. The typical side effects
of gabapentinoids are somnolence,
dizziness, and peripheral edema. Doses
must be adjusted downward if renal
function is impaired. Gabapentin is
dosed differently depending on the
preparation. Neurontin and generic
gabapentin differ from the gabapentin
extended-release (Gralise) preparation
and the gabapentin enacarbil prodrug
(Horizant) (see each manufacturer’s
recommendations).
Table 2
Mechanisms of action and dosing of systemic drugs for neuropathic pain
Medication
Maximum Recommended
Dose
Mechanism of Action
Starting Dose
Titration
Serotonin and norepinephrine reuptake inhibition,
sodium channel block,
NMDA-receptor antagonism
10–25 mg at
bedtime
Increase by 10–25 Usual effective doses in
mg every 3–7
75–100 mg/day range.
days as tolerated
Upward titration from 75
mg/day guided by blood
concentration of the drug
and its active metabolite.
Pretreatment cardiac conduction screening in older
patients and re-screening
as the dose rises may be
indicated. Do not exceed
150 mg daily.
Gabapentin
Calcium-channel a2δ binding, which reduces release
of presynaptic transmitters
100–300 mg at
bedtime
Increase by
100–300 mg
three times daily
every 1–7 days
3600 mg daily (divided into
3 doses)
Pregabalin
Calcium-channel a2δ binding, which reduces release
of presynaptic transmitters
75 mg twice
daily
Increase to 300
mg daily after 3–7
days, then by 150
mg/d every 3–7
days
600 mg daily (divided into
2–3 doses)
Tramadol
µ-opioid receptor binding and serotonin and
norepinephrine reuptake
inhibition
50 mg once or
twice daily
Increase by
50–100 mg daily
in divided doses
every 3–7 days as
tolerated
400 mg daily; in patients
older than 75, 300 mg daily
Oxycodone CR
µ-opioid receptor binding
10 mg twice
daily
Increase by 20
mg daily or more
slowly as tolerated
120 mg daily (divided into 2
doses)2
TCAs
Nortriptyline, desipramine,
(amitriptyline, imipramine)1
Gabapentinoids
Opioid Agonists
Abbreviations: CR, controlled release; TCAs, tricyclic antidepressants.
1 Secondary amine TCAs (nortriptyline, desipramine) are preferred owing to better tolerability.
2 Highest dose used in randomized controlled studies for neuropathic pain.
PAIN: CLINICAL UPDATES • MAY 2015
5
Second-Line Agents According
to the NeuPSIG Guidelines
Lidocaine patches (5%), capsaicin
patches (8%), and tramadol are recommended as a second line of treatment.
The reason for their being second-line
is a low quality of evidence (lidocaine),
a relatively small effect size (topical capsaicin), or lower tolerability or
safety (tramadol).
Topical lidocaine blocks voltagedependent sodium channels in the
area of application. Lidocaine patches
(a maximum of three patches) are applied to the region of pain once a day
for up to 12 hours. For old and frail
patients and for those with concerns
about the side effects or safety of
first-line treatments, lidocaine patches
might be a first-line option. If lidocaine
patch is not available, lidocaine gel or
cream (5%) can be tried instead (dosing
three times daily), although alternate
preparations have not been tested for
efficacy in a clinical trial.
Topical capsaicin is an agonist
of the TRPV1 ion channel and binds
its receptors, which are expressed by
nociceptive primary sensory neurons,
causing excitation of neurons and a period of enhanced sensitivity perceived
as itching, pricking, or burning, with
cutaneous vasodilatation. This phase is
followed by persistent desensitization.
A high-concentration capsaicin plaster
(8%) has shown efficacy in clinical trials
as a single treatment applied to the
painful area for 60 minutes by a medical professional. The treatment can be
repeated in every 3 months, if needed.
Tramadol has good evidence of efficacy and a lower potential for misuse,
abuse, and dependency compared to
strong opioids, but it is recommended
as a second-line drug owing to potential safety concerns. It exerts its analgesic action by increasing noradrenergic
and serotonergic neurotransmission in
the central nervous system. The parent
compound is demethylated to an active
metabolite, trans-O-desmethyltramadol, by the CYP2D6 enzyme. This
biotransformation is a prerequisite for
the clinical opioid effect of tramadol.
“Poor metabolizers” lack this bioactivation, and they have a weaker analgesic
6
response to tramadol compared to “extensive metabolizers” and “ultra-rapid
metabolizers.” The typical side effects
of tramadol are nausea, dizziness, sedation, and headache. Tramadol should
be used with caution with concomitant
antidepressant medication owing to its
interaction potential.38
Third-Line Agents According
to the NeuPSIG Guidelines
Strong opioids (particularly oxycodone
and morphine) and botulinum toxin A
are recommended as third line mainly because of safety concerns (opioids) or weak
quality of evidence (botulinum toxin A).32
Strong opioids (oxycodone, morphine and methadone) have shown
efficacy in PHN. Typical side effects
are constipation, nausea, itching, and
sweating. Opioids are recommended as
a third-line option owing to their abuse
potential and side effects, including
endocrine effects. Long-term opioid
treatment should be considered for
nonmalignant pain only when other
relevant treatment options have been
tried. Psychosocial evaluation should
precede commencement of opioid
treatment. After a treatment trial, the
achieved beneficial effects (pain relief
and improved function) are weighed
against adverse drug reactions. Slowrelease formulations are preferred.
Botulinum toxin has been studied
for PHN in two randomized controlled
trials with positive results. Currently
this treatment is recommended only
for specialist use in refractory cases.32
Combination Therapy
Few studies of drug combinations have
been published, even though combination therapy reflects actual clinical
practice. Randomized trials suggest
that the combination of pregabalin or
gabapentin and duloxetine or tricyclic antidepressants is an alternative
option to increasing doses of one class
of drugs for patients unresponsive to
moderate doses of monotherapy.32 As
multiple pain mechanisms coexist in
PHN, combining drugs with different
mechanisms of action is rational and
should be studied further to better
understand its value in the clinic.
Combining a locally acting preparation
(lidocaine or capsaicin) with a systemic
drug is reasonable and should be tried,
especially for those with comorbidities
and multiple medications, to reduce the
risk of interactions of systemic drugs.
Drugs Not Recommended by NeuPSIG
The recommendations for tapentadol,
other antiepileptics, capsaicin cream,
topical clonidine, selective serotonin
reuptake inhibitor antidepressants, and
NMDA antagonists are inconclusive,
mainly because of discrepant findings.
Cannabinoids and valproate have weak
recommendations against their use in
neuropathic pain, and levetiracetam
and mexiletine have strong recommendations against their use because
of generally negative trials or safety
concerns, or both.32
Role of Invasive Treatments for
Postherpetic Neuralgia
A recent comprehensive review on
interventional management of neuropathic pain concluded that owing to the
low quality of the available evidence
and the potential for adverse events,
the role of spinal cord stimulation,
deep brain stimulation, and intrathecal medication delivery is inconclusive
in PHN.39 The authors recommended
against sympathetic blocks for PHN because nonrandomized studies have not
shown benefit and there are no wellcontrolled prospective clinical trials.
A randomized controlled study
appeared to demonstrate efficacy over
1–2 years for four intrathecal injections of methylprednisolone performed
over 1 month compared with lidocaine
alone and with a no-treatment control
group.40 Another group attempted to
replicate the findings, but the trial was
terminated early after all six patients
randomized to intrathecal methylprednisolone experienced an increase in
pain at 8 weeks (compared to one of
four participants in the control group).41
Given the failure to replicate the striking result of the first study and the
potential risks of intrathecal methylprednisolone injections, the role of this
treatment remains inconclusive,39 and
we strongly recommend against its use.
PAIN: CLINICAL UPDATES • MAY 2015
Prevention of Postherpetic
Neuralgia
The only well-documented means of preventing PHN is the prevention of HZ. A
live attenuated VZV vaccine is approved
for immunocompetent persons of age 50
years or older. The Shingles Prevention
Study, which included people 60 years or
older, showed that the vaccine reduced
the incidence of HZ by 51% and the incidence of PHN by 66%.7 A much smaller
study involving persons 50 to 59 years of
age showed that vaccination reduced the
incidence of HZ by 70%.42 A long-term
persistence substudy showed that vaccine efficacy decreased from 51% to 21%
for incidence of HZ and from 66% to 35%
for incidence of PHN from 7 through
11 years post-vaccination. Statistically
significant vaccine efficacy for incidence
of HZ persisted only through year 8.43
Cost-effectiveness analyses of the zoster
vaccine have estimated the cost of a quality-adjusted life year from US$10,000 to
more than US$100,000 depending on assumptions regarding duration of vaccine
protection and the magnitude of the loss
in quality of life associated with HZ and
PHN.3 In the United Kingdom, researchers estimated that vaccination at either
65 or 70 years is the most cost-effective,20
whereas a German study concluded
that vaccinating individuals aged 60
years seems to represent the most costeffective vaccination strategy.44 Future
cost-effectiveness analyses should also
incorporate the employment-related productivity loss in addition to health care
costs and lost quality of life.18,45
Conclusion
HZ and PHN present challenges to
health care systems, as they are prevalent, cause suffering and impaired
function, and are difficult to treat satisfactorily, especially in societies with
aging populations. The optimal use of
the current therapies by tailoring the
treatment individually, monitoring the
patients to assess efficacy, tolerability,
and functional status, and providing support in psychosocial aspects
when needed may improve the results.
Zoster vaccine is available to prevent
zoster, and new compounds to treat
PHN are awaited.
Conflicts of Interest
Maija Haanpää has been a member of
the advisory boards of Abbvie, Allergan, Astellas, Eli Lilly, Janssen Cilag,
Pfizer, and Sanofi-Aventis. International congress attendance (registration
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