Oxford American Pocket Notes Post Herpetic Neuralgia
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POSTHERPETIC NEURALGIA
INTRODUCTION
Postherpetic neuralgia (PHN) is one of the two most com-
monly seen neuropathic pain disorders (the other is diabetic
neuropathy).These two pain disorders are, in turn, common
chronic pain syndromes.The prevalence of neuropathic pain
in the United States has been estimated at almost 3.8 mil-
lion,1 and PHN may account for as many as 1 million of
these cases.2
Postherpetic neuralgia is a chronic pain disorder that follows
an episode of shingles, usually involving acute vesicular
eruption due to the varicella zoster virus (VZV) in adults.
The primary infection with VZV occurs mostly in child-
hood, when it produces chickenpox. Following the initial in-
fection, the virus remains latent in the dorsal root or cranial
sensory ganglia until it is reactivated and produces the shin-
gles rash. Shingles is characterized by unilateral, painful,
grouped vesicular lesions with a dermatomal distribution,
most commonly on the trunk or face. The eruption is the
most distinctive feature of zoster, but frequently the most
debilitating symptom is pain.This pain may occur during the
prodrome, the acute eruptive phase, and the postherpetic
phase of the infection. Once the acute phase and its usual
rash have healed, lingering or new-onset pain related to the
expression of VZV is commonly referred to as PHN. The
pain of herpes zoster may lead the clinician to incorrectly di-
agnose migraine, myocardial infarction, acute abdomen, or
herniated disc, among many other conditions, depending on
the dermatome involved. Damage from VZV can lead to per-
sistent severe neuralgia, facial or other nerve paralysis,
1
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blindness or other visual impairments, and encephalitis.The
impact of pain on quality of life (QOL) may be severe, pro-
ducing chronic fatigue, anorexia, weight loss, physical inac-
tivity, insomnia, and depression.
EPIDEMIOLOGY
Shingles occurs in 125 of 100,000 people in the general pop-
ulation; the incidence rises to 400 of 100,000 octogenari-
ans.3 The overall incidence in the United States of herpes
zoster (HZ) is thought to be approximately 600,000 to
800,000 per year.4 Herpes zoster is essentially a reactiva-
tion/recurrence of dormant VZV (the same virus that causes
chickenpox); virus reactivation in the cranial nerve, dorsal
root, and autonomic nervous system ganglia can result in se-
vere sensory dysfunction, which is the proximate cause of
pain symptoms in PHN. The reactivation occurs because of
waning cellular immunity to VZV.The risk of VZV reactiva-
tion increases with age, as well as with the presence of con-
ditions that compromise immunity such as HIV, Hodgkin
disease, non-Hodgkin lymphomas, and leukemias. Increased
risk has also been noted in those undergoing bone marrow
and other organ transplantation, and in those taking im-
munosuppressive medications.
Studies have demonstrated the striking correlation between
the onset and severity of PHN with patient age: The overall
incidence of PHN following VZV infection/reactivation
ranges from 10% to 27%; the incidence for individuals over
the age of 50 is 40%, increasing to 50% in patients aged 50
to 70, and 75% for those over the age of 70.5,6 The risk of
2
POSTHERPETIC NEURALGIA
PHN increases markedly with age, and so too does the risk
for greater severity of acute pain, greater rash severity, and
greater degree of sensory impairment in the affected der-
matome (a specifically designated area of the skin that is en-
ervated by nerve fibers usually leading from a single pair of
dorsal roots in the spinal cord).7,8 See Figure 1.9
Although the duration of pain symptoms following HZ
generally does not exceed 3 months, a significant propor-
tion of patients (up to 20% of those with PHN over the age
of 50, despite prior treatment with an antiviral agent, and
up to 50% in those over age 70) develop chronic pain last-
ing more than 1 year.10,11 In some patients, the pain may
persist indefinitely, if not properly treated. Impact on QOL
is severe.
ETIOLOGY/PATHOPHYSIOLOGY OF PAIN
The pain associated with PHN is thought to be caused by pe-
ripheral and/or central nerve damage due to necrosis and
scarring resulting from systemic HZ infection and leading to
one or more of the following:
■ Peripheral sensitization occurs during or shortly after
the acute phase of VZV infection. Peripheral nociceptors
(pain-sensing neurons) become sensitized following acute
tissue injury, resulting in ongoing discharge and
hyperexcitability. Peripheral sensitization is almost
certainly responsible for pain in the acute phase.
■ Deafferentation refers to the destruction of nerve fibers
resulting from VZV infection.
3
Great auricular, C.2, C.3
S.2, 3
4
C.2, C.3
C.2, C.3
C.3, C.4
Figure 1. Map of the Dermatome
Reprinted from the Oxford American Handbook of Clinical Medicine., Pg 318–319.
©2007, with permission from Oxford University Press, Inc.
5
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■ Central reorganization and sensitization follows
deafferentation (specifically of the C-fibers that are
normally responsible for sensing pain) in some PHN
patients (and in others with conditions resulting in
neuronal destruction, such as those with diabetic
neuropathy).This process involves reactive organizational
changes in the nervous system and subsequent aberrant
sensory processing, such as the formation of new
connections from mechanosensitive Aβ-fibers to central
neurons.These new connections are maladaptive, causing
non–pain sensing neurons to propagate a nociceptive
signal to pain perceptual regions in the brain.This type of
mechanism may be responsible for the coexisting loss of
heat sensation and increased allodynia seen in PHN
patients (see Figure 2).12 With repeated pain, the levels of
neurotransmitters and electrical signals change, resulting
in changes in central nervous system (CNS) wiring,
thresholds for activation, and future responses to pain. In
essence, the traumatized CNS responds with attempts to
adjust to these alterations, and this produces worse pain.
This process likely plays a very important role in PHN
and may be the main reason why the associated pain may
be difficult to alleviate.
■ Peripheral and central demyelination occurs when VZV
infection results in the destruction of the myelin sheath, a
process well-established to cause pain in many
neurological diseases.
Some indications suggest that these processes may be pro-
gressive, that is, that peripheral nerve damage and sensitization
6
Figure 2. Degeneration and deafferentation: aberrant connections
due to synaptic reorganization in the central nervous system.
(A) Under physiological circumstances the central terminals of Ab-low-threshold
mechanosensitive afferent fibers directly project into dorsal horn laminae ventral to the
substantia gelatinosa (SG, shaded).Terminals of nociceptive C-fibers project primarily to
neurons in the SG. (B) Peripheral nerve injury that causes a substantial degeneration of
nociceptive C-fibers leads to a reduction in synaptic contacts made by these afferents with
SG neurons. Central terminals of surviving Ab-low-threshold mechanosensitive fibers
which normally project ventrally sprout dorsally into SG and establish functional contacts
with the deafferented second order neurons (*).
Reprinted with permission from Fields HL., 1998
OAPN
may progress to central sensitization, thus complicating the
presentation and treatment of PHN.
Studies have demonstrated that PHN can lead to damage to
sensory nerves, sensory dorsal root ganglia (DRG), and dorsal
horn cells of the spinal cord.13–15 Also noted are inflammatory
processes involving both the anterior and posterior horns of
the spinal cord, axonal damage, and myelin disruption extend-
ing peripherally from the DRG. Pathological changes in the
DRG include the presence of “ghost cells” (cells that have lost
cytoplasmic contents and have become calcified).
An important consequence of peripheral neuronal injury is
the increased expression of sodium channels at the site of in-
jury. In normal physiology, voltage-gated sodium channels
initiate and propagate neuronal action potentials, thus regu-
lating neuronal excitability. Sodium channels can form fol-
lowing HZ infection, accumulate at the site of cutaneous
nerve damage, and display abnormally high activity.The po-
tential importance of sodium channels in the pathological
mechanism of PHN has been supported by the efficacy of li-
docaine (which binds sodium channels with high affinity)
and some anticonvulsant agents (antiepileptics) that have
been shown to inhibit sodium channel activity,16 among
many other potentially analgesic actions in the CNS.The sig-
nificant contribution of ion channels, such as overly ex-
pressed sodium channels, to the pathology of neuropathic
pain has been termed channelopathy and poses potential ad-
vances for future understanding and treatment.
The pathogenesis of PHN likely involves both the central and
peripheral nervous systems, with the peripheral pain-sensing
8
POSTHERPETIC NEURALGIA
neurons (primary afferent nociceptors) playing a large role
in initiating continuous pain. In general support of the in-
volvement of central mechanisms in PHN, numerous clinical
studies evaluating PHN treatments show the efficacy of
neurotransmitter-regulating pharmacological agents (i.e.,
regulators of serotonin, norepinephrine, glutamate, sub-
stance P) as well as of anticonvulsants, which are thought to
act almost exclusively on the CNS.17
DIAGNOSIS
Herpes Zoster
Findings associated with HZ include: (a) pain along the
course of a spinal nerve or cranial nerve followed by grouped
vesicular skin lesions; (b) unilateral involvement, although
some lesions may occur outside the affected dermatome; (c)
lesions that usually appear on the trunk or the face; and (d) a
positive result on direct fluorescent antibody testing of
vesicular lesions.
Other Presentations of Herpes Zoster
The spectrum of initial presentations resulting from varicella
zoster infections and potentially leading to PHN includes:
■ Zoster multiplex. More than one dermatome is affected,
which is common in immunocompromised individuals.
■ Zoster sin herpete. The VZV infection presents without a
dermatomal rash, but instead with facial pain or palsy.
This is a less common presentation, although more
frequent in immunocompromised individuals.
9
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Varicella zoster virus can also be reactivated in the oph-
thalmic section of the trigeminal nerve (herpes ophthalmi-
cus), resulting in conjunctivitis, corneal ulcers, or blindness.
Because of the severity of these potential outcomes, zoster
related to the eye usually requires urgent consultation with
an ophthalmologist. In addition,VZV can also produce ner-
vous system deficits when it reactivates in the spinal cord or
rarely, the brain (zoster encephalitis). How to appropriately
respond to acute zoster is beyond the scope of this review—
the presenting manifestations of VZV should be thoroughly
assessed, and treatment with antiretrovirals should be initi-
ated to help avoid these potentially serious complications.
Readers are referred to the following resources for more
complete reviews:
■ Mpaka M, Karantanas AH, Zakynthinos E. Atypical
presentation of varicella-zoster virus encephalitis
in an immunocompetent adult. Heart Lung 2008;
37(1):61–6.
■ Drebber U, Preuss SF, Kasper HU, et al. Postoperative
fulminant varicella zoster virus hepatitis with fatal
outcome: a case report. Z Gastroenterol 2008;46(1):45–7.
Postherpetic Neuralgia
Postherpetic neuralgia is commonly defined as pain within
30 days of rash onset. More precise definitions of VZV-
associated neuralgia include: acute herpetic neuralgia (within
30 days of rash onset); subacute herpetic neuralgia (30 to 120
after rash onset); and PHN (pain lasting at least 120 days after
rash onset).6,18,19
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POSTHERPETIC NEURALGIA
PHYSICAL FINDINGS
There are several modes of altered pain response syndromes
common in PHN including:
■ Dysesthesia (“strange,” itching, burning sensation)
■ Paresthesia (tingling or pricking sensation)
■ Paroxysm (sudden intensification of sensation)
■ Allodynia (exaggerated response to stimuli that normally
do not cause pain, such as light touch)
■ Hyperalgesia (enhanced intensity of pain sensation)
■ Hyperesthesia (exaggerated sensitivity to painful stimuli)
While these manifestations may or may not be confined to
the area where the rash appeared, they are confined to the
affected dermatome(s). The symptoms vary in duration
and intensity among patients and may be noted in any com-
bination within the same patient’s affected dermatomal
areas.
DIAGNOSTIC TESTS
In addition to obtaining an accurate patient history, including
an evaluation of the quality and intensity of pain symptoms,
assessment for the presence of the physical findings include
simple neurological tests20:
■ Applying light touch (to test for allodynia as well as
sensory deficit)
■ Applying cold or heat (to test for sensory deficit,
allodynia)
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■ Applying pressure (to test for static mechanical
hyperalgesia)
■ Applying pin-prick (to test for hyperalgesia,
hyperesthesia)
■ Applying an irritant such as capsaicin cream to the
affected area (to test for hyperesthesia, hyperalgesia)
Other procedures, such as a skin-punch biopsy and electro-
physiological examinations to analyze the extent of denerva-
tion can be performed to assess peripheral (cutaneous) nerve
damage as well as the contribution of peripheral mechanisms
to ongoing pain. Patients with unusual presentations of sus-
pected shingles or PHN, or who are in need of more complex
neurological exams should be referred to a neurologist.
PREVENTION
Antivirals
While antiviral agents do not treat PHN, administration is
recommended within 72 hours of rash onset (or onset of
prodromal pain, if present) in order to localize nerve dam-
age to the peripheral nerves and to attenuate both periph-
eral and central sensitization. The results of recent
placebo-controlled trials for antiretroviral therapy with
acyclovir, valacyclovir, and famciclovir for HZ are summa-
rized below:
■ A meta-analysis study of several placebo-controlled trials
reveals that acyclovir administration at 800 mg , five times
daily accelerates pain resolution as assessed by a variety of
measures. Fewer patients had PHN at 3 and 6 months
12
