POST HERPETIC NEURALGIA

Background

Herpes zoster (HZ) is a viral infection that usually presents as a childhood infection of varicella
(ie, chicken pox). The pathogen is human herpesvirus-3 (HHV-3), also known as the varicella
zoster virus (VZV). Following the acute phase, the virus enters the sensory nervous system,
where it is harbored in the geniculate, trigeminal, or dorsal root ganglia and remains dormant for
many years. With advancing age or immunocompromised states, the virus reactivates and an
eruption (ie, shingles) occurs. Even after the acute rash subsides, pain can persist or recur in
shingles-affected areas. This condition is known as postherpetic neuralgia (PHN).

Pathophysiology

Some patients with postherpetic neuralgia (PHN) appear to have abnormal function of
unmyelinated nociceptors and sensory loss (usually minimal). Pain and temperature detection
systems are hypersensitive to light mechanical stimulation, leading to severe pain (allodynia).
Allodynia may be related to formation of new connections involving central pain transmission
neurons. Other patients with PHN may have severe, spontaneous pain without allodynia,
possibly secondary to increased spontaneous activity in deafferented central neurons or
reorganization of central connections. An imbalance involving loss of large inhibitory fibers and
an intact or increased number of small excitatory fibers has been suggested. This input on an
abnormal dorsal horn containing deafferented hypersensitive neurons supports the clinical
observation that both central and peripheral areas are involved in the production of pain.

Epidemiology

Frequency
United States

Frequency 1 month after onset of shingles is 9-14.3% and at 3 months is about 5%. At 1 year, 3%
continue to have severe pain.

Family history as a risk factor for herpes zoster has been described. In a case-control study of
504 patients and 523 controls, Hicks et al found that the patients were more likely to report blood
relatives with herpes zoster than the controls (39% vs 11%, p< .001). This risk was higher in
patients with multiple blood relatives with herpes zoster compared with those with a single blood
relative with herpes zoster.[1]

International
A study from Iceland demonstrated variations in risk of PHN associated with different age
groups. No patient younger than 50 years described severe pain at any time. Patients older than
60 years described severe pain: 6% at 1 month and 4% at 3 months from the onset of shingles.[2]

Mortality/Morbidity
See the list below:

Postherpetic neuralgia is not fatal.

Patients may experience significant pain for a prolonged period of time.

Older age appears to be the most significant risk factor for developing PHN.

Sex
No predilection for developing PHN is known. Although 65% of patients in a study by Watson et
al were women, this was believed to mirror the usual predominance of women in this age group.

Age
The association between greater age and PHN is strong.[3] At age 60 years, approximately 60% of
patients with shingles develop PHN, and at age 70 years, 75% develop PHN.

History
See the list below:

A painful vesicular eruption in a dermatomal distribution is typical of herpes zoster (HZ).

With resolution of the eruption, pain that continues for 3 months or more is defined as
postherpetic neuralgia (PHN).

Pain is intense and may be described as burning, stabbing, or gnawing.

HZ can reactivate subclinically with pain in a dermatomal distribution without rash.[4]

This condition is known as zoster sine herpete and may be more complicated, affecting
multiple levels of the nervous system and causing multiple cranial neuropathies,
polyneuritis, myelitis, or aseptic meningitis.[5]

Physical
See the list below:
 Area of previous HZ may show evidence of cutaneous scarring.

Sensation may be altered over involved areas, in the form of either hypersensitivity or
decreased sensation.

Allodynia is pain produced by a non-noxious stimulus, such as a light touch by a brush,

and may be present over the involved area.

Changes in autonomic function such as increased sweating over the involved area may be
seen.

Causes
See the list below:

Risk factors for development of PHN include the following:

o Advancing age

o Site of HZ involvement

Lower risk - Jaw, neck, sacral, and lumbar

Moderate risk - Thoracic

Highest risk - Trigeminal (especially ophthalmic division), brachial plexus

o Severe prodromal pain (with HZ)

o Severe rash

Differential Diagnoses

Laboratory Studies
See the list below:

No laboratory work is usually necessary in cases of postherpetic neuralgia (PHN).

Results of cerebrospinal fluid (CSF) evaluation are abnormal in 61%.

 o Pleocytosis is observed in 46%, elevated protein in 26%, and varicella zoster virus
(VZV) DNA in 22%.

o These findings are not predictive of the PHN clinical course.

Viral culture or immunofluorescent staining may be used to differentiate herpes simplex

from herpes zoster in cases that are difficult to distinguish clinically.

Antibodies to herpes zoster can be measured. A 4-fold increase has been used to support
the diagnosis of subclinical herpes zoster (zoster sine herpete). However, a rising titer
secondary to viral exposure rather than reactivation cannot be ruled out.

Imaging Studies
A study by Haanpaa et al revealed the following:[6]

MRI lesions attributable to HZ were seen in the brain stem and cervical cord in 9 patients
(56%).

At 3 months after onset of HZ, 5 patients (56%) with an abnormal MRI had developed
PHN.

Of the 7 patients who had no HZ-related lesions on MRI, none had residual pain.

Histologic Findings
Although HZ symptoms may be confined to a few sensory dermatomes, pathological changes
may be more widespread. Affected ganglia of the spinal or cranial nerve roots are swollen and
inflamed with a primarily lymphocytic reaction. Some ganglion cells are swollen while others
are degenerated.

Inflammation extends into the meninges and root entry zone and may be present in the ventral
horn and perivascular space of the spinal cord. Pathological changes in the brain stem are similar
to those in the spinal root and spinal cord. In the months following infection, fibrosis occurs in
the ganglia, peripheral nerve, and nerve root. Degeneration occurs in the ipsilateral posterior
column.

Medical Care
The financial implications for treatment of postherpetic neuralgia are becoming more important
as the population ages. Dworkin et al examined annualized costs for persistent pain in patients
with herpes zoster. Annualized costs were $4917 for commercially insured patients, $2696 for
Medicare patients and $9310 for Medicaid patients.[7]
A clinical trial has shown that a live-attenuated varicella-zoster virus vaccine is effective against
herpes zoster (HZ) and postherpetic neuralgia (PHN). Brisson estimates that for 65-year-olds, the
number needed to vaccinate (HZ vaccine efficacy=63%, PHN vaccine efficacy=67%, no waning)
to prevent a case of HZ, a case of PHN, an HZ death, a life-year lost, and a quality-adjusted life-
year lost is estimated to be 11 (90% Crl: 10-13), 43 (90% Crl: 33-53), 23,319 (90% Crl: 15,312-
33,139), 3762 (90% Crl: 1650-4629), and 165 (90% Crl: 105-197), respectively. Results of this
study show that the main benefit of HZ vaccination is prevention of morbidity caused by pain.[8]

In March 2011, the Food and Drug Administration (FDA) lowered the approved age for use of
Zostavax to 50-59 years. Zostavax was already approved for use in individuals aged 60 years or
older. Annually, in the United States, shingles affects approximately 200,000 healthy people aged
50-59 years. Approval was based on a multicenter study, the Zostavax Efficacy and Safety Trial
(ZEST).[9] The trial was conducted in the United States and 4 other countries in 22,439 people
aged 50-59 years. Participants were randomized in a 1:1 ratio to receive either Zostavax or
placebo. Participants were monitored for at least 1 year to see if shingles developed. Compared
with placebo, Zostavax significantly reduced the risk of developing zoster by approximately
70%.

Chen et al found vitamin C plasma concentrations are lower in 38 patients with postherpetic
neuralgia compared with 39 healthy volunteers (P < .001). In this study, restoration of vitamin C
concentrations decreased spontaneous pain (but not brush-evoked pain) by 3.1 on a numeric pain
scale in the postherpetic neuralgia group compared with placebo treatment (P < 0.001). The
authors concluded that vitamin C status is a component in postherpetic neuralgia and is a
component involved in spontaneous pain relief.[10]

In a small study by Kanai et al, lidocaine 4% ophthalmic drops were administered to 24 patients
with ophthalmic postherpetic neuralgia in a crossover manner. A significant reduction in eye and
forehead pain was observed in patients who received the lidocaine ophthalmic drops. Analgesic
onset was noted via a visual analog scale within 15 minutes after administration and persisted for
a median of 36 hours (range, 8-96 h).[11]

Surgical Care
See the list below:

Dorsal root entry zone (DREZ) lesions have been used.

o Efficacy - Improvement rate is 20% in long-term studies.

o Complications - Gait disturbances are experienced by 12% of treated patients.

Miscellaneous treatment

o Epidural steroids[12]
 o Nerve blocks[12]

Medication Summary

The goal of therapy for postherpetic neuralgia (PHN) is to reduce morbidity through the use of
tricyclic antidepressants, anticonvulsants, anesthetics, analgesics, corticosteroids, and antiviral
agents. A recently approved vaccine is also effective for preventing herpes zoster (HZ) outbreaks
and PHN. A recent trial demonstrated that the combination of gabapentin and nortriptyline was
more efficacious than either drug as monotherapy for neuropathic pain.[13] Another study found
that a single 60-minute treatment with the high-concentration capsaicin patch NGX-4010
reduced PHN for up to 12 weeks regardless of concomitant systemic neuropathic pain
medication use.[14]

Tricyclic antidepressants

Class Summary
Complex group of drugs that have central and peripheral anticholinergic effects as well as
sedative effects. They have central effects on pain transmission. They block the active reuptake
of norepinephrine and serotonin.

View full drug information

Amitriptyline (Elavil)
By inhibiting reuptake of serotonin and/or norepinephrine by presynaptic neuronal membrane,
may increase synaptic concentration in CNS. Useful as analgesic for certain types of chronic and
neuropathic pain.

View full drug information

Nortriptyline (Pamelor, Aventyl HCl)

Has demonstrated effectiveness in treatment of chronic pain; by inhibiting reuptake of serotonin
and/or norepinephrine by presynaptic neuronal membrane, may increase synaptic concentration
in CNS; pharmacodynamic effects such as desensitization of adenyl cyclase and down-regulation
of beta-adrenergic receptors and serotonin receptors also appear to play role in its mechanisms of
action.

Analgesics

Class Summary
Pain control is essential to quality patient care; it ensures patient comfort and promotes
pulmonary toilet. Most analgesics have sedating properties, which are beneficial for patients who
experience pain.

View full drug information

Capsaicin topical (Dolorac, Capsin, Zostrix)
Natural chemical derived from plants of Solanaceae family. By depleting and preventing
reaccumulation of substance P in peripheral sensory neurons, may render skin and joints
insensitive to pain. Substance P thought to be chemomediator of pain transmission from
periphery to CNS.

View full drug information

Capsaicin 8% transdermal patch (Qutenza)

Transient receptor potential vanilloid-1 (TRPV1) agonist indicated for neuropathic pain
associated with postherpetic neuralgia. TRPV1 is an ion channelreceptor complex expressed on
nociceptive skin nerve fibers. Topical capsaicin causes initial TRPV1 stimulation that may cause
pain, followed by pain relief by reduction in TRPV1-expressing nociceptive nerve endings.
Neuropathic pain may gradually recur over several months (thought to be caused by TRPV1
nerve fiber reinnervation of treated area).

Corticosteroids

Class Summary
These agents have anti-inflammatory properties. Glucocorticoids cause profound and varied
metabolic effects. In addition, they modify the body's immune response to diverse stimuli.

Dexamethasone (Decadron, Alba-Dex, Dalalone L.A.)

Used to treat various allergic and inflammatory diseases. Decreases inflammation by suppressing
migration of polymorphonuclear leukocytes and by reversing increased capillary permeability.

Prednisone (Deltasone, Orasone, Sterapred)

Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and by
reversing increased capillary permeability.

Methylprednisolone (Solu-Medrol, Adlone, Duralone)

Decreases inflammation by suppression of migration of polymorphonuclear leukocytes and
reversal of increased capillary permeability.

Antiviral agents

Class Summary
The goal of antivirals is to shorten the clinical course, prevent complications, prevent the
development of latency and/or subsequent recurrences, decrease transmission, and eliminate
established latency.
Famciclovir (Famvir)
Pro-drug that, when biotransformed into active metabolite penciclovir, may inhibit viral DNA
synthesis/replication.

Anesthetics

These agents stabilize the neuronal membrane so the neuron is less permeable to ions. This
prevents the initiation and transmission of nerve impulses, thereby producing the local anesthetic
action.

Lidocaine anesthetic (DermaFlex gel, Lidoderm 5% patch)

Several recent studies have advocated topical administration of lidocaine as treatment of PHN.
Lidocaine gel (5%) in placebo-controlled study showed significant relief in 23 patients studied.
Lidocaine tape also decreases severity of pain.

Anticonvulsants

Class Summary
These agents are used to manage severe muscle spasms and provide sedation in neuralgia. They
have central effects on pain modulation. Prescribing information for gabapentin products (ie,
Neurontin, Gralise, Horizant) describe a statistical improvement in pain scores (ie, a decrease by
at least 50% from baseline) compared with placebo when treated for postherpetic neuralgia.

Pregabalin (Lyrica)
Approved by FDA for use in PHN. Freynhagen et al describe a statistically significant reduction
in mean pain score and in pain-related sleep interference compared with placebo. Pregabalin
binds with high affinity to alpha2-delta subunit of voltage-gaited calcium channels, thereby
reducing excitatory neurotransmitters. Has half-life of approximately 6 h and is eliminated by
renal excretion. Decrease in creatinine clearance results in decrease elimination and, therefore,
increase in plasma concentration. Peak plasma concentration occurs at one and one half hours
after oral intake. Bioavailability is 90%. Following repeated dosing, steady state concentration is
achieved at 24-48 h. Can be taken with or without food.

Gabapentin (Neurontin, Gralise)

This medication has been approved by the FDA for the treatment of PHN. Has properties
common to other anticonvulsants and antineuralgic effects. Exact mechanism of action is not
known. Structurally, gabapentin is related to GABA, but it does not interact with GABA
receptors. Believed to have a binding site at the alpha 2-delta protein, an auxiliary subunit of
voltage-gaited calcium channels. In the rat brain, binding is localized on neuronal dendritic areas.
Relevance of these observations to treatment of PHN is not known.
Gabapentin enacarbil (Horizant)
Gabapentin prodrug that provides a longer duration of action compared with gabapentin.
Structurally related to neurotransmitter GABA, but has no effect on GABA binding, uptake, or
degradation. The mechanism for analgesic activity is unknown. Approved by the FDA for PHN.

Vaccines

Used for prevention of HZ outbreak.

Zoster vaccine live (Zostavax)

A randomized, double-blind, placebo-controlled trial included 38,560 patients age 60 years and
older for 3.1-year median surveillance; 95% completed the trial. HZ development decreased
51.3% (P < 0.001) and PHN decreased 66.5% (P < 0.001). In the ZEST trial, the vaccine
significantly reduced the risk by 70% in individuals aged 50-59 years.

Prognosis
See the list below:

The natural history of postherpetic neuralgia (PHN) involves slow resolution of the pain
syndrome.

In those patients who develop PHN, most will respond to analgesic agents such as the
tricyclic antidepressants.

A subgroup of patients may develop severe, long-lasting pain that does not respond to
medical therapy. Continued research for new agents is necessary.