Post Herpetic

Neuralgia
Candy Lauwrenz

Introduction
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.

Introduction
Background

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.

Pathophysiology
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.

Incidence

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

Mortality/Morbidity

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.

At age 60 years, approximately 60% of patients with shingles develop PHN, and at
age 70 years, 75% develop PHN.

Clinical
History

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. 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.

Physical
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

asa 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
Risk factors for development of PHN include the following:

Advancing age
Site of HZ involvement

Lower risk - Jaw, neck, sacral, and lumbar

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

Severe prodromal pain (with HZ)

Severe rash

Differential Diagnoses

Differential Diagnoses

Cavernous Sinus Syndromes

Chronic Paroxysmal Hemicrania
Cluster Headache
Head Injury
Hemifacial Spasm
Migraine Headache
Migraine Headache : NeuroOphthalmic Perspective

Migraine Variants
Pathophysiology and Treatment of
Migraine and Related Headache
Persistent Idiopathic Facial Pain
Tolosa-Hunt Syndrome
Traumatic Peripheral Nerve Lesions
Trigeminal Neuralgia

Laboratory

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

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

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

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:

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.

Treatment
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

Treatment
Medical
Care

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 lifeyear 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: 15,31233,139), 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.

Treatment
Medical
Care

Chen et al found vitamin C plasma concentrations are lower in 38

patients with postherpetic neuralgia compared with 39 healthy
volunteers (P <0.001).

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.9

Surgical Care

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

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

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

Miscellaneous treatment

Epidural steroids
Nerve blocks

Medication

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.11

Medicati
on

Tricyclic antidepressants

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.

Medication Amitriptyline

(Elavil)

By inhibiting reuptake of serotonin and/or norepinephrine by

presynaptic neuronal membrane,

increase synaptic concentration in CNS.
Useful as analgesic for certain types of chronic and neuropathic pain.

Adult
Early in course of HZ: 25 mg/d PO hs to prevent PHN
After PHN develops: 30-100 mg PO qhs
Pediatric
Children: 0.1 mg/kg/d PO hs and increase, as tolerated, over 2-3 wk to 0.5-2 mg/d
hs
Adolescents: 25-50 mg/d PO; increase gradually to 100 mg/d in divided doses

Medicati
on

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
down-regulation of beta-adrenergic receptors and serotonin receptors
also appear to play role in its mechanisms of action.
Adult

25 mg PO tid/qid; not to exceed 150 mg/d

Pediatric
<25 kg: Not established
25-35 kg: 10-20 mg/d PO
35-54 kg: 25-35 mg/d PO
>25 kg: Administer as in adults

Medicati
on Capsaicin cream (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.
Adult

Cream: Apply to skin tid/qid for 3-4 consecutive wk and evaluate efficacy;
not to exceed 4 applications/d

Pediatric

Administer as in adults

Medicati
on
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).

Medicati
on
Capsaicin 8% transdermal
patch (Qutenza)
Adult

Only physicians or healthcare professionals are to administer patch

Recommended dose:
Each patch contains 8% capsaicin (640 mcg/cm2; 179 mg/patch)
Single, 60-min application of up to 4 patches to dry, intact (unbroken) skin
May repeat no more frequently than q3mo
Pediatric

<18 years: Not established

Adult

Loading dose: 125-250 mg IV

Maintenance dose: 0.5-1 mg/kg/dose IV q6h for up to 5 d

Pediatric

Loading dose: 2 mg/kg IV

Maintenance dose: 0.5-1 mg/kg/dose IV q6h for up to 5 d

Corticosteroids

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.

Corticosteroids
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.
Adult

0.75-9 mg/d PO in divided doses q6-12h

Pediatric

0.08-0.3 mg/kg/d PO or 2.5-10 mg/m 2/d divided q6-12h

Corticosteroids
Prednisone (Deltasone, Orasone, Sterapred)
Decreases inflammation by suppressing migration of polymorphonuclear
leukocytes and by reversing increased capillary permeability.
Adult

5-60 mg/d PO qd or divided bid/qid; taper over 2 wk as symptoms

resolve
Pediatric

4-5 mg/m2/d PO; alternative: 1-2 mg/kg/d PO; taper over 2 wk as

symptoms resolve

Corticosteroids
Methylprednisolone (Solu-Medrol, Adlone, Duralone)
Decreases inflammation by suppression of migration of
polymorphonuclear leukocytes and reversal of increased capillary
permeability.
Adult

Loading dose: 125-250 mg IV

Maintenance dose: 0.5-1 mg/kg/dose IV q6h for up to 5 d

Pediatric
Loading dose: 2 mg/kg IV

Maintenance dose: 0.5-1 mg/kg/dose IV q6h for up to 5 d

Antiviral agents
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

Antiviral agents

Famciclovir (Famvir)

Pro-drug that, when biotransformed into active metabolite penciclovir,

may inhibit viral DNA synthesis/replication.
Adult

500-700 mg PO tid for 72 h

Pediatric
Not established

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 (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.

Anesthetics
Adult
Gel (5%): Apply to affected area prn
Patch (5%): Apply to most painful area up to 3
patches per application;

patch may remain in place for up to 12 h in any 24 h

period

Pediatric
Administer as in adults

Anticonvulsants

These agents are used to manage severe muscle spasms and provide
sedation in neuralgia. They have central effects on pain modulation.

Anticonvulsants
Pregabalin (Lyrica)

Approved by FDA for use in PHN.

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.

Anticonvulsants
Pregabalin (Lyrica)
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.
Adult

75 mg PO bid initially; may increase to 150 mg bid in 1 wk;

may increase to 300 mg bid if needed and tolerated

Pediatric

Not established

Anticonvulsants
Gabapentin (Neurontin)
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.
Adult

100 mg PO tid; titrate dose prn; recommended dose is 900-1800 mg PO qd;

not to exceed 900 mg PO qid

Pediatric

<12 years: Not established

>12 years: Administer as in adults

Vaccines
Used for prevention of HZ outbreak.
Zoster Vaccine, Live (Zostavax )

HZ development decreased 51.3% (P <.001) and PHN

decreased 66.5% (P <.001).
Dosis :

Adult >60 years: 1 mL SC once

Pediatric
Not indicated

AAN GUIDELINES FOR THE TREATMENT of

PHN

Evidence-based recommendations to identify which treatments

provide benefit in terms of decreased pain and improved quality of

life in patients with PHN

Recommendations:
pregabalin, gabapentin opioids, topical lidocaine,tricyclic

antidepressants

have class-l evidence for efficacy in the treatment of PHN

Topical aspirin and capsaicin creams are possibly-effective, although the

magnitude of benefit is low,

AAN: American Academy of Neurology

EFNS GUIDELINES FOR THE

Recomendations
:
TREATMENT
of PHN
First Line Therapy

TCAs, pregabalin,
gabapentin and topical
lidocaine (evidence level A)

Second Line Therapy

Strong opioids, tramadol and

capsaicin, Topical lidocain :
more prefer to be used in
elderly and in allodynia /small
area of pain, (evidence level
B)

Lack of or Weak Efficacy

Mexiletine and MNDA

antagonists (evidence level A)
EFNS: European Federation of Neurology Societies

Primary care
remains
responsible for
the diagnosis,
treatment
prescribing of
medication and
monitoring of their
patient

POSTHERPETIC NEURALGIA ALGORITHM

Typical history of prodrome & ras in a dermatoma distribution
Shooting/burning pain in the same area as the rash? Allodynia
YES

Patient < 60 years old

Patient > 60 years old or cardiovacular problem

Drugs used in the treatment plan

may indude the following :
TCA e.g. amitiptytine, nortriptylina
Gabapentin
Pregabalin (see drug table),
Lidocaine 5% plaster
Duloxetine
Tramadol
Oxycontin
Capsaicin cream 0,075%

Drugs used in the treatment plan

may indude the following :
Gabapenlin
Pregabalin (see drug table)
Lidocaine 5% plaster
Duloxetine
Tramadol
TCA e.g. amitiptytine, nortriptylina
Oxycontin
Capsaicin cream 0,075%

ALL TO BE TRIED FOR 3 MONTHS ;

SIDE EFFECTS PERMITTING If
ineffective & adequate dosage or
in combination, drugs should be
stopped
Has drug treatment

ALL TO BE TRIED FOR 3 MONTHS ;

SIDE EFFECTS PERMITTING If
ineffective & adequate dosage or in
combination, drugs should be
stopped
been effective ?

No
Referal to Pain Service,UHL

Prognosis
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.