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 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
• 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 : Neuro-
Ophthalmic 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 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.
 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
Medication

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
Medication
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
Medication
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
Medication
Capsaicin 8% transdermal
patch (Qutenza)

Transient receptor potential vanilloid-1 (TRPV1) agonist indicated for neuropathic

pain associated with postherpetic neuralgia.
TRPV1 is an ion channel–receptor 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).
 Medication
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/m2/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 TREATMENT of
Recomendations : 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 POSTHERPETIC NEURALGIA ALGORITHM
responsible for
the diagnosis, Typical history of prodrome & ras in a dermatoma distribution
treatment
prescribing of
medication and
monitoring of their
Shooting/burning pain in the same area as the rash? Allodynia
patient
YES
Patient < 60 years old Patient > 60 years old or cardiovacular problem

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

ALL TO BE TRIED FOR 3 MONTHS ; SIDE ALL TO BE TRIED FOR 3 MONTHS ; SIDE
EFFECTS PERMITTING If ineffective & EFFECTS PERMITTING If ineffective &
adequate dosage or in combination, drugs adequate dosage or in combination, drugs
should be stopped should be stopped

Has drug treatment 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.