Postherpetic Neuralgia

Author: W Alvin McElveen, MD, Director, Stroke Unit, Lakewood Ranch Medical Center; Neurologist, Manatee Memorial Hospital Coauthor(s): Ralph F Gonzalez, MD, Private Practice, Bradenton Neurology, Inc; Consulting Staff, Department of Neurology, Blake Hospital, Lakewood Ranch Medical Center, Manatee Memorial Hospital; Douglas Sinclair, DO, Consulting Staff, Department of Neurology, Blake Medical Center and Bradenton Neurology, Inc Contributor Information and Disclosures Updated: Jan 8, 2010 http://emedicine.medscape.com/

Introduction
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.

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

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.

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.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

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: 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

Laboratory Studies

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.

Treatment
Surgical Care

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 steroids10 o Nerve blocks10

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

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.

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.

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 Metabolized by P 450 2D6 system, thus drugs that inhibit this enzyme system (eg, cimetidine, quinidine) may increase tricyclic levels; phenobarbital may increase metabolism, decreasing its effects, and block uptake of guanethidine, thus preventing its hypotensive effects; may interact with thyroid medications, alcohol, CNS depressants, barbiturates, and disulfiram Documented hypersensitivity, MAOIs in past 14 d

Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions
Use with caution in patients with cardiac conduction disturbances, cardiac arrhythmias, seizures, glaucoma, urinary retention history, hyperthyroidism, renal or hepatic impairment; Because of pronounced effects in cardiovascular system, best to avoid in elderly persons

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.

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 Cimetidine may increase levels; may increase PT in patients stabilized with warfarin Documented hypersensitivity, narrow-angle glaucoma, MAOIs in past 14 d

Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions
Use caution in renal or hepatic impairment, cardiac conduction disturbances, or history of hyperthyroidism

Analgesics
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.

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

Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions
Avoid contact with eyes; do not bandage tightly; if condition worsens or symptoms persist 14-28 d, discontinue use and consult physician; for external use only

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 TRPV1expressing nociceptive nerve endings. Neuropathic pain may gradually recur over several months (thought to be caused by TRPV1 nerve fiber reinnervation of treated area).

Adult
Only physicians or healthcare professionals are to administer patch Application preparation: Use nitrile gloves during application process; latex gloves do not provide adequate protection Clip hair if necessary (do not shave) Gently wash treatment area with mild soap and water; dry thoroughly Patch may be cut to match size and shape of treatment area (cut to size/shape before removing protective release liner) Pretreat area with topical anesthetic such as EMLA cream for 1 hour to reduce pain associated with patch application 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 Patch removal: Gently remove and slowly roll patch inward (avoid aerosolization) Cleanse skin by generously applying cleansing gel (supplied with patch) to affected area; leave on for at least 1 min, then remove with dry wipe and gently wash area with mild soap and water

Pediatric
<18 years: Not established

Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions
Monitor for at least 1 h after patch application because of risk for increased blood pressure; may cause transient increased pain, erythema, swelling, pruritus, and papules at application site; do not apply to face or scalp to avoid exposure to eyes or mucous membranes; remove patch gently to avoid aerosolization (airborne capsaicin can result in coughing or sneezing); apply patch within 2 h of opening package; treated area may be sensitive to heat for several days (eg, hot water, direct sunlight, vigorous exercise)

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. 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 Barbiturates, phenytoin, and rifampin can decrease effects; decreases effects of salicylates and vaccines used for immunization Documented hypersensitivity, untreated active infection, fungal disease of eye

Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions
Monitor for adrenal insufficiency when tapering drug; because of risk of adverse effects, use cautiously in elderly, in smallest possible dose and for shortest possible time 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 Concurrent estrogens may decrease clearance; when used concurrently with digoxin, may increase digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism (may require dose increase); patients taking diuretics must be monitored for hypokalemia Documented hypersensitivity; viral, fungal, or tubercular skin lesions

Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions
Caution in hyperthyroidism, cirrhosis, nonspecific ulcerative colitis, osteoporosis, peptic ulcer, diabetes, or myasthenia gravis; adrenal crisis may occur if withdrawn abruptly; increased risk for possible complications, including infections, hyperglycemia, edema, osteonecrosis, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, growth suppression, myopathy

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 Concurrent estrogens may decrease clearance; when used concomitantly with digoxin, may increase digitalis toxicity secondary to hypokalemia Documented hypersensitivity; viral, fungal, or tubercular skin lesions

Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions
Caution in patients with hyperthyroidism, cirrhosis, nonspecific ulcerative colitis, osteoporosis, peptic ulcer, diabetes, or myasthenia gravis

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. 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

Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions
Caution in renal failure or with other nephrotoxic drugs

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.

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 Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions
For external or mucous membrane use only; do not use in eyes

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

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.

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 May cause additive effects on cognitive and gross motor functioning when coadministered with drugs that cause dizziness or somnolence Documented hypersensitivity

Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions
Discontinue gradually (over a minimum of 1 wk) to minimize increased seizure frequency in patients with seizure disorders; may cause insomnia, nausea, headache, or diarrhea with abrupt withdrawal; common adverse effects include dizziness, somnolence, blurred vision, weight gain, and peripheral edema; may elevate creatinine kinase level, decrease platelet count, and increase PR interval; doses >300 mg/d associated with higher rate of adverse effects and treatment discontinuation; decrease dose with elderly or renal impairment (ie, CrCl <60 mL/min) 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 Antacids may significantly reduce bioavailability, should be administered > 2 h following antacid; cimetidine may reduce clearance, but this may not be of clinical significance; may significantly increase norethindrone levels Documented hypersensitivity

Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions
Caution in severe renal disease

Vaccines
Used for prevention of HZ outbreak.

Follow-up
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.

Patient Education
For excellent patient education resources, visit eMedicine's Bacterial and Viral Infections Center. Also, see eMedicine's patient education articles Shingles and Chickenpox.

References
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