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).
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Hypopigmented rash in thoracic dermatome of postherpetic lesion.
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 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.
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]
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.
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.
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 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%.
In 2017, the FDA approved Shingrix (zoster vaccine recombinant, adjuvanted) for the prevention of shingles in adults aged ≥50 years. Approval is based on findings from a Phase III clinical trial program assessing its efficacy, safety, and immunogenicity in 38,000 patients. Data from a pooled analysis of 2 clinical trials demonstrated efficacy against shingles greater than 90% across all age groups, as well as sustained efficacy over a follow-up period of 4 years.[10, 11]
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.[12]
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).[13]
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.[15] 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.[16]
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.
Clinical Context:
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.
Clinical Context:
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.
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.
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.
Clinical Context:
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.
The extend-release formulation is available in 82.5mg, 165mg, and 330mg tablets strength. It is administered once daily after an evening.
Clinical Context:
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.
Clinical Context:
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.
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.
In October 2017, FDA approved Lyrica CR (pregabalin extended-release tablets), a once-daily treatment for the management of neuropathic pain associated with diabetic peripheral neuropathy (pDPN) and the management of postherpetic neuralgia (PHN). The approval was based on data from a randomized placebo-controlled trial conducted in 801 patients with PHN. The trial included a 6-week single-blind, dose optimization phase followed by a 13-week double-blind phase. Compared to placebo, more patients in the Lyrica CR group experienced at least a 50% improvement in pain intensity (73.6% vs. 54.6%).
Clinical Context:
Used to treat various allergic and inflammatory diseases. Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and by reversing increased capillary permeability.
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.
Clinical Context:
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.
Clinical Context:
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).
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.
Clinical Context:
Indicated for pain associated with postherpetic neuralgia. Lidoderm 5% transdermal patch contains 700 mg of lidocaine per patch. ZTlido 1.8% transdermal patch contains 36 mg per patch. Pharmacokinetic studies have demonstrated bioequivalence of the 2 patches. The ZTlido 1.8% patch is engineered to provide improved adhesion and flexibility to provide targeted transdermal absorption, so a lower amount of lidocaine can be used.
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.
What is the pathogenesis of postherpetic neuralgia (PHN)?What is the pathophysiology of postherpetic neuralgia (PHN)?What is the prevalence of postherpetic neuralgia (PHN) in the US?Which age group is at highest risk for postherpetic neuralgia (PHN)?What is the morbidity of postherpetic neuralgia (PHN)?How does the prevalence of postherpetic neuralgia (PHN) vary by sex?How does the prevalence of postherpetic neuralgia (PHN) vary by age?What are the signs and symptoms of postherpetic neuralgia (PHN)?Which physical findings are characteristic of postherpetic neuralgia (PHN)?What are the causes of postherpetic neuralgia (PHN)?What are the differential diagnoses for Postherpetic Neuralgia?What is the role of lab studies in the diagnosis of postherpetic neuralgia (PHN)?What is the role of imaging studies in the diagnosis of postherpetic neuralgia (PHN)?Which histologic findings are characteristic of postherpetic neuralgia (PHN)?Which vaccines are FDA approved for the prevention of shingles and postherpetic neuralgia (PHN)?What is the cost for medical care of postherpetic neuralgia (PHN)?What is the role of vaccines in the prevention of postherpetic neuralgia (PHN)?What is the role of vitamin C in the treatment of postherpetic neuralgia (PHN)?What is the role of lidocaine 4% ophthalmic drops in the treatment of postherpetic neuralgia (PHN)?What is the role of surgery in the treatment of postherpetic neuralgia (PHN)?Which medications are used in the treatment of postherpetic neuralgia (PHN)?Which medications in the drug class Anesthetics, Topical are used in the treatment of Postherpetic Neuralgia?Which medications in the drug class Analgesics, Topical are used in the treatment of Postherpetic Neuralgia?Which medications in the drug class Corticosteroids are used in the treatment of Postherpetic Neuralgia?Which medications in the drug class Anticonvulsants are used in the treatment of Postherpetic Neuralgia?Which medications in the drug class Antiviral agents are used in the treatment of Postherpetic Neuralgia?Which medications in the drug class Tricyclic antidepressants are used in the treatment of Postherpetic Neuralgia?Which medications in the drug class Anesthetics are used in the treatment of Postherpetic Neuralgia?What is the prognosis of postherpetic neuralgia (PHN)?Where are patient educations resources for postherpetic neuralgia (PHN) found?
W Alvin McElveen, MD, Director, Stroke Unit, Lakewood Ranch Medical Center; Neurologist, Manatee Memorial Hospital
Disclosure: Nothing to disclose.
Coauthor(s)
Douglas Sinclair, DO, Consulting Staff, Department of Neurology, Blake Medical Center and Bradenton Neurology, Inc
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Chief Editor
Robert A Egan, MD, NW Neuro-Ophthalmology
Disclosure: Received honoraria from Biogen Idec and Genentech for participation on Advisory Boards.
Additional Contributors
Joseph Carcione, Jr, DO, MBA, Consultant in Neurology and Medical Acupuncture, Medical Management and Organizational Consulting, Central Westchester Neuromuscular Care, PC; Medical Director, Oxford Health Plans
Disclosure: Nothing to disclose.
Acknowledgements
Ralph F Gonzalez, MD Private Practice, Bradenton Neurology, Inc; Consulting Staff, Department of Neurology, Blake Hospital, Lakewood Ranch Medical Center, Manatee Memorial Hospital
Ralph F Gonzalez, MD is a member of the following medical societies: American Academy of Neurology and Florida Medical Association
Schmader K, Levin M, Gnann J, McNeil S, Vesikari T, et al. Efficacy, immunogenicity, safety, and tolerability of zoster vaccine (ZV) in subjects 50 to 59 years of age (Poster/Abstract). Infectious Diseases Society of America. The 48th Annual Meeting of the Infectious Diseases Society of America. 10-21-2010. Vancouver, British Columbia, Canada:Ref Type: Abstract: 3363.
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