Herpes zoster (HZ), also known as shingles, is a viral infection caused by reactivation of the dormant Varicella Zoster Virus (VZV). Postherpetic neuralgia (PHN) is the most common complication of HZ in the immunocompetent patient, and is defined as dermatomal pain that persists for longer than 120 days after the initial rash.1
HZ results from the reactivation of the dormant VZV virus. Initial infection by VZV causes chicken pox. After resolution of the initial infection, the virus remains dormant in the dorsal sensory ganglia or cranial nerve ganglia for years. As immunity declines with age VZV can reactivate, resulting in a HZ flare.
Epidemiology including risk factors and primary prevention
In the United States, 99% of adults over the age of 40 have been exposed to VZV and therefore are at risk for developing HZ.2 The incidence of HZ ranges from 3.4 to 4.8 cases per 1000 people per year.1 Age greater than 50 years is the principal risk factor for developing HZ. While the life-time risk of developing HZ is 25 to 30%, it increases to 50% at age 80 years or older, largely as a result of diminished cell-mediated immunity.3 Human immunodeficiency virus, lymphoproliferative disorders, immunosuppressive therapies, and certain autoimmune diseases also increase HZ risk. Other potential factors may include physical and psychological stress and Caucasian ethnicity.
The incidence of developing PHN is 10-25%,1 and increases with age, more severe rash and acute HZ pain, ophthalmic involvement, and presence of prodromal symptoms (pain, dysesthesia, and allodynia). Other risk factors include immunosuppression, diabetes, sensory abnormalities in the affected dermatomes, polyneuropathy, and trauma. There is limited evidence that smoking history and female gender may also contribute to increased PHN risk.4,5
The reactivation of VZV in the sensory ganglia causes inflammation and neuronal destruction of the dorsal root ganglion. The virus travels along the sensory nerve to the skin resulting in vesicular lesions, primary afferent nerve damage, and generalized cell necrosis.5
Nerve damage starts early in the acute phase of HZ prior to rash onset and may correlate with the severity of painful neuropathy. Histopathology reveals intraepidermal blisters with surrounding inflammatory infiltrate. On biopsy multinucleated giant cells with intranuclear inclusions are characteristic
A single, unilateral dermatome is typically affected. Clinical features of HZ depend on the site of involvement. Although it has a predilection for the cranial and spinal sensory ganglia, it may also affect anterior horn cells, autonomic neurons, and the leptomeninges.
Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)
The initial HZ rash resolves typically in 2-4 weeks. Despite treatment, approximately 20% of patients over the age of 60 years will develop persistent pain 6 months after initial onset of the rash. If PHN develops, pain may last for months to years. In a study of patients aged 65 and older, the mean duration of pain was 3.3 years, but lasted over 10 years in some individuals.6
Specific secondary or associated conditions and complications
Serious complications include HZ ophthalmicus, disseminated HZ, secondary bacterial infections, motor neuropathy, and vasculitis. When HZ involves the tip of the nose, eye involvement should be suspected. Patients with HZ ophthalmicus should have a prompt evaluation by an ophthalmologist, given the associated risk of blindness. Disseminated zoster occurs mainly in immunocompromised patients and, in cases of visceral involvement, can lead to pneumonia, encephalitis, and hepatitis with a 5 to 10% mortality rate.7 Vasculitis is associated with increased risk of MI, TIA, and stroke, especially in patients under the age of 40 8,9
As HZ can be the presenting sign of HIV infection, patients at risk for HIV should undergo serologic testing. While certain malignancies are associated with increased incidence of HZ, screening for malignancy in otherwise healthy patients is not recommended.
2. ESSENTIALS OF ASSESSMENT
HZ presents with fatigue, malaise, and flu-like symptoms, often with prodromal pain followed by pruritus, paresthesias, and dysesthesia. These symptoms typically last 2-3 days, but can continue up to a week prior to rash onset.
PHN presents as neuropathic pain with a burning, throbbing, sharp, and/or shooting nature. Tactile allodynia is the most debilitating sign. PHN usually occurs in the same dermatome as the preceding vesicular eruption. A secondary musculoskeletal component can result as a result of muscle spasm in response to acute pain or actual motor weakness caused by involvement of anterior horn cells.
Clinical features depend on the location of skin lesion, with thoracic dermatomes, particularly T5-T10, being the most commonly involved,1followed by the cranial nerves, cervical, lumbar, and sacral dermatomes. Involvement of the ophthalmic division of the trigeminal nerve may lead to ocular involvement. The rash usually involves one unilateral dermatome and consists of painful vesicles that eventually develop crusts. There may be associated regional lymphadenopathy. PHN presents with pain, hyperalgesia/allodynia, dermatomal sensory deficits, trigger points, muscle atrophy, and reduced joint range of motion. It can be associated with autonomic and temperature dysregulation as well as variable cutaneous changes, including hypo- or hyperpigmentation and scarring.
Pain severity and location, as well as the patient’s behavioral response to pain, can interfere with quality of life and functional status/independence.7Common sequelae of PHN include impaired sleep, psychosocial dysfunction, chronic fatigue, anorexia, weight loss, diminished libido, and depression, which can substantially interfere with social life and self-care.10, 11
Laboratory studies are not required to establish the diagnosis. Serology is typically not indicated. In cases where definitive clinical diagnosis cannot be made (i.e., atypical rash or disseminated disease without cutaneous lesions in an immunocompromised host), VZV polymerase chain reaction is preferred over VZV direct fluorescent antibody staining of early vesicular lesions.11 Skin biopsy can also be considered. Pain in the absence of a rash may indicate the need to evaluate the patient for other causes such as radiculopathy or plexopathy. In young or African-American patients, central nervous system or visceral involvement, and in disseminated HZ, underlying immune compromise can be considered. Chest or abdominal pain in absence of a rash should warrant a typical evaluation for cardiopulmonary or abdominal pathology.
Imaging is not typically useful from a diagnostic or therapeutic perspective. Of note, in the absence of rash, nerve enlargement caused by inflammation could potentially be seen on focused magnetic resonance imaging.
Social role and social support system
As with other chronic pain syndromes, social factors may affect pain-related behaviors, efficacy of treatment modalities, recovery, and development of a chronic dysfunctional pain syndrome. HZ and PHN can be socially limiting. As such, patients may benefit from additional family, social, and professional support, such as counseling.
HZ can be spread from droplet and airborne routes, typically through close contact. The infected individual is most contagious during the vesicular stage of HZ. At this time, the rash should be kept covered and frequent hand washing should be encouraged. Contact with immune compromised, non-immunized, seronegative, and pregnant women, should be avoided. Once HZ lesions have crusted over, the infected individual is no longer considered contagious. HZ does not pose a risk of exposure to seropositive individuals.
3. REHABILITATION MANAGEMENT AND TREATMENTS
Available or current treatment guidelines
Treatment of HZ is targeted at preventing viral multiplication and pain, thereby decreasing symptom duration and severity. No current treatments prevent PHN. There is, however, strong evidence that antivirals can decrease the severity of PHN.12 A general overview of antiviral treatment is presented in Table 1. Corticosteroids do not appear to reduce the incidence of PHN.12,13
Table 1: Antiviral Treatment of Herpes Zoster
|Patient Demographics||Antiviral Agent||Route||Duration of Therapy|
|>50 years of age, preferably within 72 hours of rash onset||Valacyclovir, Famciclovir, Acyclovir*|
|<50 years, within 72 hours of rash onset|
|Immunocompromised, irrespective of time from rash onset||Intravenous, then transition to oral||No established guidelines **|
|Ophthalmic zoster, neurologic involvement, or disseminated zoster, irrespective of time from rash onset||May require intravenous or oral: case dependent||No established guidelines **|
* Famciclovir and valacyclovir are the preferred over acyclovir due to their significant reduction of pain, superior pharmacokinetics, and more convenient dosing regimens.14 Acyclovir is the only antiviral available in intravenous formulation.
**In elderly or immunocompromised patients a prolonged course of therapy may be required.7,11
Corticosteroid use is controversial. A meta-analysis demonstrated that combination therapy with acyclovir and corticosteroids did not provide additional benefits compared to acyclovir alone. In fact, corticosteroids were shown to potentially increase the risk of secondary bacterial skin infections.13
Because the severity of HZ acute pain is a risk factor for the development of PHN, aggressive pain control is an important aspect of treatment.
PHN can be treated with either topical or systemic agents. The first line of treatment consists of gabapentinoids followed by TCAs. Topical lidocaine (5%), opioids, and topical capsaicin are second-line of treatments. Antivirals, carbamazepine, topical benzydamine, cyclo-oxygenase inhibitors, and N-methyl-d-aspartate receptor antagonists are ineffective in relieving PHN.11,15
The anticonvulsants gabapentin and pregabalin act as calcium channel alpha-2 delta ligands to inhibit the release of nociceptive neurotransmitters. Side effects include somnolence, dizziness, and peripheral edema. Compared to gabapentin, pregabalin has increased bioavailability, fewer dose-related adverse side effects, anxiolytic properties, and twice daily dosing with a similar side effect profile.11 Pregabalin, however, is typically more expensive than gabapentin.
TCAs, include amitryptiline, nortryptiline, and desipramine and act by inhibiting the reuptake of norepinephrine and serotonin, inhibiting spinal nociceptive neurons, and sodium-channel blockade. They are often not tolerated well, particularly in elderly patients. Desipramine, the least sedating, and nortriptyline are as equally effective as amitriptyline, are better tolerated, and have fewer side effects.
Lidocaine, either in transdermal or gel form, affects ectopic activity of sensory nerves involved in nociception. The role of topical lidocaine on neuropathic pain is supported by some anecdotal clinical evidence, though large-scale studies remain conflicted on its efficacy. As such, lidocaine can be considered a second-line agent for PHN, with selective first-line use when there is mild neuropathic pain limited to a defined area of superficial allodynia/hyperalgesia or when systemic therapy is contraindication or poorly tolerated, such as in the elderly.11,16
Topical capsaicin is a second-line agent for PHN, based on high cost, required in -clinic administration of high dose treatment, and efficacy. It acts as an agonist for the vanilloid receptors, depleting substance P and desensitizing nocicptors, and is available as an 8% patch or as over the counter 0.075% cream and 0.05% ointment. High-concentration capsaicin is more efficacious, providing relief up to 3-5 months, than the low-concentration form, though it is associated with more cutaneous irritation.17Side effects are mainly local application site reactions.
Opioids have been shown to be effective in PHN and can be considered if first-line therapies fail to achieve adequate pain relief. As a result of their limitations, such as physical dependence and development of analgesic tolerance, opioids are generally considered third-line therapeutic agents. Referral to a pain specialist should be considered especially when higher doses are required.11,15
Of note, multiple agents are often needed for pain relief and combination treatment has been shown to be more effective than single agents. Interventions such as sympathetic and peripheral nerve blocks and epidural injections of both local anesthetic and steroids and have short duration benefits. Spinal cord stimulation potentially provides pain relief, but also has limited supporting evidence.5 Subcutaneous injection of botulinum toxin has been shown to be superior to topical lidocaine with longer lasting benefits.18Transcutaneous electrical nerve stimulation has been tried for acute HZ and prevention of PHN without consistent evidence supporting efficacy; it can, however, safely be offered as part of treatment.19 Acupuncture has not been shown to be effective.15
At different disease stages
In PHN, there can be absence of a pain-free period after the initial rash, or a quiescent period of up to 12 months1 following the rash after which pain returns. History of rash may not always be present. In such cases, establishing diagnosis may require serial immunologic assays.
Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills
Childhood vaccination decreases the incidence of HZ. VZV immunoglobulin followed by HZ immunization is recommended in immunocompromised seronegative patients who have been exposed to VZV or HZ, as well as in neonates, in patients with severe disease, and in pregnant women. The Centers for Disease Control recommends HZ vaccination in adults over the age of 50 regardless of previous history of HZ.20 Of note, the HZ vaccine is 14 times more potent than the VZV vaccine and is more efficacious for the prevention of HZ in patients between the age of 50 to 69, compared to those over 70 years. The vaccine conferred similar protection against PHN in all age groups, but was superior in preventing the incidence and severity of PHN in the older compared to the younger age group.10,15,21 In addition, HZ vaccination was shown to increase quality-life adjusted years.
Contraindications to HZ vaccination include primary or secondary immunodeficiency disease, pregnancy or potential pregnancy, and history of allergic reaction to neomycin, gelatin, or vaccine components. The vaccine can be administered with other vaccines.
4. CUTTING EDGE/EMERGING AND UNIQUE CONCEPTS AND PRACTICE
New therapies are under investigation for the treatment and prevention of HZ and PHN. For example, EMA401, an oral highly selective angiotensin II type 2 receptor antagonist, has been shown to provide significant relief against PNH when compared to placebo and demonstrates analgesic efficacy comparable to gabapentinoids.22 Novel vaccine preparations are also being examined. Alternative recombinant subunit vaccines, compared to the current live-attenuated vaccine, may be safely utilized in immunocompromised individuals and have demonstrated improved efficacy in adults over age 70.23 Pain control in PHN is also being studied. A pilot study demonstrated that patients could alter pain perception by learning to voluntarily regulate over-activation in the rostral anterior cingulate cortex through real-time functional MRI neurofeedback.24
5. GAPS IN THE EVIDENCE-BASED KNOWLEDGE
PHN treatment continues to remain challenging and frustrating for patients and clinicians alike. While several oral and topical therapies exist for PHN, it has been shown that meaningful analgesia defined as greater than or equal to 50% pain relief, is provided to roughly 11 to 50% of patients, often at the cost of treatment-related adverse events.22 In addition, the efficacy of different treatment modalities for prolonged periods of time, as is often needed for PHN, remains poorly understood. Indeed, data from clinical trials does not typically extend beyond treatment periods of a few weeks. Furthermore, randomized controlled trials have failed to compare different drug classes and treatment modalities. Combination treatments, which are frequently employed by patients, require further investigation.15
- Thakur R, Kent JL, Dworkin RH. Herpes zoster and postherpetic neuralgia. In: Fishman SC, Ballantyne JC, Rahtmell JP. Bonica’s Management of Pain. 4th ed. Philadelphia, PA: Lippincott Williams and Wilkens; 2010: 338-357.
- Reynolds MA, Chaves SS, Harper R, et al. The impact of the Varicella vaccination program on herpes zoster epidemiology in the US: a review. J Infect Dis. 2008;197 Suppl 2:S224-227.
- Argoff CE. Review of current guidelines on the care of postherpetic neuralgia. Postgrad Med. 2011;123:134-142.
- Forbes HJ, Thomas SL, Smeeth L, et al. A systematic review and meta-analysis of risk factors for postherpetic neuralgia. Pain. 2016;157(1):30-54. doi:10.1097/j.pain.0000000000000307.
- Tontodonati M, Ursini T, Polilli E, et al. Post-herpetic neuralgia. International Journal of General Medicine. 2012;5: 861-871. doi:10.2147/IJGM.S10371.
- Johnson RW, Bouhassira D, Kassianos G, et al. The impact of herpes zoster and post-herpetic neuralgia on quality-of-life. BMC Med. 2010,8:37.
- Johnson RW, Alvarez-Pasquin M-J, Bijl M, et al. Herpes zoster epidemiology, management, and disease and economic burden in Europe: a multidisciplinary perspective. Therapeutic Advances in Vaccines. 2015;3(4):109-120. doi:10.1177/2051013615599151.
- Sreenivasan N, Basit S, Wohlfahrt J, et al. The Short- and Long-Term Risk of Stroke after Herpes Zoster – A Nationwide Population-Based Cohort Study. Dowd JB, ed. PLoS ONE. 2013;8(7):e69156. doi:10.1371/journal.pone.0069156.
- Breuer J, Pacou M, Gautier A, Brown MM. Herpes zoster as a risk factor for stroke and TIA: a retrospective cohort study in the UK. Neurology. 2014; 83: e27–e33. doi: 10.1212/WNL.0000000000000584.
- De Boer PT, Wilschut JC, Postma MJ. Cost-effectiveness of vaccination against herpes zoster. Human Vaccines & Immunotherapeutics. 2014;10(7): 2048-2061. doi:10.4161/hv.28670.
- Gan EY, Tian EA, Tey HL. Management of herpes zoster and post-herpetic neuralgia. Am J Clin Dermatol. 2013;14(2): 77–85.
- Chen N., Li Q., Yang J., Zhou M., Zhou D., He L. (2014a) Antiviral treatment for preventing postherpetic neuralgia. Cochrane Database Syst Rev 2: CD006866.
- Han Y, Zhang J, Chen N, He L, Zhou M, Zhu C. Corticosteroids for preventing postherpetic neuralgia. Cochrane Database of Systematic Reviews 2013, Issue 3. Art. No.: CD005582. DOI: 10.1002/14651858.CD005582.pub4.
- McDonald EM, De Kock J, Ram Felix FSF. Antivirals for management of herpes zoster including ophthalmicus: A systematic review of high-quality randomized trials. Antiviral therapy. 2012; 17: 255–264.
- Johnson RW, Rice AS. Clinical practice. Postherpetic neuralgia. N Engl J Med. 2014;371(16):1526–1533.
- Derry S, Wiffen PJ, Moore RA, Quinlan J. Topical lidocaine for neuropathic pain in adults (Protocol). Cochrane Database of Systematic Reviews 2014, 2: Art. No.: CD010958. DOI: 10.1002/14651858.CD010958.
- Webster LR, Nunez M, Tark MD, et al. Tolerability of NGX4010, a capsicin 8% dermal patch, following pretreatment with lidocaine 2.5%/prilocaine2.5% cream in patients with post-herpetic neuralgia. BMC Anesthesiol. 2011;11: 25.
- Xiao L, Mackey S, Xong D, et al Subcutaneous injection of botulinum toxin A is beneficial in postherpetic neuralgia. Pain Med. 2010;11: 1827-1833.
- Kolsek M. TENS–an alternative to antiviral drugs for acute Herpes zoster treatment and post herpetic neuralgia prevention. Swiss Med Wkly. 2012;141: w13229.
- Centers for Disease Control and Prevention. Update on herpes zoster vaccine: licensure for persons aged 50 through 59 years. Available at: www.cdc.gov/mmwr/preview/mmwrhtml/mm6044a.5.htm. Accessed November 11, 2011.
- Oxman MN, Levin MJ, Johnson GR, et al. A vaccine to prevent herpes zoster and post herpetic neuralgia in older adults. N Engl J Med. 2005;352: 2271-2284.
- Rice AS, Dworkin RH, McCarthy TD, Anand P, Bountra C, McCloud PI, et al. EMA401, an orally administered highly selective angiotensin 2 type II receptor antagonist, as a novel treatment for postherpetic neuralgia: a randomised, double-blind, placebo-controlled, phase 2 clinical trial. Lancet. 2014;383(9929): 1637–1647. doi: 10.1016/S0140-6736(13)62337-5.
- Lal H, Cunningham AL, Godeaux O, et al. Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults. N Engl J Med. 2015;372(22): 2087–96. 10.1056/NEJMoa1501184
- Guan M, Ma L, Li L, et al. Self-Regulation of Brain Activity in Patients with Postherpetic Neuralgia: A Double-Blind Randomized Study Using Real-Time fMRI Neurofeedback. Hampson M, ed. PLoS ONE. 2015;10(4): e0123675. doi:10.1371/journal.pone.0123675.
Original Version of the Topic:
Jane W. Wang, MD. Acute herpes zoster and post-herpetic neuralgia. Publication Date: 2012/07/30.
K. Rao Poduri, MD, FAAPMR
Nothing to Disclose
Mark Bauernfeind, MD
Nothing to Disclose
Rajbala Thakur, M.B.B.S
Nothing to Disclose