Acute 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 90 days (3 months) after resolution of the initial rash,1 although this defined duration varies in the literature, anywhere from 1 to 6 months post rash resolution, it should be noted. The timeframe of pain experienced between acute herpes zoster to PHN can be described as “zoster-associated pain.”
Initial infection by VZV causes varicella, also known as “chicken pox.” After resolution of the initial infection, the virus remains dormant in the dorsal sensory ganglia or cranial nerve ganglia of the nervous system. As immunity declines with age, VZV can reactivate, resulting in an acute HZ flare, due to reactivation of the virus.
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.3,4 Human immunodeficiency virus (HIV), 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. 5,6
The reactivation of VZV in the sensory ganglia causes inflammation and neuronal destruction. The virus travels along the sensory nerve to the skin, resulting in vesicular lesions, primary afferent nerve damage, and generalized cell necrosis. 4,6
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. 7
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 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. Vasculitis is associated with increased risk of myocardial infarction, transient ischemic attack, and stroke, especially in patients under the age of 40. 9,10
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.
Essentials of Assessment
HZ presents with fatigue, malaise, and flu-like symptoms, often with prodromal pain followed by pruritus, paresthesias, and dysesthesias. These prodromal 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 occur as a result of muscle spasm in response to acute pain, or actual motor weakness caused by (rare) involvement of anterior horn cells.
Clinical features depend on the location of the skin lesion, with thoracic dermatomes, particularly T5-T10, being the most commonly involved1,followed by the cranial nerves, cervical, lumbar, and then sacral dermatomes. Involvement of the ophthalmic division (known as V1) 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. 8 Common 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. 11,12.
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 (PCR) is preferred over VZV direct fluorescent antibody staining of early vesicular lesions. 12 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 (MRI).
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.
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. 13 A general overview of antiviral treatment is presented in Table 1. Corticosteroids do not appear to reduce the incidence of PHN.13,14
Table 1: Antiviral Treatment of Herpes Zoster
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. 14
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 tricyclic antidepressants (TCAs). Topical lidocaine (5%), opioids, and topical capsaicin are second-line treatments. Antivirals, carbamazepine, topical benzydamine, cyclo-oxygenase inhibitors, and N-methyl-d-aspartate (NMDA) receptor antagonists are ineffective in relieving PHN. 12,16
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. 12 Pregabalin, however, is typically more expensive than gabapentin.
TCAs, including amitriptyline, nortriptyline, and desipramine, act by inhibiting the reuptake of norepinephrine and serotonin, inhibiting spinal nociceptive neurons, and by sodium-channel blockade. They are often not tolerated well, particularly in elderly patients, due to anti-cholinergic side effects, such as orthostasis, dry mouth, and urinary retention. Secondary amines (which more selectively block reuptake of norepinephrine), such as desipramine and nortriptyline, are as equally effective as the tertiary amine amitriptyline (which blocks reuptake of both norepinephrine and serotonin), and are better tolerated with fewer side effects, such as sedation. Of note, combining a TCA with an anticonvulsant may be more effective than monotherapy for neuropathic pain states. 17,18
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 contraindicated or poorly tolerated, such as in the elderly. 12,19
Topical capsaicin is a second-line agent for PHN, based on high cost, required in-clinic administration of high-dose treatment (8%), and efficacy. It acts as an agonist for the vanilloid receptors, depleting substance P and desensitizing nociceptors, 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. 20 Side effects are mainly local application site reactions.
Compounded topical agents that include amitriptyline (a TCA) and ketamine (a general anesthetic), in varying concentrations, have shown effectiveness in neuropathic pain states, including PHN. 21,22
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. 12,16
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. Subcutaneous injection of botulinum toxin has been shown to be superior to topical lidocaine with longer lasting benefits. 23 Transcutaneous 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. 24 Acupuncture has not been shown to be effective. 16
At different disease stages
In PHN, there can be absence of a pain-free period after the initial rash, or there may be 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
VZV immunoglobulin followed by HZ immunization is recommended in immunocompromised seronegative patients who have been exposed to VZV, 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. There are currently two forms of the HZ vaccine approved by the FDA for this age group, one being a live-attenuated zoster vaccine, and the other, a recombinant zoster vaccine. 25,26 Of note, HZ vaccines are 14 times more potent than the VZV vaccine and is more efficacious for the prevention of HZ in patients between the ages 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. 11,16,27 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.
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 PHN when compared to placebo and demonstrates analgesic efficacy comparable to gabapentinoids. 28
Film-forming systems are novel methods of drug delivery that are alternatives to topical and transdermal delivery systems. Bupivacaine, in a film-forming metered-dose dermal spray preparation, is being evaluated for its potential effectiveness for neuropathic pain conditions, like PHN. 29
Non-pharmacologic pain control methods for PHN are 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. 4
Repetitive transcranial magnetic stimulation (rTMS) has been found to be effective for pain, sleep, and anxiety in patients with PHN. Pei, et al 30 conducted a prospective, randomized, controlled clinical trial that concluded that, compared to sham, patients who underwent either 5 Hertz (Hz) or 10 Hz rTMS of the primary motor cortex had significantly lower visual analogue scale (VAS) pain scores, up to the studies’ follow up period of 3 months. In addition, the patients in the treatment groups, compared to sham, had significantly higher scores for quality of life (QOL) scale, sleep quality (SQ) scale, and patient global impression of change (PGIC) scale.
Neuromodulation is a means of altering neuronal activity by direct delivery of an electrical or pharmaceutical agent to the target nervous tissue structure. There are various forms of neuromodulation, including intrathecal drug delivery and neurostimulator devices that target the dorsal columns of the spinal cord, the dorsal root ganglion, or peripheral nerves, to name a few structures. These modalities have proven beneficial in PHN, 31 with evidence that early neurostimulation may even prevent PHN, if provided during the acute/subacute phase of HZ. 32
SCRAMBLER therapy is a non-invasive electro-analgesia therapy used to manage a number of pain conditions, particularly neuropathic pain. One explanation by which this therapy works is that it substitutes pain information with “non-pain” information within nociceptive C–fibers, via “artificial neurons” through cutaneous electrodes. SCRAMBLER was evaluated as a novel method to treat PHN in a study by Smith, et al 33. In this study, 10 patients with refractory PHN were given 30-minute daily sessions of SCRAMBLER therapy for 10 days. The average pain reduction by numerical rating scale improved by 95% at 1 month, and analgesic benefit continued into month 3.
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. 28 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. 16
- Thakur, R. and A.G. Philip, Chronic pain perspectives: Treating herpes zoster and postherpetic neuralgia: an evidence-based approach. J Fam Pract, 2012. 61(9 Suppl): p. S9-15.
- Reynolds, M.A., et al., The impact of the varicella vaccination program on herpes zoster epidemiology in the United States: a review. J Infect Dis, 2008. 197 Suppl 2: p. S224-7.
- Argoff, C.E., N. Katz, and M. Backonja, Treatment of postherpetic neuralgia: a review of therapeutic options. J Pain Symptom Manage, 2004. 28(4): p. 396-411.
- Guan, M., et al., Self-regulation of brain activity in patients with postherpetic neuralgia: a double-blind randomized study using real-time FMRI neurofeedback. PLoS One, 2015. 10(4): p. e0123675.
- Forbes, H.J., et al., A systematic review and meta-analysis of risk factors for postherpetic neuralgia. Pain, 2016. 157(1): p. 30-54.
- Tontodonati, M., et al., Post-herpetic neuralgia. Int J Gen Med, 2012. 5: p. 861-71.
- Johnson, R.W., et al., The impact of herpes zoster and post-herpetic neuralgia on quality-of-life. BMC Med, 2010. 8: p. 37.
- Johnson, R.W., et al., Herpes zoster epidemiology, management, and disease and economic burden in Europe: a multidisciplinary perspective. Ther Adv Vaccines, 2015. 3(4): p. 109-20.
- Sreenivasan, N., et al., The short- and long-term risk of stroke after herpes zoster – a nationwide population-based cohort study. PLoS One, 2013. 8(7): p. e69156.
- Breuer, J., et al., Herpes zoster as a risk factor for stroke and TIA: a retrospective cohort study in the UK. Neurology, 2014. 83(2): p. e27-33.
- de Boer, P.T., J.C. Wilschut, and M.J. Postma, Cost-effectiveness of vaccination against herpes zoster. Hum Vaccin Immunother, 2014. 10(7): p. 2048-61.
- Gan, E.Y., E.A. Tian, and H.L. Tey, Management of herpes zoster and post-herpetic neuralgia. Am J Clin Dermatol, 2013. 14(2): p. 77-85.
- Chen, N., et al., Antiviral treatment for preventing postherpetic neuralgia. Cochrane Database Syst Rev, 2014(2): p. CD006866.
- Han, Y., et al., Corticosteroids for preventing postherpetic neuralgia. Cochrane Database Syst Rev, 2013(3): p. CD005582.
- McDonald, E.M., J. de Kock, and F.S. Ram, Antivirals for management of herpes zoster including ophthalmicus: a systematic review of high-quality randomized controlled trials. Antivir Ther, 2012. 17(2): p. 255-64.
- Johnson, R.W. and A.S. Rice, Clinical practice. Postherpetic neuralgia. N Engl J Med, 2014. 371(16): p. 1526-33.
- Gilron, I., et al., Nortriptyline and gabapentin, alone and in combination for neuropathic pain: a double-blind, randomised controlled crossover trial. Lancet, 2009. 374(9697): p. 1252-61.
- Finnerup, N.B., et al., Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol, 2015. 14(2): p. 162-73.
- Derry, S., et al., Topical lidocaine for neuropathic pain in adults. Cochrane Database Syst Rev, 2014(7): p. CD010958.
- Webster, L.R., et al., Tolerability of NGX-4010, a capsaicin 8% dermal patch, following pretreatment with lidocaine 2.5%/prilocaine 2.5% cream in patients with post-herpetic neuralgia. BMC Anesthesiol, 2011. 11: p. 25.
- Sawynok, J. and C. Zinger, Topical amitriptyline and ketamine for post-herpetic neuralgia and other forms of neuropathic pain. Expert Opin Pharmacother, 2016. 17(4): p. 601-9.
- Mercadante, S., Topical amitriptyline and ketamine for the treatment of neuropathic pain. Expert Rev Neurother, 2015. 15(11): p. 1249-53.
- Xiao, L., et al., Subcutaneous injection of botulinum toxin a is beneficial in postherpetic neuralgia. Pain Med, 2010. 11(12): p. 1827-33.
- Kolsek, M., TENS – an alternative to antiviral drugs for acute herpes zoster treatment and postherpetic neuralgia prevention. Swiss Med Wkly, 2012. 141: p. w13229.
- Lu, P.J., et al., Shingles Vaccination of U.S. Adults Aged 50-59 Years and >/=60 Years Before Recommendations for Use of Recombinant Zoster Vaccine. Am J Prev Med, 2020. 59(1): p. 21-31.
- Hurley, L.P., et al., Primary care physicians’ experience with zoster vaccine live (ZVL) and awareness and attitudes regarding the new recombinant zoster vaccine (RZV). Vaccine, 2018. 36(48): p. 7408-7414.
- Oxman, M.N., Vaccination to prevent herpes zoster and postherpetic neuralgia. Hum Vaccin, 2007. 3(2): p. 64-8.
- Rice, A.S.C., et al., EMA401, an orally administered highly selective angiotensin II type 2 receptor antagonist, as a novel treatment for postherpetic neuralgia: a randomised, double-blind, placebo-controlled phase 2 clinical trial. Lancet, 2014. 383(9929): p. 1637-1647.
- Ngo, A.L., et al., Postherpetic Neuralgia: Current Evidence on the Topical Film-Forming Spray with Bupivacaine Hydrochloride and a Review of Available Treatment Strategies. Adv Ther, 2020. 37(5): p. 2003-2016.
- Pei, Q., et al., Repetitive Transcranial Magnetic Stimulation at Different Frequencies for Postherpetic Neuralgia: A Double-Blind, Sham-Controlled, Randomized Trial. Pain Physician, 2019. 22(4): p. E303-E313.
- Kapoor, S., Pain management in postherpetic neuralgia: emerging new therapeutic options besides spinal cord stimulation. Neuromodulation, 2012. 15(3): p. 267.
- Huang, J., et al., Early Treatment with Temporary Spinal Cord Stimulation Effectively Prevents Development of Postherpetic Neuralgia. Pain Physician, 2020. 23(2): p. E219-E230.
- Smith, T.J. and G. Marineo, Treatment of Postherpetic Pain With Scrambler Therapy, a Patient-Specific Neurocutaneous Electrical Stimulation Device. Am J Hosp Palliat Care, 2018. 35(5): p. 812-813.
Original Version of the Topic:
Jane W. Wang, MD. Acute herpes zoster and post-herpetic neuralgia. 7/30/2012
Previous Revision(s) of the Topic
K. Rao Poduri, MD, FAAPMR, Mark Bauernfeind, MD, Rajbala Thakur, M.B.B.S. Acute herpes zoster and post-herpetic neuralgia. 8/16/2016
Thomas Chai, MD
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Girish S Shroff, MD
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Sheetal Shroff, MBBS
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Larry C Driver, MD
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