Herpes zoster (HZ) is the reactivated form of the varicella zoster virus (VZV), the same virus responsible for chickenpox. HZ is more commonly known as shingles, from the Latin cingulum for ‘girdle’. This is because a common presentation of HZ involves a unilateral rash that can wrap around the waist or torso like a girdle. Similarly, the name zoster is derived from classical Greek, referring to a belt-like binding (known as a zoster) used by warriors to secure armor 1.
A 60-year-old male patient reported to the department of oral and maxillofacial surgery, CSMSS Dental College and Hospital, Aurangabad, with a chief complaint of pain and rashes on the right side of his face. On examination, multiple vesicles and rashes were found on the lower lip, angle of the mandible region, in front of the ear, lateral to the eye, and intraorally on the lateral border of the tongue and the floor of the mouth.
The patient reported prodromal signs of fever and malaise 3–4 days before the appearance of rashes. These rashes then became pustules, which formed crusts. The patient reported unilateral pain along the distribution of the trigeminal nerve of the right side. He also reported lack of sleep because of pain. Because of unilateral pain and rashes along the nerve distribution, coupled with prodromal signs, a diagnosis of HZ was made.
Treatment with acyclovir 800 mg five times a day was started. Combiflam was also started to combat pain. Antiviral treatment was carried out for 7 days. The patient responded well to acyclovir and the rashes disappeared after 7–10 days. However, he developed severe neuralgic pain along the course of the trigeminal nerve on the right side. Trigger zones were the cheek, the skin below the infraorbital ridge, and the intraoral buccal mucosa. The patient did not shave for fear of activating trigger zones. On the basis of the clinical findings and history of HZ, a diagnosis of postherpetic neuralgia (PHN) was made as a complication of HZ.
Treatment with carbamazapine 200 mg three times a day was started to control neuralgic pain. The patient responded well and pain was relieved. This treatment was continued for 1 month. On completion of 1 month, carbamazapine tables were discontinued and the patient was fine.
There is no way to predict who will develop HZ, when the latent virus may reactivate, or what may trigger its reactivation. However, the elderly and those with compromised immunity – such as those who have undergone organ transplantation or recent chemotherapy for cancer, or individuals with HIV/AIDS – are at a greater risk for developing HZ. Between 10 and 20% of normal (immunocompetent) adults will get shingles during their lifetime. This figure increases markedly to 50% for those older than 85 years of age 1.
Spontaneous pain, pain induced by trivial stimuli, and altered sensation accompany HZ and may continue long after its characteristic rash has healed – a condition known as PHN. Many approaches have been proposed to treat the pain of acute zoster, to avert its progression to PHN, and to alleviate PHN. Few of these approaches have been shown to be beneficial, and PHN remains a source of frustration for both patients and physicians 2.
Etiology and pathology 1–4
VZV is one of eight known herpes viruses that infect humans. Its structure is characterized by an icosahedral nucleocapsid surrounded by a lipid envelope. Double-stranded DNA is located at its center. The virus is ∼150–200 nm in diameter and has a molecular weight of ∼80 million.
During its viremic phase, cell-associated VZV gains access to epidermal cells, causing the typical varicella rash. The virus then enters the sensory nerves in mucocutaneous sites and travels by retrograde axonal transport to the sensory dorsal-root ganglia adjacent to the spinal cord, where the virus establishes permanent latency in neuronal cell bodies. Latent VZV is present in ∼1–7% of sensory ganglion neurons, with less than 10 genomic copies per infected cell. Seeding of the dorsal-root ganglia might also occur during viremia. The magnitude of viremia, the number of skin lesions, and the burden of VZV that establishes latency during primary varicella infection might be linked. As with other members of the herpes virus family, VZV is noninfectious in its latent form, but can reactivate at a later time to form intact virions in the involved sensory neurons. These virions then migrate to the skin through axons, spread from cell to cell, and penetrate the epidermis. In its full clinical expression, zoster causes pain, which is followed by a vesicular rash distributed across closely overlapping dermatomes of the involved sensory nerve roots.
The triggers for the reactivation of VZV have not been identified and probably involve multiple factors. However, specific components of cell-mediated immunity (CMI) play an important role in controlling the development of zoster by preventing reactivation within the neuron or the full clinical expression of reactivated VZV as zoster. The effectiveness of these protective components of CMI is well maintained in immunocompetent individuals during childhood and early adulthood. These CMI components are believed to be partially or substantially maintained by periodic immunologic boosting. ‘Endogenous boosting’ might occur in response to the subclinical reactivation of latent VZV or to the development of zoster itself, and ‘exogenous boosting’ might occur in response to exposure to VZV circulating in the population as chickenpox.
Primary infection is clinically identified as varicella or chickenpox. VZV is ubiquitous and highly contagious, with initial exposure typically occurring during childhood. The virus enters the host through the respiratory system, replicates at an undefined site (presumably the nasopharynx), infiltrates the reticuloendothelial system, and eventually makes its way into the bloodstream. Evidence of viremia is manifested by the scattered nature of the telltale skin lesions on the body.
The usual incubation period for varicella is 14–16 days, with communicability ranging from 10 to 21 days after initial exposure. An individual can no longer transmit VZV once the final skin lesions have crusted. Indirect transmission (through an immune third person) is not believed to occur.
Once the initial outbreak has subsided, VZV then retreats into the dorsal-root ganglia, where it can remain dormant for years until some excitatory factor triggers reactivation. The associated outbreak is then clinically identified as HZ or shingles. Microscopic examination of select dorsal-root ganglia tissue during active HZ shows the presence of hemorrhage, edema, and lymphocytic infiltration. Figure 1 shows the typical progression of VZV from varicella to zoster 3–5.
Reduced cellular immunity places an individual at risk for HZ, hence the susceptibility of immunocompromised individuals and the elderly. It has been proposed that one reason why VZV may not recur as frequently as other herpes viruses, such as Herpes simplex virus, type 1 (HSV-1), or Herpes simplex virus, type 2 (HSV-2), is that genes involved in the reactivation of HSV are missing in VZV.
Signs and symptoms 1–5
The classic presentation of HZ starts with a prodrome of mild-to-moderate burning or tingling (or in some cases numbness) in or under the skin of a given dermatome, often accompanied by fever, chills, headache, stomach upset, and general malaise. Within 48–72 h from the prodrome, an erythematous, maculopapular rash forms unilaterally along the dermatome and rapidly develops into vesicular lesions reminiscent of the original chickenpox outbreak. The pain associated with shingles varies in intensity from mild to severe, such that even the slightest touch or breeze can elicit excruciating spasms. The lesions usually begin to dry and scab 3–5 days after appearing Figs 2–4.
Prodromal stage – sensations such as burning, tingling, etching, boring, prickly, and knife like occurring along the nerve distribution.
Active stage – rash forms after a few hours to several days, with malaise, low-grade fever, and headache.
Rash changes from papules and edema to vesicles in 12–24 h and to pustules in 1–7 days.
Pustules dry and form crusts that fall off in 14–21 days and leave erythematous lesions leading to hypopigmentation or hyperpigmentation.
Intraoral lesions appear after cutaneous lesions.
Pain and dysasthesia are minimal during the active stage. However, during crusting, it returns.
Chronic stage PHN – constant deep pain, sharp shock like a tic.
Radiating dysasthesia with trigger zones.
Differential diagnosis – trigeminal neuralgia, maxillary sinusitis, periodic migrainous neuralgia, atypical facial pain.
HZ typically erupts within one or two adjacent dermatomes, with thoracic, cervical, and ophthalmic involvement being the most common.
Most patients report a deep aching or burning pain, altered sensitivity to touch (paresthesia) that may be painful (dysesthesia), exaggerated responses to stimuli (hyperesthesia), or electric shock-like pain.
Pain induced by otherwise trivial stimuli (allodynia), unbearable itching, and escalating pain in response to repeated stimulation (windup pain) are also reported.
These abnormal sensations resolve or persist unpredictably, making it difficult to draw absolute distinctions between pain associated with zoster and PHN. Pain-induced disruption of sleep, mood, and work contributes toward the impact of zoster on the quality of life, in both the short and the long term.
Zoster rash is typically unilateral and does not cross the mid-line, erupting in one or two adjacent dermatomes. The frequency of zoster occurrence in different dermatomes has been evaluated in certain studies. In general, thoracic, cervical, and ophthalmic involvements are most common. Small numbers of lesions can occur outside the primary or adjacent dermatome.
A common and potentially debilitating consequence of zoster is PHN, a persistent pain after resolution of the rash. Pathologic observations believed to distinguish PHN from uncomplicated zoster include axonal and cell body degeneration, atrophy of the spinal cord dorsal horn, scarring of the dorsal-root ganglion, and loss of epidermal innervation of the affected area. Some experts believe that this neuronal damage might be caused by ongoing viral replication. In addition, consensus is lacking on the criteria required to distinguish the quality, duration, or underlying pathophysiology of pain occurring with zoster versus PHN. Therefore, the duration of pain used to define PHN has been inconsistent, ranging from any duration after resolution of the rash to periods from greater than 30 days to greater than 6 months after the onset of rash.
The nature of PHN pain varies from mild to excruciating in severity, constant, intermittent, or triggered by trivial stimuli. Approximately half of patients with zoster or PHN describe their pain as ‘horrible’ or ‘excruciating’, ranging in duration from a few minutes to constant on a daily or an almost daily basis. The pain can disrupt sleep, mood, work, and activities of daily living, adversely impacting the quality of life, and leading to social withdrawal and depression. Anecdotes of suicide among patients with PHN have been reported. Among patients experiencing zoster, predictors of PHN include the occurrence and severity of pain both before and after the onset of the rash, the extent of the rash, trigeminal or ophthalmic distribution, and the occurrence of viremia.
In addition to PHN, zoster is associated with a variety of other complications. Among patients with zoster, 10–25% have eye involvement, called herpes zoster ophthalmicus (HZO). HZO can occur when reactivation involves the nasociliary branch of the trigeminal nerve, sometimes preceded by the presence of zoster vesicles on the nose (Hutchinson sign). Keratitis occurs in approximately two-thirds of patients with HZO, often causing corneal ulceration. Other complications include conjunctivitis, uveitis, episcleritis and scleritis, retinitis, choroiditis, optic neuritis, lid retraction, ptosis, and glaucoma. Extraocular muscle palsies also occur. Prolonged or permanent sequelae of HZO include pain, facial scarring, and loss of vision.
An uncommon complication of zoster is Ramsay Hunt syndrome, a peripheral facial nerve palsy accompanied by zoster vesicles on the ear, hard palate, or tongue. The pathophysiology of this complication involves the reactivation of VZV in the geniculate ganglion of the facial nerve. Additional signs and symptoms of Ramsey Hunt syndrome can include pain, vertigo, hearing loss, sensitivity to sound, tinnitus, and loss of taste. Many patients do not recover completely. Idiopathic facial palsy (Bell’s palsy) might be caused by inapparent VZV reactivation.
Occasionally, zoster can cause motor weakness in noncranial nerve distributions, called zoster paresis. The mechanism has not been determined. The weakness develops abruptly within 2–3 weeks after onset of the rash and can involve the upper or the lower extremities. Diaphragmatic paralysis has also been described. The prognosis of zoster paresis is good. Zoster can also result in autonomic dysfunction, causing urinary retention and colon pseudo-obstruction.
Rarely, patients will experience acute focal neurologic deficits weeks to months after resolution of the zoster rash, involving the trigeminal distribution contralateral to the initial rash. This ischemic stroke syndrome, termed granulomatous angiitis, is believed to be caused by the direct extension of VZV from the trigeminal ganglion to the internal carotid artery or its branches, resulting in inflammation. Mortality from this syndrome is substantial. Other rare neurologic complications of zoster include myelitis, aseptic meningitis, and meningoencephalitis. The prognosis for these conditions is good, although encephalomyelitis can be life threatening. Guillain–Barré syndrome has also been reported in association with zoster.
In immunocompromised individuals, zoster initially might present typically. However, the rash tends to be more severe and its duration may be prolonged. One specific risk for patients with some immunosuppressive conditions is dissemination of the zoster rash. True cutaneous dissemination generally occurs only among immunocompromised patients, occurring in up to 37% of zoster cases in the absence of antiviral treatment. Dissemination usually begins with a dermatomal rash; however, the rash sometimes begins with no primary dermatomal involvement.
The risk for neurologic zoster complications is generally increased in immunocompromised individuals. These complications, which can be aggressive and even fatal, include myelitis, chronic encephalitis, ventriculitis, meningoencephalitis, and cranial palsies. However, the risk for PHN is not appreciably increased among immunocompromised patients who develop zoster.
The diagnosis of zoster might not be possible in the absence of rash (e.g. before rash or in cases of zoster sine herpete). Patients with localized pain or altered skin sensations might undergo evaluation for kidney stones, gallstones, or coronary artery disease until the zoster rash appears and the correct diagnosis is made. In its classical manifestation, the signs and symptoms of zoster are usually distinctive enough to make an accurate clinical diagnosis once the rash has appeared. Occasionally, zoster might be confused with impetigo, contact dermatitis, folliculitis, scabies, insect bites, papularurticaria, candidal infection, dermatitis herpetiformis, or drug eruptions. More frequently, zoster is confused with the rash of the HSV, including eczema herpeticum. The accuracy of diagnosis is lower for children and younger adults in whom the incidence of zoster is lower and its symptoms are less often classic.
In some cases, particularly in immunosuppressed individuals, the location of rash appearance might be atypical or a neurologic complication might occur well after resolution of the rash. In these instances, laboratory testing might clarify the diagnosis. Tzanck smears are inexpensive and can be used at the bedside to detect multinucleated giant cells in lesion specimens, but they do not distinguish between infections with VZV and HSV. VZV obtained from lesions can be identified using tissue culture, but this can take several days and false-negative results occur because viable virus is difficult to recover from cutaneous lesions. Direct fluorescent antibody staining of VZV-infected cells in a scraping of cells from the base of the lesion is rapid and sensitive. Direct fluorescent antibody and other antigen-detection methods can also be used on biopsy material, and eosinophilic nuclear inclusions (Cowdry type A) are observed on histopathology. PCR techniques performed in an experienced laboratory can also be used to detect VZV DNA rapidly and sensitively in properly collected lesion material, although VZV PCR testing is not available in all settings. A modification of PCR diagnostic techniques has been used at a few laboratories to distinguish wild-type VZV from the Oka/Merck strain used in the licensed varicella and zoster vaccines.
In immunocompromised individuals, even when VZV is detected by laboratory methods in lesion specimens, differentiation of chickenpox from disseminated zoster might not be possible by physical examination or serologically. In these instances, a history of VZV exposure, a history that the rash began with a dermatomal pattern, and the results of VZV antibody testing at or before the time of rash onset might help guide the diagnosis.
Zoster transmission 1–5
Zoster lesions contain high concentrations of VZV that can be spread, presumably by the airborne route, and cause primary varicella in exposed susceptible individuals. Localized zoster is only contagious after the rash erupts and until the lesions crust. Zoster is less contagious than varicella.
The pain associated with acute zoster and PHN is neuropathic and results from injury of the peripheral nerves and altered central nervous system signal processing.
After the injury, peripheral neurons discharge spontaneously, have lower activation thresholds, and show exaggerated responses to stimuli. Axonal regrowth after the injury produces nerve sprouts that are also prone to unprovoked discharge.
The excessive peripheral activity is believed to lead to hyperexcitability of the dorsal horn, resulting in exaggerated central nervous system responses to all input.
These changes may be so complex that no single therapeutic approach will ameliorate all the abnormalities.
Histopathological features 2,3
In acute zoster, the skin is inflamed and already partially denervated, and the dorsal-root ganglion shows inflammation, hemorrhagic necrosis, and neuronal loss.
Inflammation in the peripheral nerves may persist for weeks to months and usually leads to demyelination, wallerian degeneration, and sclerosis.
Ultimately, there may be scarring of the skin, peripheral nerves, and dorsal-root ganglia.
Pathologic changes are also evident in the central nervous system during zoster. They include acute degeneration of the dorsal horn of the spinal cord, unilateral segmental myelitis and leptomeningitis, and the involvement of spinal cord segments at levels adjacent to the affected skin. In patients who have had zoster, atrophy of the dorsal horn has been found at autopsy in those with PHN, but not in those without PHN.
Neurologic Guillian–Barre syndrome, encephalitis, myelitis, ramsay hunt syndrome, horner’s syndrome.
The four main domains of complications (excluding PHN) identified in patients with acute HZ.
Antiviral agents 2–8
The first line of treatment and the most widely used agents for zoster infection are antiviral agents. As nucleoside analogs, they block viral replication. Antiviral agents accelerate healing in the acute phase of illness by reducing the duration of viral shedding as well as time to crusting and scabbing. In addition, they prevent the formation of new lesions. Pharmacotherapy with antiviral agents must be initiated within 72 h of symptom onset (i.e. rash) for maximum effectiveness. Any delay in administration may result in neuronal destruction – leading to the derangements of the central nervous system that are responsible for the neuropathic pain syndrome associated with PHN.
However, a course of therapy with an antiviral agent is recommended beyond the 72-h window, especially in immunosuppressed patients as well as those with ophthalmic zoster. Administration of an antiviral agent is recommended for 7–10 days – although it is acceptable to extend treatment to up to 15 days, especially for individuals who are immunosuppressed.
Ideally, antivirals should be administered until no new lesions have been observed for about 2 days. Acyclovir, valacyclovir, and famciclovir are available antiviral agents. Valacyclovir is the prodrug of acyclovir; famciclovir is the prodrug of penciclovir.
Oral acyclovir is used for the management of acute HZ. It is also commonly used in immunosuppressed patients or those with central nervous system disease. Intravenous acyclovir may be administered to immunosuppressed patients 72 h after rash onset. Acyclovir is initially phosphorylated by only the viral thymidine kinase; therefore, it is active only within cells infected with the VZV. Cellular kinases metabolize the monophosphate to the triphosphate form, which acts as a competitive inhibitor of viral DNA polymerase.
Placebo-controlled trials four to six have shown that oral acyclovir shortens the duration of viral shedding, halts the formation of new lesions, and accelerates the rate of healing, reducing the severity of acute pain.
Malaise was the most frequent adverse effect with both acyclovir (11.5%) and placebo (11.1%). Adverse effects associated with intravenous acyclovirare are local problems such as phlebitis or inflammation. Transient elevations in serum creatinine may also be observed.
Oral acyclovir has a limited oral bioavailability of 10–30%, which necessitates frequent dosing. The recommended dosing for oral acyclovir is 800 mg five times a day for 7–10 days.
Valacyclovir is the L-valyl ester of acyclovir. It is rapidly converted into acyclovir after oral administration and, in humans, results in three to five times greater bioavailability than that of acyclovir. The recommended dose of this medication is 1 g three times daily for 7 days, with each gram of valacyclovir yielding ∼700 mg acyclovir and 300 mg of the essential amino acid valine.
Famciclovir is the diacetyl, 6-deoxy ester of penciclovir, which is a guanosine nucleoside analog. Metabolism of the prodrug to penciclovir begins with uptake by intestinal cells and is completed by the liver.
The current recommended dose is 500 mg three times daily. Famciclovir has been shown to accelerate zoster lesion healing and viral shedding. Famciclovir at 250 mg three times daily for 7 days was as effective as – and had a more favorable safety profile than – acyclovir at a dosage of 800 mg five times daily for 7 days. Moreover, famciclovir at a dose of either 750 mg once daily or 500 mg twice daily plus 250 mg once daily is as effective as acyclovir 850 mg five times daily. Thus, famciclovir is as effective as acyclovir when administered only once a day, a regimen that leads to better patient compliance.
Limitations of antiviral agents
As reported previously, therapy must be initiated within 72 h of rash onset for maximal effectiveness. Finally, although they may reduce the duration of PHN, they do not function prophylactically.
Oral corticosteroids 2,5–7
As an adjuvant option in the treatment of patients with acute zoster infection, oral corticosteroids have been shown to ameliorate the inflammatory characteristics of this condition, cosmetically improving the rash. Moreover, oral corticosteroids have been shown to reduce acute pain but not the chronic pain associated with PHN.
Finally, corticosteroids are associated with upper gastrointestinal adverse events such as dyspepsia, and they have been shown to exacerbate diabetes, hypertension, and osteoporosis. These adverse effects are especially undesirable among older patients, the majority of individuals in whom zoster infection is diagnosed.
Pharmacotherapeutic options for postherpetic neuralgia 2,4–8
Treatment goals include alleviating the pain associated with PHN and improving the quality of life, allowing the patients to maintain sleep, physical activity, and nutrition. Tricyclic antidepressants(TCAs), anticonvulsants, opioid analgesics, and topical agents are recommended first-line therapies for PHN.
Neuroactive agents 2,4–8
TCAs are important components of therapy for PHN. Because of their ability to block the reuptake of norepinephrine and serotonin, these drugs may relieve pain by increasing the inhibition of spinal neurons involved in pain perception.
Amitriptyline decreases neuronal reuptake of both norepinephrine and serotonin. In one trial, desipramine, a selective inhibitor of norepinephrine reuptake, also significantly reduced pain at 3 and 6 weeks.
Serotonin-selective drugs are of little value in the treatment of PHN.
Adverse reactions to TCAs, including confusion, urinary retention, postural hypotension, and arrhythmias, limit their usefulness in older patients, and plasma concentrations should be monitored to ensure compliance and help determine the optimal dose.
Lorazepam, postulated to inhibit neurotransmission in the spinal cord and brain stem, also proved inferior to amitriptyline in a controlled trial.
The phenothiazine chlorprothixene is of no value, but in controlled studies, other phenothiazines combined with TCAs resulted in the partial relief of pain.
In a double-blind, controlled study, carbamazepine reduced lancinating pains but was ineffective for continuous pain. The combination of clomipramine and carbamazepine led to only partial relief in a controlled trial, and combinations of other antidepressant and anticonvulsant drugs had some benefit in uncontrolled trials.
Tricyclic antidepressants 2,4–8
They block the reuptake of norepinephrine and serotonin. Thus, they may relieve pain by increasing the inhibition of spinal neurons involved in pain perception. Animal studies have shown that TCAs may also work as sodium channel antagonists within the peripheral nervous system, another mechanism that may be responsible for pain relief.
Amitriptyline was found to be superior to lorazepam, and nortriptyline hydrochloride, a metabolite of amitriptyline, was also found to be effective in ameliorating the pain associated with PHN. However, physicians prefer nortriptyline to amitriptyline because the former has fewer anticholinergic effects.
Adverse events associated with TCAs, which are mainly because of anticholinergic effects, include sedation, confusion, urinary retention, dry mouth, blurred vision, postural hypotension, and arrhythmia. These adverse events limit the usefulness of TCAs for the treatment of older patients.
Two anticonvulsants are indicated for the treatment of PHN: gabapentin and pregabalin. Anticonvulsants are believed to work in neuropathic pain syndromes because they are involved in membrane stabilization, which reduces neuronal derangement. Although gabapentin’s mechanism of action is currently unknown, it appears to be independent of aminobutyric acid receptors. It is lipophilic and penetrates the blood–brain barrier (Tables 1 and 2).
Adverse events that occurred more frequently in the gabapentin group compared with those in the group receiving placebo were somnolence, dizziness, ataxia, peripheral edema, and infection. Pregabalin was initially reported to be effective in alleviating neuropathic and nociceptive pain in a variety of animal models.
Opioid analgesics 2,4–8
The opioid analgesics morphine and methadone were found to be as effective as the TCAs nortriptyline or desipramine in a randomized double-blind, placebo-controlled cross-over trial. Intravenous morphine sulfate infusions have been shown to be effective in reducing the pain and hyperalgesia of PHN.
Adverse events observed with opioids are minimal and include constipation, nausea, loss of appetite, dizziness, and drowsiness. A theoretical limitation to the use of opioids is the potential for addiction.
Topical treatment 2,4–8
Topical treatment is also a good therapeutic option for patients in whom systemic treatment is contraindicated. Topical treatment is currently divided into three groups: combined aspirin and NSAID formulations, local analgesics, and capsaicin cream.
Topical nonsteroidal anti-inflammatory drugs 2,4–8
NSAIDs applied topically are useful in the treatment of patients with zoster during the active and early postherpetic phase of illness because pain symptoms are associated with tissue trauma and inflammation as well as an increased level of tissue prostaglandins.
NSAIDs inhibit cyclooxygenase, decreasing the synthesis of prostaglandins. Thus, there has been a recent focus on developing topical NSAIDs, such as powdered aspirin in chloroform or ethyl ether, to treat patients for PHN.
Over-the-counter creams and topical indomethacin, diclofenac, and benzydamine hydrochloride cream have also been investigated for their pain-alleviating properties in PHN. Topical aspirin has been shown to be superior to placebo in reducing PHN, whereas other topical NSAIDs such as indomethacin, diclofenac, and benzydamine have not.
A topical lidocaine 5% patch is a targeted peripheral analgesic that is indicated for the treatment of patients with PHN. When four patches were applied for up to 24 h, the systemic absorption of lidocaine from the patch was minimal in healthy adults and even lower among patients with PHN, thus eliminating adverse systemic events.
Capsaicin cream is also indicated for the treatment of patients with PHN. At high concentrations, capsaicin depletes substance P, a principal peptide neurotransmitter.
This depletion first causes a burning sensation, and then anesthetic effects. Capsaicin cream is the only drug approved by the Food and Drug Administration for the treatment of PHN.
Natural treatment options 1
As with conventional protocols, the objective of natural therapeutics in the prevention and treatment of HZ and PHN is to aid healing of skin lesions, reduce pain, and prevent complications. An underlying goal for the use of natural therapies is to strengthen CMI, thereby allowing the body’s natural defense mechanisms to control the virus and prevent recurrence. Natural therapies can provide solutions to effectively manage herpes viruses, prevent and treat complications, and minimize the risk of developing viral resistance.
The incidence of HZ increased considerably after the age of 50 years. Maintaining adequate nutrition is one contributing factor to ensuring healthy CMI.
Vitamin A 9,10
Vitamin A functions both as a fat-soluble vitamin and as a hormone, contributing to the visual pigment rhodopsin and controlling gene transcription that allows for the normal proliferation and differentiation of epithelial cells. Vitamin A is a key immune modulator, involved in the synthesis of lymphocytes, neutrophils, cytokines, and immunoglobulins.
Vitamin A deficiency has been associated with increased susceptibility to numerous infectious diseases, and is of particular concern in patients undergoing bone marrow transplants. An observational trial on 120 bone marrow transplant patients has shown an association between an increased incidence of hyporetinolemia and an increased risk of HZ infection.
Enzyme therapy 11,12
Before the introduction of acyclovir, pancreatic enzyme preparations were used effectively in Germany as a treatment for HZ. The suspected mechanisms of action for the enzyme formula included stimulating the breakdown of immune complexes and enhancing CMI.
Other nutritional considerations
Nutrients such as vitamin C, vitamin E, lysine, and zinc have shown potential in the treatment of HSV-1 and HSV-2. Consequently, they may also be helpful against HZ, although evidence for this is primarily in the realm of anecdotal reports and speculative extrapolation.
Licorice (Glycyrrhiza glabra) 13–17
Licorice is one of the most widely used herbs in traditional medicine, spanning many generations and several continents. Its properties as an anti-inflammatory, mucoprotectant, and antiviral agent may be potentially valuable in the treatment of HZ. One constituent, glycyrrhizin, inhibits virus growth and may also inactivate viral particles. It has shown antiviral activity in vitro against various forms of herpes virus, including VZV, and induces interferon production both in vitro and in vivo. When glycyrrhizin is taken orally, it is converted into glycyrrhetinic acid, with loss of its systemic antiviral effects. However, as a topical agent, both glycyrrhizin and licorice may provide antiviral activity, and as such may be beneficial in cases of both HSV and HZ. Further investigation of this application is warranted.
Madonna Lily (Lilium candidum) 18,19
In northern Italy, traditional folk medicine identifies L. candidum as a herbal treatment for HZ. Bulbs of cultivated L. candidum have yielded successful results when fried in olive oil and applied externally as a poultice on HZ lesions. Its healing properties are believed to be a result of the presence of eight spirostanolsaponins and two furostanolsaponins identified in the bulb of the plant.
Reishi Mushroom (Ganoderma lucidum) 20,21
A few small studies have examined the effect of G. lucidum, either by itself or in combination with other herbs, for the treatment of HZ or PHN. One case study on two patients with HZ and two patients with PHN showed that administration of hot-water-soluble extracts of G. lucidum (36–72 g dry weight/day) led to a considerable decrease in pain.
Bi Phaya Yaw (Clinacanthus nutans) 22
A small shrub found in Southeast Asia, has long been used in Thailand as a traditional medicine for snake and insect bites and various skin ailments. Several small studies have examined its benefit for HZ. One randomized, placebo-controlled trial was carried out on 51 HZ patients using a topical preparation of C. nutans extract applied five times daily for 7–14 days until the lesions were healed. The number of patients with lesions crusting within 3 days and healing within 7–10 days was significantly higher in the experimental group than in the placebo group (P<0.01); the pain scores were significantly reduced as well. No side effects were reported with the medication.
Since ancient times, bee products, specifically honey and propolis, have been recognized in traditional medicine as aids in wound healing. Today, their healing properties for select herpes viruses are being confirmed in both the laboratory and the examination room; they may prove to be beneficial in the management of HZ.
A small, nonblinded, cross-over study comparing the topical application of honey with acyclovir cream on patients with HSV found a significantly shorter duration of episodes and faster healing time when using a honey application versus the antiviral drug. Similarly, a randomized, blinded-investigator study, comparing the use of a topical propolis ointment with acyclovir and placebo for 90 patients with confirmed HSV, concluded that after 10 days, a significant number of patients in the propolis group (24/30) had healed, compared with those in the acyclovir (14/30) or the placebo (12/30) group. These findings coincide with in-vitro studies proposing the potential antiviral property of propolis against HSV.
Sangre de Grado (Croton lechleri) 27
Extracts of Sangre de Grado have shown activity against a number of viruses, including influenza, parainfluenza, hepatitis A and B, and HSV-1 and HSV-2.
Aloe (Aloe vera) 28,29
Topical administration of A. vera has been used widely for wound healing. Aloe emodin, an anthraquinone prepared from A. vera, was shown in vitro to inactivate HSV-2. In another study, acemannan (another ingredient of Aloe) was reported to act synergistically with acyclovir against HSV in vitro.
St John’s wort (Hypericum perforatum) 30–33
St John’s wort is widely known in traditional medicine to be an effective treatment for viral infections and afflictions related to the nerves. In terms of its effect on herpes viruses, several studies have shown promising results.
Hypericum species have been observed in vitro to show potent antiviral activity against HSV-1. In addition, two double-blind, placebo-controlled studies have shown the efficacy of an orally administered H. perforatum extract against HSV.
Other treatment options
Traditional Chinese Medicine Acupuncture has long been considered as an effective therapy for pain management. Preliminary studies have shown that Chinese medicine may show promise when used in conjunction with conventional therapies in the management of PHN. A variety of different treatment methods are available; these fall into the following five main categories:
- Treatment according to the pathogenic factor.
- Treatment according to the channels involved.
- Treatment of the local area.
- Use of empirical points.
- Ear acupuncture.
Transcutaneous electrical nerve stimulation 5,7
The use of transcutaneous electrical nerve stimulation therapy has been beneficial in the management of PHN. In one review, the use of combination therapy consisting of amitriptyline, topical capsaicin, and transcutaneous electrical nerve stimulation was recommended for the treatment of PHN over antiviral therapy.
Nonpharmacologic interventions 5
Neurosurgical procedures are treatments of last resort for intractable pain. In small studies, electrical stimulation of the thalamus and anterolateral cordotomy to interrupt the spinothalamic tract led to relief in patients with PHN.
Electrocoagulation of well-defined areas of the dorsal root has been attempted, but the procedure has a substantial risk of prolonged hemiparesis and sensory deficits, and a recent consensus conference did not advocate its use.
A phenomenon known as ‘counterirritation’ has been reported to relieve PHN by reintroducing normal inhibition of the small fibers in the spinal cord.
Data from small studies suggest that ethyl chloride spray, which evaporates rapidly and causes a freezing sensation, and transcutaneous electrical nerve stimulation provide partial to complete relief of pain in some patients with PHN.
Many options are available to the clinician for the treatment of HZ and PHN, albeit with variable degrees of success. Antiviral agents, such as acyclovir, valacyclovir, and famciclovir, have been shown to reduce both the pain and the healing time of skin lesions associated with HZ, but have marginal success in the prevention and treatment of PHN. Corticosteroids may be used for pain management in HZ, but do not seem to be effective in the prevention of PHN. Analgesics provide effective temporary pain relief for both HZ and PHN. Nerve block injections offer more long-term pain relief in both conditions, provided they are administered early in the course of the disease. TCAs may provide pain relief in cases of PHN, but require at least 3 months for positive effects. The potential for antiviral resistance, particularly in immunosuppressed individuals, is of growing concern, as this group is at a greater risk of developing HZ and PHN. Furthermore, the increased cost of antiviral therapy can represent a financial obstacle for at-risk individuals to obtain conventional medication. These issues underscore the need to investigate and identify alternative therapeutic options.
Although vitamin A deficiency appears to be associated with increased susceptibility to HZ in immunosuppressed individuals, further investigation is required to determine whether a causal relationship exists. Enzyme therapy may serve as an effective alternative to acyclovir. The topical use of capsaicin in the management of pain has been shown to be effective in PHN, whereas topical applications of licorice extract, Madonna lily bulb, and C. nutans have been used in the treatment of skin lesions associated with HZ; further investigation is required to determine clinical efficacy. Small case studies using hot-water-soluble extracts of reishi mushroom by itself or in combination with other herbs indicate potential benefit in both HZ and PHN. As with the other herbs mentioned, further rigorous investigation is required to determine clinical relevance.
Conflicts of interest
There are no conflicts of interest.
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