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Varicella zoster virus is known to be the common cause of varicella disease chicken pox. Following the initial insult caused by the varicella zoster virus, the reactivation of the dormant form of the varicella zoster virus in dorsal root ganglia or cranial nerves, results in herpes zoster (Gnann and Whitley, 2002). Herpes zoster or shingles is a localised skin (cutaneous) lesion as shown in fig. 1 (Cohen et al., 1999). The occurrence of shingles per annum ranges from 1.5 to 3.4 cases per 1000 persons. At about the range of 2 cases per 1000 persons, there are approximately a quarter of a million incidents in the United Kingdom (UK) and twice as much in the United States of America (USA) annually (Donahue et al., 1995). The best-established risk factors for herpes zoster are, firstly, increasing age (usually common in people older than 65 years of age). In support of the incidence of herpes zoster with increasing age, a number of studies including Dworkin and Schmader (2001) documented that incidence of herpes zoster among individuals older than 65 years of age is about 12 cases per 1000 persons annually. Secondly, reduced cell mediated immunity associated with cancer (lymphoma) and human immunodeficiency virus (HIV) infection. Also, the use of immunosuppressive drugs such as corticosteroids following organ transplant operation, and chemotherapy or radiotherapy treatment for cancer results in increased risk of herpes zoster due to impaired immune system (T cell immunosuppression) (Johnson and Dworkin, 2003). During the onset of acute herpes zoster syndrome or after the cutaneous rash healing, a number of several serious complications such as post-herpetic neuralgia are developed (Gnann and Whitley, 2002).
Figure 1. (A & B) Shows a localised skin lesion caused by herpes zoster infection. (B) Shows a close-up shot of cutaneous eruption (formation of clusters of vesicles or pustules).
Gnann, J. W. & Whitley, R. J (2002) Herpes Zoster. N Engl J Med. 347: 340-346.
Aetiology and pathogenesis of post-herpetic neuralgia
Post-herpetic neuralgia is a long-term neuropathic pain syndrome that usually persists at least 120 days from an erythematous maculopapular skin rash onset or after an acute herpes zoster episode (Johnson and Dworkin, 2003). The incidence of post-herpetic neuralgia increases with ageing population (common in people over the age of 50). The severity of acute herpes zoster, an early symptom of dermatomal pain prior to the rash onset and immunocompromised systems associated with HIV infection and use of immunosuppressive drugs are also risk factors. As much as 25% of patients with herpes zoster subsequently develops chronic neuropathic pain (Hempenstall et al., 2005). The pathophysiology of post-herpetic neuralgia complication starts with aberrant cutaneous sensation progressing to localized skin lesion in a couple of days. Subsequently, this leads to the formation of clusters of blister-like vesicles or pustules, which is associated with itching and severe pain. Either at the onset of cutaneous eruption or after healing of the skin rash, pain becomes persistent and more severe (Gnann and Whitley, 2002). This pain has been defined as chronic neuropathic pain. The molecular and cellular mechanism of this neuropathic pain syndrome is poorly understood. However, neuropathic pain syndrome is a neurological defect of the afferent (sensory) nerves, which is associated with peripheral sensory nerve impairment in the skin. Overexpression and relocalization of voltage-gated sodium channels is thought to lead to spontaneous activity in impaired afferent neurons. Also impaired sensory neurons can express ¡-adrenergic receptors, which they do not normally express under physiological condition. This abnormal expression causes damaged sensory neurons to become sensitive to noradrenaline, which leads to the stimulation of sympathetic responses and in turn, generation of intense pain (Rang et al., 2007).
Furthermore, it has been documented that cutaneous eruption leads to the release of peripheral chemical mediators including ATP, K+ and prostaglandin as shown in fig. 2. ATP activates P2X3 receptors (a ligand-gated ion channel), which is primarily present in the nociceptive nerve terminals. High [H+] also activates nociceptive sensory neurons to some extent by opening proton-activated (acid-sensitive) cation channels. Prostaglandins strongly intensify the nociceptive-generating effect of serotonin or bradykinin. All the chemical mediators as described above, therefore enhance repetitive application of pain signals to the dorsal root ganglia and dorsal horn of the spinal cord. Nociceptive afferent sensory myelinated A¤ and unmyelinated C fibres terminate on projection neurons in the superficial layers (laminae I, II, V) of the dorsal horn of the spinal cord. The pain signal is then, projected to the ventral posterior lateral nucleus and central lateral nuclei of the thalamus of the brain via the spinothalamic tract of the anterolaterol pathway systems. The enhanced and repetitive sensitization of nociceptors is the primary cause of hyperalgesia, and scarring of the dorsal root ganglia and degeneration of cells of the dorsal horn associated with post-herpetic neuralgia (fig. 2) (Kandel et al., 2000).
Figure 2. Shows a schematic representation of chemical mediators such as prostaglandins released from the site of lesion or damaged area of the skin, which acts on peripheral nociceptive neurons. This leads to repetitive firing of the afferent nociceptive neurons and transmission of pain response to the dorsal root ganglia and dorsal horn of the spinal cord. The blue circles represent scarred region of the dorsal root ganglion as a consequence of post-herpetic neuralgia complication.
Taken from: Kandel, E.R. et al (2000) Principles of Neural Science, 4th edition, McGraw-Hill, p.472-482.
Signs and symptoms
Signs and symptoms of post-herpetic neuralgia are intractable chronic neuropathic pain most frequently described as progressive burning or extreme paroxysmal, and hyperalgesia (increased amount of pain evoked by a gentle noxious stimuli) and depression, which can often lead to poor quality of life. Furthermore, cutaneous eruption that exists during herpes zoster is followed with sclerosis (scarring) of the dorsal root ganglia and degeneration of cells of the dorsal horn on the aberrant region. In addition, patients suffer from allodynia such as cutaneous allodynia (pain resulting from stimuli which are not normally painful or a non-noxious stimuli), for example a patient experiences pain when brushing the hair or bathing (Cunningham and Dworkin, 2000; Johnson and Dworkin, 2003). This is understood to be as a result of a transient increase in the sensitivity of aberrant somatosensory pain neurons in the central nervous system or the afferent peripheral nervous system that process information originating from the skin (http://www.medterms.com/script/main/art.asp?articlekey=25196).
Treatment of post-herpetic neuralgia
The therapeutic management of post-herpetic neuralgia chronic neuropathic pain syndrome is extremely complex and is often accompanied by adverse side effects. However, evidence of current therapy, clinical trials and plethora of recent studies including Johnson and Dworkin (2003) have documented that the neuropathic pain, a hallmark symptom of post-herpetic neuralgia can be treated to a certain extent and that the risk of post-herpetic neuralgia complications in general can be controlled or prevented at the level of varicella disease (chicken pox), herpes zoster and post-herpetic neuralgia. Using medications such as antiviral therapy, tricyclic antidepressants, anticonvulsants, opioids, corticosteroids and local anaesthetic (lidocaine 5%). These pharmacologic interventions can be grouped into three different therapeutic approach options: firstly, topically acting drugs that act on the affected cutaneous region for example lidocaine patch 5%; secondly, drugs that modulate sensory axon conduction and nerve hyper-responsiveness (excitability) such as opioids; and lastly, drugs that act at synaptic nerve terminals including tricyclic antidepressants (Bonezzi and Demartini, 1999).
Firstly, at the level of varicella disease and herpes zoster, a number of antiviral agents such as acyclovir, famciclovir and valaciclovir recommended in the United States of America are used to treat herpes zoster disease and to reduce the risk of developing long-term complications arising during or after shingles episode and also after the initial chicken pox infection (Johnson and Dworkin, 2003). The antiviral drug acyclovir is a synthetic nucleoside analogue, which is incorporated into viral DNA and functions by decreasing the duration of viral shedding, inhibits the replication of varicella zoster virus, and subsequently, attenuates the rate at which new lesion is formed. Furthermore, acyclovir also hastens the rate of cutaneous healing, and relieves the severity and shortens the duration of acute pain (Gnann and Whitley, 2002). The significance of acyclovir therapeutic effects are supported by patient's positive responses after use and by randomised clinical trials, which showed that the risk of developing chronic pain, neural damage and the frequency of post-herpetic neuralgia complications are significantly reduced by about 50% (Cunningham and Dworkin, 2000). However, the use of acyclovir is without its associated limitations such as poor bioavailability (a regimen of higher dosing). Prodrugs famciclovir and valaciclovir are other antiviral drugs preferred to acyclovir for the treatment of shingles as a result of their better pharmacokinetic profiles and bioavailability (Johnson and Dworkin, 2003). However, recent clinical data has shown that as much as 20% of sufferers with herpes zoster of at least 50 years of age, still reported chronic pain at least six months after rash onset in spite of treatment with acyclovir or famciclovir or valaciclovir (Cunningham and Dworkin, 2000).
Secondly, tricyclic antidepressant agents (TCAs) such as nortriptyline; opioid analgesics (oxycodone) and anticonvulsant agents including gabapentin are used to reduce chronic neuropathic pain occurring during post-herpetic neuralgia. Monotherapy commenced during herpes zoster with each of these drugs can provide partial therapeutic measures, but usually when recommended in combinations with TCAs, opioids and/or with antiviral drugs, does provide adequate pain control and reduce the risk of other post-herpetic neuralgia symptoms (Johnson and Dworkin, 2003). Opioid analgesics act peripherally or centrally to inhibit nociceptors excitability through G-protein coupled receptors (-, ¤-, or «-opioid receptors), which downstream signalling is coupled to inhibitory G-protein (Go), which in turn inhibits the activity of adenylyl cyclase a membrane bound effector, therefore opposing the effects of prostaglandins and other pain mediators (Rang et al., 2007). Past clinical trials data showed that as much as 50% of patients treated with tricyclic antidepressants reported effective pain relief (Bonezzi and Demartini, 1999). Unfortunately, tricyclic antidepressants trial data also showed that elderly patients suffering with post-herpetic neuralgia poorly tolerated these drugs. Trials data also indicated that gabapentin is an effective analgesic for the short-term treatment of post-herpetic neuralgia (effectiveness of gabapentin is maintained for approximately 2 months). The use of gabapentin is safe and well tolerated, and was also documented to have positive effects on sleep, mood, and improvement in the overall quality of life (Singh and Kennedy, 2003).
Lastly, the use of corticosteroids in combination with any of the antiviral drugs in clinical trial events were reported to provide adequate relief of pain and accelerated the rate of rash healing during herpes zoster, but had no effect on the occurrence of post-herpetic neuralgia. Thus combination therapy involving the use of corticosteroids has effect at the level of herpes zoster, however not completely effective at the level of post-herpetic neuralgia (Gnann and Whitley, 2002). In addition, adverse effects associated with the administration of tricyclic antidepressants including dry mouth and blurred vision, and opioids use such as tolerance and addiction have led to the development of a newer and potentially risk-free therapeutic agent, a local anaesthetic called lidocaine patch 5% (Davies and Galer, 2004). Lidocaine patch 5% is a peripheral analgesic medicated plaster, which acts locally at the site of affected skin area with low systemic effect. Lidocaine patch 5% has been documented by a number of trials to relieve pain associated with herpes zoster and other symptoms of post-herpetic neuralgia. In addition, minimal side effects were reported in patients with post-herpetic neuralgia, however, side effects were limited to application sites. Lidocaine patch 5% has been recommended as a first-line medication for the treatment of post-herpetic neuralgia based on the proven efficacy and safety results (Garnock-Jones and Keating, 2009).
Prevention of Herpes zoster and Post-herpetic neuralgia
Vaccination of children against varicella zoster virus with a live attenuated vaccine is a good measure used to reduce the incidence and prevalence of varicella disease and herpes zoster, which is the preceding infection prior to the development of post-herpetic neuralgia complications. This vaccine is widely used in the United States of American and other industrialised nations (Johnson and Dworkin, 2003). In addition, adult vaccine called zostavax has been developed and put through clinical trial phases for individuals over the age of 60 and have had an episode of varicella disease. This zostavax vaccine has been reported to reduce the incidence of herpes zoster and post-herpetic neuralgia complications by more than 60%. The zostavax was approved a couple of years ago in the United States based on its efficacy and safety results (http://www.medicinenet.com/shingles/page3.htm).
Post-herpetic neuralgia is the most predominant complication of herpes zoster. Post-herpetic neuralgia is common in elderly and immunocompromised individuals. Post-herpetic neuralgia is a neuropathic pain syndrome associated with other neurological disorders including hyperalgesia and allodynia that can persist for months or years. Post-herpetic neuralgia poses a significant clinical problem, as it is difficult to treat in spite of the use of antiviral therapy alone or in combination with tricyclic antidepressants and opioid analgesics. However, the incidence of post-herpetic neuralgia can be significantly reduced with zostavax vaccine by as much as 60%. In addition, therapy for post-herpetic neuralgia complications can be approached at the level of herpes zoster and varicella zoster disease with anticonvulsants, antiviral agents, opioids, and tricyclic antidepressants and topical capsaicin. These medications function by reducing the duration of viral shedding, accelerating the rate of rash healing, and reducing the severity of neuropathic pain and allodynia. The functional significance of these drugs in the management of post-herpetic neuralgia has been validated by reports from clinical trials and primary care data on patients with post-herpetic neuralgia. As a result, these drugs either alone or in combination with other medications such as lidocaine patch 5% are recommended as a first-line therapy for patients with post-herpetic neuralgia. Finally, treatment in the early stage of post-herpetic neuralgia is likely to be more effective than later therapy.
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