Supportive treatment with calamine lotion, cleansing oatmeal baths (to prevent bacterial superin- fection) and analgesics or antipyretics (to control fever.
Journal of
Oral Pathology & Medicine doi: 10.1111/j.1600-0714.2009.00802.x
J Oral Pathol Med (2009) 38: 673–688 ª 2009 John Wiley & Sons A/S Æ All rights reserved interscience.wiley.com/journal/jop
REVIEW ARTICLE
Varicella zoster virus: review of its management M. B. Mustafa1, P. G. Arduino2, S. R. Porter3 1 Oral Medicine Section, Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, University of Khartoum, Khartoum, Sudan; 2Oral Medicine Section, Department of Clinical Physiopathology, University of Turin, Turin, Italy; 3Oral Medicine, UCL, Eastman Dental Institute, London, UK
Varicella zoster virus (VZV) is one of eight herpes viruses known to infect humans. Primary infection causes varicella (chickenpox), after which virus becomes latent. Years later, VZV reactivates and causes a wide range of neurological diseases. The aim of the present report was to critically examine the published literature to evaluate advantages and limitations of therapy of VZV infection in both immunocompetent and immunocompromised patients. Aciclovir (ACV) has been the drug of choice for many years for the treatment of VZV infections. Recently, other antiviral agents have been developed to overcome the low oral bioavailability of ACV, as well as to provide a more flattering dosage regime. Chickenpox is a benign self-limiting disease in the majority of cases and usually no specific treatment is required. Treatment of shingles is indicated to reduce the acute symptoms of pain and malaise, to limit the spread and duration of the skin lesions and to prevent the development of postherpetic neuralgia. Different classes of drugs have been used for the treatment of post-herpetic neuralgia. The first choice of any of these medications should be guided by the patient’s medical health, the likely adverse effects of the drug and the patient’s preference. J Oral Pathol Med (2009) 38: 673–688 Keywords: antiviral; oral; perioral; therapy; VZV
Introduction Infection by varicella zoster virus (VZV) has a worldwide distribution. The primary infection typically gives rise to varicella (chickenpox) among previously healthy children and tends to be influenced by climate and geographical factors. Following primary infection the virus remains latent; afterwards, reactivation gives Correspondence: Dr Mayson B Mustafa, Oral medicine Section, Department of Oral & Maxillofacial Surgery, Faculty of Dentistry, University of Khartoum, P.O Box 102, Khartoum, 11111, Sudan. Tel: +249914103720, Fax: +249 183 745612, E-mail: maysonmustafa@ yahoo.com Accepted for publication May 14, 2009
rise to shingles and related disorders. By contrast, secondary infection usually affects adults, has no seasonal pattern and tends to be associated with other factors such as age and immunosuppression (1). Oral lesions in varicella occur frequently and the prevalence of it correlates with the severity of the disease. Reactivation of the virus in the trigeminal nerve gives rise to herpes zoster (shingles), which is characterized by a painful prodromal rash in the oro-facial region. After the rash resolves, shingles may be complicated by pain or dysaesthesia, often termed postherpetic neuralgia (2). The present review adds to the current knowledge of VZV infection management. A MEDLINE review up to June 2008 was undertaken and the computer search was complemented by a hand search of all bibliographic references. The objective of this review is to analyse critically the literature to evaluate the advantages and limitations of antiviral agents in the treatment of VZV infections for immunocompetent and immunocompromised patients.
Antiviral agents Most of the antiviral agents used for the treatment of VZV infections are nucleoside analogues that require phosphorylation by a viral thymidine kinase (TK) (3). The reference antiviral agent is aciclovir (ACV), which has been the drug of choice for many years for the treatment of VZV infections. Recently, other antiviral agents have been developed to over come the low oral bioavailability of ACV as well as to provide a more favourable dosage regime (Table 1) (4, 5). Antiviral drugs are generally safe and well tolerated but, sometimes, they can be associated with side effects such as nausea, diarrhoea, abdominal pain and headache. Rare but reversible neurological reactions, such as dizziness and confusion, have been reported in patients with limited renal clearance who were given high doses of ACV intravenously. The symptoms were directly associated with the high plasma concentration of the drug (6). Furthermore, exacerbation of the renal failure occurs when it is given to patients with renal
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Table 1
Antiviral agents used for the treatment of varicella zoster virus infections
Drug Aciclovir (Zovirax)
Valaciclovir (Valtrex)
Mode of action
Pharmacokinetics
Aciclovir is phosphorelated by viral thymidine kinase to aciclovir monophsphate and then by cellular enzymes to aciclovir diphosphate and triphosphate Aciclovir triphosphate is a competitive inhibitor of viral DNA synthesis and act as a chain terminator Similar action to aciclovir
Penciclovir (Denavir)
Similar action to aciclovir
Famciclovir (Famvir)
Similar action to aciclovir
Brivudin (Zostex) and Sorivudine
Targeted at the viral DNA polymerase, both drugs can act as competitive inhibitors after intracellular phosphorylation to BVDU-5-triphosphate. They can also act as alternative substrates and be incorporated into viral DNA, leading to reduced integrity and functioning of viral DNA
Vidarabine
Mode of action is unclear. May act by selective incorporation of vidarabine monophosphate into viral DNA causing a decrease in the rate of primer elongation and chain termination Foscarnet inhibits viral DNA synthesis independent of viral thymidine kinase. It acts as a pyrophosphate analogue that interferes with the binding of the pyrophosphate to its binding site of viral DNA polymerase during DNA synthesis
Foscarnet (Foscavir)
Low oral bioavailability, only 15–20% of the dose reaches the plasma
Following oral uptake, 54% of valaciclovir is converted to aciclovir by intestinal and hepatic first metabolism, thus increase the bioavailability of aciclovir by three to four times Penciclovir inhibitory concentrations for HSV and VZV DNA are 100-fold higher than aciclovir. However, penciclovir has longer intracellular half-life (7–20 h) compared with aciclovir (1 h). Penciclovir is poorly absorbed when given orally Rapidly absorbed when given orally, reaches maximum concentration in the blood in about 15–20 min. First pass metabolism in the liver results in rapid conversion of famciclovir to penciclovir, with an oral bioavailability of penciclovir of 77% Famciclovir has oral bioavailability three to five times that of aciclovir Brivudin and sorivudine have better bioavailability than aciclovir. Both drugs are more potent inhibitors for VZV replication than aciclovir in vitro Brivudin is administrated in a more convenient does (once daily) compared with other aciclovir (five times a day) and valaciclovir and famciclovir (three times a day). Vidarabine has relatively low activity, rapid degeneration rate and poor aqueous solubility, which require the infusion of large amounts of liquid Foscarnet is active against thymidine kinase deficient VZV strains, which tends to be resistant to aciclovir in immuno compromised patients
BVDU, (E)-5-2-bromovinyl-2¢-deoxyuridine; VZV, Varicella zoster virus.
insufficiency. Therefore, dosage modification of ACV is required in patients with abnormal creatinine clearance (7, 8). Mutations at the level of the VZV TK are responsible for the development of VZV resistance to antiviral agents, which depend upon the viral TK for their phosphorylation. Recently, several case reports have appeared on the emergence of ACV resistant strains in patients with human immunodeficiency virus (HIV) following long-term ACV therapy. Foscarnet may circumvent infections caused by ACV resistant VZV (9, 10).
Management of chickenpox Chickenpox is a benign mild self-limiting disease in the majority of cases and usually no specific therapy is required. Supportive treatment with calamine lotion, cleansing oatmeal baths (to prevent bacterial superinfection) and analgesics or antipyretics (to control fever and pruritus) may be useful (4). Paracetamol is the preferred antipyretic to be used in children with chickenpox. The use of non-steroidal anti-inflammatory drugs was found to be associated with an increased risk J Oral Pathol Med
of severe skin and soft tissue complications among children with varicella (11, 12). A number of clinical studies have been undertaken to evaluate the benefit of using ACV for the treatment of chickenpox in different age groups (Table 2). These studies concluded that ACV is effective in reducing the severity and duration of chickenpox in healthy children, adolescents and adults, reflecting the inhibitory effect of the drug upon the virus transport to the epithelial cells as well as its replication in the skin. The time of ACV administration during the clinical illness is important for the drug to be effective. Among all age groups, clinical benefit is observed when ACV is given within 24 h following the appearance of the skin lesions (13–16). The benefit of using oral ACV in adolescents and adults is more significant than in children (15, 16). This marked clinical effect is due to the fact that chickenpox is associated with more extensive cutaneous lesions, fever and malaise among adolescents and adults as compared with younger individuals. Particularly in healthy adolescents, chickenpox may be associated with residual lesions that persist for years or months after the infection. ACV therapy among this age group in a placebo-controlled trial resulted in a marked reduction
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Table 2 Studies for the use of aciclovir in immunocompetent patients with chickenpox
References (13) (14)
Type of study Randomized double-blind placebo-controlled Randomized double-blind placebo-controlled
Total study population
Age (years)
105
5–16
815
2–12
13–18
(15)
Randomized double-blind placebo-controlled
68
(16)
Randomized double-blind placebo-controlled
148
>17
in the development of such residual hypopigmented skin lesions at 4 weeks, indicating its effect in reducing viral spread and destruction of skin cells in the deeper layers of the dermis (15). A reduction of the skin lesions in adolescents and adults following the use of ACV indicates a lowering in VZV associated viraemia, which may subsequently reduce the risk of a chickenpox-associated pneumonia in this age group. Therefore, the risk of such a life threatening complication in adults may be prevented by early administration of antiviral therapy (8). Healthy adults who develop chickenpox-associated pneumonia should be hospitalized and treated with intravenous ACV (17). Antiviral therapy given to children and adolescents does not interfere with the induction of effective humoral and cell mediated immunity against VZV (18). There was no significant difference in the antibody titre between individuals treated with ACV and those who were not (14, 15). In one study, children treated with antivirals had a transient reduction in serum antibody titre to VZV than the placebo recipients 4 weeks after the onset of illness, both antibody titres were similar 1 year later (13). Moreover, ACV given during chickenpox does not increase the susceptibility of shingles among treated patients (8). Furthermore, the degree of viral spread to the environment is not affected by therapy. A study showed that VZV DNA was detected in 33–100% of throat sample swabs from children with chickenpox by day 7 of the illness, even after the administration of oral ACV (19). Therefore, based on these studies, the use of ACV for the treatment of chickenpox in healthy children is optional as the disease is generally self-limiting and symptoms can be controlled and reduced with supportive therapy (8).
Drug used Aciclovir 20 mg ⁄ day four times a day for 5–7 days Aciclovir 20 mg ⁄ day four times a day for 5 days
Aciclovir 800 mg ⁄ day four times a day for 5 days
Aciclovir 800 mg five times a day for 7 days
Findings Aciclovir caused sooner onset of healing Aciclovir was started within 24 h of rash onset. It reduced the new lesions formation, accelerated healing, reduced pruritus and resulted in lower rate of residual lesions after 28 days Aciclovir was started within 24 h of rash onset. It reduced the new lesions formation and the maximum number of lesions, alleviate constitutional illness and also reduced the residual hypopigmented lesions Aciclovir therapy was started within 24 h of rash onset and caused reduction on the maximum number of lesions and the duration and severity of illness. Aciclovir given 25–72 h after rash onset had no clinical effect
The American Academy of Paediatrics does not recommend the routine use of ACV in healthy children with chickenpox. Instead, they recommended that it should be considered for treatment in children 12 years or older, those with chronic cutaneous or pulmonary disease, those being treated with short or intermittent courses of corticosteroids or aerosol corticosteroids and those receiving long-term salicylate therapy. The recommended dose is 20 mg ⁄ kg (maximum single dose of 800 mg) administrated four times a day for 5 days (20). To date, the use of other antiviral therapy such as valaciclovir, famciclovir or penciclovir for the treatment of chickenpox in healthy individuals has not been evaluated in clinical trials and they are not licensed for the treatment of chickenpox (8). Recently, sorivudine has been investigated for the treatment of chickenpox in healthy adults. In a placebo controlled trial, sorivudine given p.o. in a dose of 10 or 40 mg once a day for 5 days, shortened the mean time of cutaneous crusting and cessation of new lesion formation. Unlike ACV, the effectiveness of sorivudine was not affected by the duration of the rash before the onset of the therapy (21). Treatment for immunocompromised patients Intravenous ACV is used for the treatment of chickenpox in immunocompromised children and adults. Rapid and effective inhibition of the virus is achieved by its administration at a dose of 500 mg ⁄ m2 ⁄ day every 8 h as a 1-h infusion (8). In a placebo controlled trial, intravenous ACV given to children with malignancy reduced the incidence of chickenpox-associated pneumonia from 45% to none (22). The recommended duration of ACV therapy is for 7 days or until no new lesions have appeared for 48 h (8). In immunocompromised individuals, ACV can still be effective even if it is started up to 72 h after the appearance of J Oral Pathol Med
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the skin lesions because of the prolonged course of illness in this high-risk group. However, the disease is better controlled when the therapy is started within 24 h and before visceral dissemination has occurred (8, 23). Relapse of the cutaneous rash can still occur after the use of antiviral therapy for 7 days. Some patients may develop new lesions within few days or 24 h after treatment has ceased, which necessitates the use of a second course. Furthermore, relapsing fever or new symptoms should raise the possibility of secondary invasive bacterial infection which may need antibiotic administration along with the antiviral therapy (8). Vidarabine has also proved to be effective in the treatment of chickenpox among immunocompromised individuals. In a double-blind placebo-controlled study, patients who received vidarabine in a dose of 10 mg ⁄ kg ⁄ day had more rapid reduction in the formation of new lesions and fever than those who received the placebo. Furthermore, the incidence of life threatening complications was significantly lower in the former group than in the latter group (24). Although no randomized trials have compared ACV with vidarabine, an analysis at a paediatric centre showed that of the 16 children given ACV, none developed chickenpox pneumonitis, while 29% of patients treated with vidarabine progressed to pneumonia (25). The use of oral ACV, famciclovir or valaciclovir has not been evaluated in the treatment of chickenpox in immunocompromised children (8). Limited clinical trials have investigated the use of other agents for the treatment of chickenpox among high-risk individuals. For example, interferon-a has been used in the treatment of chickenpox in a group of children with cancer. Intramuscular administration of interferon-a 0.4 to 3.5 · 105 IU ⁄ kg ⁄ day for 5 days significantly reduced the duration of lesion formation and visceral dissemination (26). Treatment for maternal and neonatal chickenpox Prophylaxis, as well as treatment, is mandatory if chickenpox occurs during pregnancy. Pregnant women who have significant exposure to chickenpox – defined as living in the same household with a person with active chickenpox or shingles or face-to-face contact with a person with chickenpox or uncovered shingles for at least 5 min – and have no history of chickenpox, seronegative or in situations that serological testing is not readily available, should receive zoster immunoglobulin (27, 28). Zoster immunoglobulin takes some time to be absorbed from the injection site to achieve an immunoprotective level in the blood, therefore, it should be given within 72–96 h following chickenpox exposure to prevent or modify the course of the disease (29, 30). It has been recommended that oral ACV should be considered as a prophylaxis for susceptible pregnant women with significant exposure who have not received zoster immunoglobulin or who have any underlying risk factors such as chronic lung disease or impaired immunity (31). Intravenous ACV should be given when severe chickenpox complications occur at any stage of
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pregnancy such as pneumonia, neurological symptoms or haemorrhagic fever (27, 32). Zoster immunoglobulin should also be given prophylactically to an infant whose mother develops chickenpox up to 7 days before delivery or if the mother develops chickenpox up to 28 days after delivery because of the risk of severe neonatal infection. Infants should be given zoster immunoglobulin as early as possible after delivery or exposure and should be carefully followed up as severe chickenpox may still occur in about 50% of the infants despite receiving passive immunization (33–35). A recent study suggests that the combination of intravenous immunoglobulin given to high risk neonates soon after birth or postnatal contact, and prophylactic ACV given intravenously starting from 7 days after the onset of maternal rash can effectively prevent the clinical perinatal chickenpox (36). However, there is still a lack of sufficient evidence to support the use of this combination prophylactically (31). Intravenous ACV should be administrated to infants presenting with chickenpox and feeling unwell whether or not they received immunoglobulin, and also to immunocompromised infants who develop chickenpox, including premature babies (31, 37).
Management of shingles Treatment of shingles is indicated to reduce the acute symptoms of pain and malaise, to limit the spread and duration of the skin lesions and to prevent the development of post-herpetic neuralgia and ophthalmological complications in herpes zoster ophthalmicus (38). The pharmacological approach for the treatment of shingles is based on symptomatic relief and antiviral therapy. Symptomatic treatment Symptomatic treatment of shingles depends upon the patient’s condition, the stage of the rash, the severity of pain and also upon patient’s response to antiviral therapy. Skin lesions should be kept clean and dry to reduce the risk of bacterial superinfection. Sterile, nonocclusive, non-adherent dressings placed over the involved dermatome will protect the lesion from contact with clothing (39). Topical application of crushed aspirin tablets dissolved in chloroform on the painful skin surface was found to be effective in reducing the pain during the acute phase (40). Pain relief can also be achieved by the use of an appropriate non-opioid or opioid analgesic that is often combined with neuroactive agents such as amitriptyline (41). Injections of local anaesthesia for selective sympathetic nerve block have been widely used for symptom relief during the acute stage of shingles. It is recommended that in patients with severe acute pain that is not controlled by any other means, sympathetic regional or local anaesthetic nerve blocks may be used to provide pain relief and possibly reduce the development of postherpetic neuralgia (42, 43). The efficacy of this treatment approach is based on controlled trials and case series studies in which nerve blocks administrated during the
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course of the acute shingles provided effective, immediate and total pain relief (44, 45). It has been hypothesized that decreased pain, inflammation and tissue damage during the acute phase of shingles may reduce peripheral nerve sensitization and central hyperactivity, which in turn lessen the likelihood of having post-herpetic neuralgia (43); however, the impact of using analgesics during the acute stage of shingles upon reducing the incidence of post-herpetic neuralgia is not known (41). This may be due to the lack of adequate sample size, inappropriate follow up to determine the duration of post-herpetic neuralgia, the concomitant use of other therapies such as antiviral agents as well as the non-standardized approach to define post-herpetic neuralgia (42). A retrospective study showed that sympathetic nerve blocks terminated the pain of acute shingles and prevented or relieved postherpetic neuralgia in more than 80% of patients treated within 2 months of the onset of the acute phase of the disease, after which time the success rate of this procedure decreased significantly (46). In a small-randomized double blind placebo-controlled trial, the use of amitriptyline during the acute phase of shingles was significantly associated with reduced incidence of post-herpetic neuralgia among elderly people. However, the drug is poorly tolerated by this age group (47). In another study, the use of epidural local anaesthetic and steroid was proved to be significantly more effective in preventing post-herpetic neuralgia at 12 months in comparison with intravenous ACV and prednisolone (48). Antiviral agents Shingles is a self-limiting disease and complete healing usually occurs when it affects the trunk or the extremities of young individuals without risk factors. Antiviral therapy has the benefit of shortening the healing process and seems to be important when a complicated course of the disease is expected (38). Urgent systemic antiviral treatment is necessary in patients over 50 years of age, in immunodeficient patients, in those with cranial nerve involvement (as in herpes zoster ophthalmicus or zoster oticus) and in patients with vesicles involving more than one segment. Systemic antiviral therapy must be initiated as early as possible in the disease course, within 48 h to a maximum of 72 h after the onset of the skin lesions. Later therapy may still be effective in special situations such as disseminated shingles with evidence of immunosuppression and involvement of inner organs and in persisting herpes zoster ophthalmicus and zoster oticus (38, 43). To date, ACV, valaciclovir, famciclovir and, in Europe, brivudin are the standard antiviral agents for the treatment of shingles in immunocompetent patients. There is no role for topical antiviral drugs in the management of shingles (39). Aciclovir
Aciclovir is widely used for the treatment of shingles and, unlike other antiviral agents, is the only agent that can be given enterally or parenterally. It was found to reduce the number of days for new-lesion formation, the
extent of involvement of the primary dermatome and the time of crusting and healing (49, 50). The drug is particularly effective when used for the treatment of herpes zoster ophthalmicus, as it reduces the incidence and severity of ocular complications such as pseudodendritic keratopathy, episcleritis, iritis and stromal keratitis (51, 52). ACV was also found to be effective in reducing the severity of zoster-associated acute phase pain. A meta-analysis of all the placebo-controlled trials of ACV treatment for shingles showed a significant reduction in zoster associated pain among treated recipients (53). ACV is given in an oral dose of 800 mg, five times a day for 7 days. This high and frequent dose is necessary due to its poor oral bioavailability (15–20%), low anti-zoster virus activity and its short half-life (7). ACV has a limited and less predictable effect in preventing the development of post-herpetic neuralgia because of the conflicting results from associated clinical trials (50, 54). However, re-analysis of data from a placebo-controlled treatment trial of 187 immunocompetent people with shingles demonstrated that pain duration among ACV recipients was 20 days compared with 62 days for their placebo counterparts, indicating that ACV reduces zoster associated chronic pain (55). Moreover, a meta-analysis of five clinical trials found that oral ACV, given in a dose of 800 mg ⁄ day, within 72 h of the rash onset, may reduce the incidence of residual pain at 6 months by 46% in immunocompetent adults (56). The use of ACV, in combination with corticosteroids has been investigated in two clinical trials. In both studies, combination of the two drugs resulted in moderate but statistically significant acceleration in the rate of cutaneous healing and remission of acute pain with improvement in the patients’ quality of life. However, neither study demonstrated any effect of corticosteroids on the incidence or the duration of post-herpetic neuralgia (57, 58). The use of corticosteroids for shingles without concomitant antiviral therapy is not recommended (39).
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Valaciclovir
Valaciclovir is an effective and well-tolerated antiviral agent for the treatment of shingles. Because of its better bioavailability compared with ACV, it is recommended orally in a more convenient, less frequent dose of 1000 mg, three times a day for 7 days, which results in better patient compliance and low incidence of adverse side effects (59). Valaciclovir has similar efficacy to ACV on the resolution of the cutaneous lesions and on the prevention of long-term ocular complications of herpes zoster ophthalmicus (60, 61). More importantly, patients treated with valaciclovir have more satisfactory outcome in pain control than those treated with ACV. In comparative trials, valaciclovir was significantly more superior than ACV in shortening the duration of herpes zoster-associated pain (60, 62) and in reducing the prevalence of post-herpetic neuralgia as well as the duration of abnormal sensations such as hypersensitivity, numbness, and allodynia (60). J Oral Pathol Med
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Famciclovir
Famciclovir is used for the treatment of shingles in immunocompetent people in a dose of 500 mg orally three times a day for 7 days (7). The efficacy of famciclovir in the treatment of shingles was proved in a large placebo-controlled double blind trial involving 419 immunocompetent adults who received famciclovir in a dose of 500 or 750 mg three times a day for 7 days. Famciclovir accelerated the rate of cutaneous lesion healing and reduced the duration of viral shedding. Most importantly, this study revealed its significant effect on the reduction in the duration of post-herpetic neuralgia (63). In comparison with ACV, when treatment was commenced within 72 h following onset of rash, all dose levels of famciclovir (250, 500 and 750 mg) administered three times daily were found to be as effective as ACV (800 mg) for cutaneous lesion healing (as indicated by the time to full crusting), cessation of new lesion formation, loss of vesicles, loss of crusts and time to loss of acute pain (64, 65). However, time to resolution of zoster-associated pain occurred at a significantly faster rate in patients treated with famciclovir within 48 h of rash onset compared with ACV treatment (64). These two studies did not report the impact of famciclovir on post-herpetic neuralgia in comparison to ACV. A recent study demonstrated that famciclovir is effective in the treatment of shingles when given less frequently than three times a day. Famciclovir administrated in doses of 750 mg once daily, 500 mg twice daily or 250 mg three times daily is as effective as ACV administrated five times a day, in the cutaneous healing and the reduction of the acute phase pain, thus improving convenience for patients and provide greater adherence to the therapy (66). Famciclovir and valaciclovir were compared for the treatment of shingles in immunocompetent patients. In a randomized comparison study, famciclovir, in a dose of 500 mg three times a day, was therapeutically equivalent to valaciclovir in speeding the resolution of zoster associated pain, rash healing and post-herpetic neuralgia (67). Brivudin
Brivudin was first available for the treatment of severe shingles in immunocompromised people. Later it became available in Germany and other European countries (Austria, Belgium, Greece, Italy, Luxembourg, Portugal and Spain) for the treatment of shingles in immunocompetent individuals (68). Brivudin, given in a single dose orally of 125 mg, was confirmed by many clinical studies to be superior to other antiviral agents in the treatment of shingles. In a double-blind randomized study, brivudin 125 mg once daily for 7 days was found to be superior to ACV 800 mg five times daily in terminating the vesicle formation and hence stopping the viral replication in acute shingles (69). Furthermore, treatment with brivudin 125 mg once daily for 7 days during acute shingles in immunocompetent elderly patients resulted in a significantly lower incidence of J Oral Pathol Med
post-herpetic neuralgia than the standard treatment of ACV; however, the mean duration of the post-herpetic neuralgia was similar in the two groups (70). Comparing the efficacy of brivudin (125 mg, once a day) and famciclovir (250 mg, three times a day), both drugs given orally for 7 days for the treatment of shingles, resulted in equivalent efficacy in being able to accelerate the stop of vesicle formation and lesion healing. They also demonstrated equivalent efficacy regarding the prevention of post-herpetic neuralgia (71). Thus, the results of comparative studies of brivudin vs. ACV and famciclovir showed‘ the importance of brivudin in respect to reduced total daily dose (125 mg) and a reduced dosing frequency (once daily drug intake) which provide a more convenient treatment for elderly patients (68). Treatment for immunocompromised patients Several antiviral agents were found to be effective in the treatment of shingles in immunocompromised patients (Table 3). ACV is given intravenously in immunocompromised patients, who are at high risk for disseminated disease, at a dose of 5–10 mg ⁄ kg given every 8 h. Treatment is continued for 7 or 2 days after the cessation of new-lesion formation (72). However, recurrent episodes of shingles may still occur in some immunocompromised patients within few days or weeks after antiviral therapy has ceased but most patients respond to a second course of ACV. These episodes are usually attributed to the poor host response rather than to the drug resistance. Oral ACV may be accepted for the treatment of recurrent shingles in immunocompromised patients who are at low risk for visceral dissemination (73). Although shown superior efficacy in the management of shingles, the use of valaciclovir in the treatment of zoster among immunocompromised patients has not been fully evaluated. However, a recent study shows that valaciclovir 1 and 2 g, three times a day are safe and effective in cutaneous healing and reducing pain among immunocompromised patients with zoster (74). In a randomized, double-blind, multicentre, ACVcontrolled study, oral famciclovir was found to be a convenient, effective and well-tolerated regimen for immunocompromised patients with herpes zoster (75). Vidarabine is also used for the treatment of shingles among high-risk groups. It is given in a dose of 10 mg ⁄ kg ⁄ day over 12 h for 7 days. Studies have compared the efficacy of ACV and vidarabine in the treatment of shingles in immunocompromised peoples. The results showed that ACV may be equal or more effective than vidarabine in accelerating the cutaneous healing and preventing the dissemination of shingles in immunocompromised patients (76, 77). Brivudin and its counterpart sorivudine are the most potent inhibitors for VZV replication in vitro that have ever been described (68). As a result of this unique potency, both agents have been investigated for the treatment of shingles in immunocompromised patients in limited clinical trials which proved their efficacy (78,
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Table 3 Studies for the treatment of shingles in immunocompromised patients Total study population
References
Type of study
Drug used
Findings
(73)
Randomized - controlled
27
Oral vs. intravenous aciclovir
(74)
Randomized doubleblind, controlled Randomized doubleblind - controlled
87
Valaciclovir 1 g and 2 g dosage 3 times ⁄ day Famciclovir vs. Aciclovir
No difference was found between 2 treated groups in the days of healing and persistence of pain. Both dosage were effective in reducing zoster associated pain and abnormal sensation. No difference between the effect of both drugs on new lesions formation, full crusting and loss of pain. Aciclovir was better than vidarabine in accelerating healing and preventing dissemination of the disease. No difference between the effect of both drugs on vesicles healing and frequency of post-herpetic neuralgia. Brivudin stopped the progression of the disease within 1 day after initiation of treatment. Sorivudine was superior to aciclovir in reducing the time for new vesicles formation and total lesion crusting. No significant difference between the effect of both drugs on new lesions formation or visceral dissemination.
(75)
148
(76)
Randomized - controlled
22
Vidarabine vs. aciclovir (intravenous)
(77)
Randomized doubleblind - controlled
73
Aciclovir vs. vidarabine
(78)
Randomized double-blind, Placebo – controlled Randomized double-blind, comparative
20
Brivudin
(79) (80)
Randomized doubleblind, comparative
170
Sorivudine vs. aciclovir
48
Oral brivudin vs. aciclovir (intravenous)
79). Recently, in a randomized double-blind trial, brivudin given orally at 7.5 mg ⁄ kg ⁄ day (that is 125 mg four tablets per day) proved to be as effective as ACV given intravenously at 30 mg ⁄ kg ⁄ day in the treatment of shingles in immunocompromised patients (80). Moreover, in another randomized double-blind clinical trials, sorivudine given orally at 40 mg daily was compared with ACV given orally at the standard dose of 800 mg five times a day. Both drugs were given over a 10-day course to HIV patients with shingles. The sorivudine treatment resulted in similar efficacy to ACV regarding the time to the resolution of zoster-associated pain, the frequency of dissemination and the frequency of zoster recurrence. Moreover, sorivudine significantly accelerated cutaneous healing (79). Although proven to be effective in the treatment of shingles among immunocompromised patients, the use of brivudin and sorivudine has not been licensed worldwide. Serious interactions have been documented in immunocompromised patients receiving sorivudine or brivudin with intravenous 5-fluorouracil (used for treatment of solid tumours). Bromovinyluracil is a metabolite of sorivudine, as well as brivudin, which acts as an inhibitor of dihydropyrimidine dehydrogenase (DPD) which is needed for the degeneration of fluorouracil. This protects the breakdown of fluorouracil and significantly increases its half-life, hence enhancing its antitumour activity and toxicity (68, 80). Marked increase in 5-fluorouracil half-life have been demonstrated in cancer patients who had been given 5fluorouracil intravenously, concomitantly with oral brivudin (81). In addition, fifteen deaths occurred in 1993 among Japanese patients following the co-administration of sorivudine with 5-fluorouracil 40 days following the approval of sorivudine by the Japanese government to be used clinically (68, 82). Sorivudine was also found to produce a profound depression on
DPD activity, which recovered after 4 weeks from the completion of sorivudine therapy. Thus the life-threatening synergistic effect between the two drugs continued for the following few weeks after the last dose of sorivudine (83, 84).
Management of post-herpetic neuralgia Different classes of medication have been used for the treatment of post-herpetic neuralgia. The initial choice of any of these medications should be guided by the patient’s medical health, the likely adverse effects of the drug and the patient’s preference. Drugs that are currently available for the treatment of post-herpetic neuralgia are rarely associated with complete pain relief, hence the pharmacological treatment for patients with post-herpetic neuralgia is considered as a component for a more comprehensive treatment approach which may include various non-pharmacological therapies such as psychological counselling and physical isolation of the affected area to prevent any provoking stimuli (85, 86). A recent meta-analysis revealed that there is evidence to support the use of tricyclic antidepressants, strong opioids, gabapentin, pregabalin as well as topical lidocaine 5% patches and capsaicin for the treatment of post-herpetic neuralgia (87). Gabapentin and lidocaine patch 5% are considered to be the first-line therapies for post-herpetic neuralgia with opioid analgesics and tricyclic antidepressants being the second-line treatment. This is because opioid analgesics and tricyclic antidepressants have poorer tolerability and require greater caution, particularly in elderly patients with post-herpetic neuralgia. There are no data regarding the synergistic benefits of the use of combination therapies for post-herpetic neuralgia, which may be associated with increase risk of side effects (86). J Oral Pathol Med
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Topical analgesics The use of topical analgesics provides pain relief in postherpetic neuralgia with minimum side effects because these topical agents are formulated to produce local effect without achieving high plasma concentrations and hence a reduction in the risk of systemic toxicity and drugs interactions (88). Topical lidocaine patches in a 5% concentration have proven efficacy, tolerability and safety that support its use as a first-line therapy in the treatment of postherpetic neuralgia either alone or in combination with systemic agents (88–91). Lidocaine patches act as a targeted peripheral analgesic that should be applied to the painful skin section, covering as much of the affected area as possible. Up to three patches can be applied once daily for a maximum of 12 h ⁄ day. The most frequent adverse effects of the lidocaine patches are mild skin rashes, redness or irritation at the application site. Systemic lidocaine toxicity has not been reported with the use of topical lidocaine preparations (92, 93). Topical application of 0.075% capsaicin cream, a derivative of hot chilli pepper, three to four times daily has been reported to provide significant pain relief when used for the treatment of post-herpetic neuralgia (89, 94). However, compliance with this treatment is low because of the intense burning sensation, stinging and ⁄ or erythema at the application site. These adverse effects have limited the number of the placebo-controlled double blind studies undertaken because of lack of compliance among the treated patients. Topical application of aspirin dissolved in ether, chloroform or acetone has been poorly investigated. Some clinical advantage was observed (40), however, the extent of this benefit, and its safety, is still unclear. In additon, there is lack of evidence for the benefit of vincristine in the treatment of post-herpetic neuralgia (95). Table 4
(98) (103) (102)
Type of study Multicentre randomized double-blind placebo controlled Multicentre randomized double-blind placebo-controlled Multicentre randomized double-blind placebo-controlled Multicentre randomized double-blind placebo-controlled
Total study population
Drug used
Duration (weeks)
229
Gabapentin titred dose – maximum 3600 mg
8
334
Gabapentin 1800 and 2400 mg
7
338
Pregabalin fixed and flexible dosage
12
238
Pregabalin 150 or 300 mg ⁄ day
8
Oxcarbazepine Monotherapy, titred dose maximum of 900 mg ⁄ day Divalproex sodium
8
(104)
Preliminary open – label Trial
24
(105)
Randomized double-blind placebo-controlled
48
J Oral Pathol Med
Anticonvulsants A number of clinical trials have been undertaken to investigate the potential role of anticonvulsants in the treatment of post-herpetic neuralgia (Table 4). Gabapentin is a second generation anticonvulsant that has proven to be significantly effective in the treatment of post-herpetic neuralgia when compared with placebo in two large controlled clinical trials. In both trials, gabapentin, at a daily dose of 1800–3600 mg titrated over 1–2 weeks, caused a statistically significant reduction in the daily pain rating as well as an improvement in sleep, mood and quality of life (97, 98). The side effects of gabapentin include somnolence, dizziness, ataxia and, less commonly, mild peripheral oedema which may sometimes require dose adjustment. Moreover, gabapentin may cause or exacerbate abnormal gait, balance problems and cognitive impairment in elderly people. Therefore, to reduce the side effects and increase patient’s compliance with the treatment, gabapentin should be initiated at a low dose (100–300 mg in a single dose taken at bed time or 100 mg taken three times per day) and then titrated by 100 mg three times a day as tolerated. Because of patients’ variability in gabapentin absorption, the final dose should be determined on the basis of either pain relief or the appearance of unacceptable side effects that do not resolve over a few weeks (86, 97, 98). Pregabalin is a selective high-affinity ligand for alphadelta subunit protein of the calcium channels, which are
Studies for the use of anticonvulsants for the treatment of post-herpetic neuralgia
References (97)
The use of sympathetic nerve blocks for the treatment of post-herpetic neuralgia has been described in several studies. Despite the beneficial effect of sympathetic nerve blocks in relieving the pain during the acute stage of shingles, this procedure does not appear to provide significant pain relief in patients with long-standing post-herpetic neuralgia (96).
8
Findings Reduction in the pain score from 6.3 to 4.2 among gabapentin group and from 6.5 to 6.0 in placebo recipients Change in the pain score from baseline, )34.5% for 1800 mg dose, )34.4% for 2400 mg dose and )15.7% for placebo Fixed and flexible dosage given twice daily were significantly superior to placebo in pain relief 26–28% of the patients in both pregabalin groups had ‡50% decrease in the mean pain score than patients in placebo group (10%) Therapy caused a marked reduction in pain and allodynia with improvement in the quality of life in 84% of the patients 58.2% of patients who received divalproex sodium had moderate or marked pain improvement, in comparison with 14% patients treated with placebo
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thought to play an important role in modulating neuropathic pain. Pregabalin has been developed as a follow-up compound to gabapentin and it has proved to be effective in reducing the neuropathic pain by decreasing the release of neurotransmitters when bound to alpha-delta subunits (99, 100). In 2004, pregabalin received both EU and US Food and Drug Administration (USFDA) approval for the treatment of peripheral neuropathic pain, which include post-herpetic neuralgia and diabetic polyneuropathy, and for adjunctive therapy for the treatment of partial seizures in adults (101). The efficacy of pregabalin in the treatment of postherpetic neuralgia was investigated in a randomized placebo-controlled clinical trial. Oral pregabalin 150– 300 mg ⁄ day administered in two or three divided doses was superior to placebo in relieving pain and improving pain related sleep interference in both studies. The drug was well tolerated by elderly people involved in both trials. Dizziness, somnolence and peripheral oedema of mild to moderate intensity were the most common side effects (102). A more recent study compared the efficacy and safety of pregabalin, given in a flexible dose schedule of 150, 300, 450 and 600 mg ⁄ day titrated at weekly intervals and a fixed dose of 300 mg ⁄ day for 1 week, among patients with post-herpetic neuralgia or diabetic polyneuropathy. Twice daily administration of pregabalin either in a flexible or fixed dosing regimen, was significantly superior to the placebo in relieving chronic neuropathic pain and improving the sleeping interference associated with post-herpetic neuralgia or diabetic polyneuropathy. However, rapid onset of action was noticed with fixed dose pregabalin which may reflect the higher dose during the first week of treatment with this regime (103). Recent studies have evaluated the effectiveness and safety of oxcarbazepine and divalproex sodium (valproic acid and sodium valproate) for the treatment of postherpetic neuralgia (104, 105). In an open-label trial, oxcarbazepine monotherapy administered for 8 weeks
resulted in a statistically significant effect on pain reduction, allodynia and improvement in quality of life among patients with post-herpetic neuralgia (104). Divalproex sodium also resulted in significant pain relief in comparison with placebo recipients in a randomized double-blind study (105). Both drugs were well tolerated with very few side effects such as dizziness and nausea. The use of other anticonvulsants such as phenytoin, carbamazepine, sodium valproate and lamotrigine for the treatment of post-herpetic neuralgia is not supported by the literature (43).
681
Tricyclic antidepressants A number of tricyclic antidepressants, such as amitriptyline, desipramine and nortriptyline, have been used for the treatment of post-herpetic neuralgia based upon positive findings from several randomized controlled trials (Table 5). Tricyclic antidepressants are believed to exert an analgesic effect unrelated to any antidepressant effect via inhibition of the neuronal reuptake of norepinephrine and serotonin, which potentiates the inhibition of spinal neurons involved in pain perception (106). Clinically, amitryptiline is the most widely used tricyclic antidepressant for post-herpetic neuralgia, being the most studied for such treatment and resulting in pain relief approximately 47–66% of patients (107–109). Similar rates of response were found in patients who received desipramine (63%) and nortriptyline (55%). The latter was proven to be equivalent in efficacy and have better tolerability than amitriptyline (110, 111). Despite the analgesic effect of tricyclic antidepressants in the treatment of post-herpetic neuralgia, their use has been limited because of their adverse side effects. Dry mouth is the most common side effect occurring in approximately 40% of patients treated with amitriptyline and 25% of patients treated with nortriptyline. Constipation, sweating, dizziness, disturbed vision and drowsiness are reported by as many as 20–30% of those treated with amitriptyline and 5–15% of those treated
Table 5 Studies for the use of antidepressants for the treatment of post-herpetic neuralgia
References
Type of study
Total study population
Drug used
Duration (weeks)
(107)
Randomized double-blind crossover
35
Amitriptyline 12.5–25 mg Maprotiline 12.5–25 mg
12
(108)
Open label crossover study
15
Amitriptyline 10–25 mg Zimeldine 100–300 mg
7
(109)
Randomized double-blind placebo-controlled crossover
58
Amitriptyline 12.5–150 mg Lorazepam 0.5–6 mg
6
(110)
Randomized double-blind placebo crossover
31
Amitriptyline 10–20 mg Nortriptyline 10–20 mg
12
(111)
Randomized double-blind placebo-controlled crossover
19
Desipramine 167 mg
6
Findings Pain was releived in 15 patients (37%) who were treated with amitriptyline, and in 12 patients (38%) who had maprotiline Pain was reduced in eight patients (53%) who were treated with amitriptyline, and in one patient (7%) received zimeldine Pain was reduced in 47% of the patients who had amitriptyline, and in 15% of the patients who were treated with lorazepam Both drugs had similar results Pain relief occurred in 21 patients (67%) who had any of the two drugs Pain was reduced in 12 patients (63%) with desiramine therapy, and in two patients who had placebo
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with nortriptyline. Tricyclic antidepressants should be used with caution among elderly people with a history of cardiovascular disease, glaucoma, urinary retention and autonomic neuropathy (86, 112). The tolerability of treatment can be improved by gradual dose titration and the use of more selective tricyclic antidepressants such as nortriptyline, which seem to have less adverse effects in comparison with amitriptyline (112). The optimum duration of tricyclic antidepressant therapy is unknown, however, it is generally accepted that treatment should be maintained for several months before attempting dosage reduction (113). Opioids Recently there is increased evidence that patients with post-herpetic neuralgia may respond to chronic opioid therapy. In a placebo controlled cross over trial, 38 patients with post-herpetic neuralgia received an average of 45 mg controlled released oxycodone. Patients treated with oxycodone had significantly greater pain relief and reduction of allodynia compared with those receiving placebo (114). Opioid analgesics should be used very cautiously in elderly people with post-herpetic neuralgia because of the associated risk of side effects such as constipation, nausea, sedation, cognitive impairment and problems with mobility (86). In a recent randomized double-blind study, comparison of the efficacy and tolerability of two opioids (slow release morphine and methadone) and two tricyclic antidepressants (nortryptiline and amitriptyline) was investigated in patients with post-herpetic neuralgia. Analgesic efficacy of methadone was comparable to amitriptyline and nortriptyline, while slow release morphine was significantly greater than nortriptyline. Despite the side effects of opioid therapy, the majority of patients (54%) preferred opioid therapy to tricyclic antidepressants treatment, probably because of the greater pain relief experienced with these agents (115). Other therapies A variety of other treatments have been investigated for reducing the pain and allodynia in post-herpetic neuralgia. These include the use of N-methyl-D-aspartate receptor antagonists such as ketamine and dextromethorphan, antiviral agents, intrathecal corticosteroids administration, spinal stimulation and also surgical removal of the painful skin area. The efficacy of these methods has not been adequately investigated and some are only based on case reports (112). However, the use of intrathecal methylprednisolone has been evaluated in a recent study involving 277 patients with intractable post-herpetic neuralgia. Patients were randomized to receive a preparation of intrathecal methylprednisolone with lidocaine, lidocaine alone or no treatment. About 90% of the patients who received the combined preparation of methylprednisolone with lidocaine reported excellent pain relief compared with 6% of those who received lidocaine and 4% who received no treatment (116). However, the safety of this approach is still of concern because of the possible association between this
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treatment approach and serious side effects such as aseptic meningitis in patients with pre-existing neurological disease (112).
Varicella vaccine The live attenuated varicella vaccine is the first human herpesvirus vaccine that is licensed for clinical use in several countries. Varicella vaccine was first developed in Japan in 1974 following extensive passage of a clinical isolate of VZV, the Oka strain, through human and nonhuman cells in vitro (117). Varivax is a monovalent vaccine that was licensed by the USFDA in March 1995 for use in people 12 months and older. One dose of vaccine was recommended for children aged 12 months through 12 years and two doses were recommended for susceptible adolescents and adults. Use of the vaccine dramatically decreased varicella morbidity and mortality (118, 119). However, for additional improvement of disease control, a second dose of varicella vaccine was added to the childhood immunization schedule in 2006. The Advisory Committee on Immunization Practices and the American Academy of Pediatrics recommended a universal 2-dose childhood varicella vaccination programme (120). The first dose is recommended routinely at age 12–15 months and the second at 4–6 years. A second dose of varicella vaccine among children produces an improved humoral and cellular immune response that correlates with improved protection against disease (121, 122). Another vaccine is the ProQuad [measles–mumps– rubella varicella vaccine (MMRV)], which combines the varicella vaccine with attenuated MMR viruses and was licensed by the FDA in September 2005 for use in children 12 months through 12 years of age. Varicella, measles, mumps and rubella antibody concentrations after administration of a single dose of MMRV vaccine are comparable with concentrations after administration of MMR vaccine and monovalent varicella vaccine concomitantly at separate injection sites (123). A number of studies have proved that the live attenuated varicella vaccine is highly immunogenic and protective against chickenpox. In a clinical trial undertaken before licence, children younger than 12 years of age had a seroconversion rate of about 97% following administration of a single dose of varicella vaccine with maintenance of the viral antibodies for 1 year after immunization (124). Varicella vaccine also produces T lymphocytes that recognize the VZV proteins. Circulating lymphocytes are present in the peripheral blood within 2 to 4 weeks after immunization in about 98%–100% of healthy children given the vaccine. Persistence of T lymphocytes has been documented for up to 6 years following vaccine administration (125). Adults respond less effectively to varicella vaccine than children. Achieving seroconversion rate of more than 95% in adults requires the administration of two doses of vaccine, separated by at least a 4-week interval (126, 127). The cell-mediated immune response and the persistence of VZV antibodies are lower in healthy adults who received varicella vaccine than in vaccinated children. In one study, only 70% of vaccinated adults
VZV literature review Mustafa et al.
had detectable VZV IgG antibodies 2–6 years after immunization (128). Varicella vaccine is available for administration to children with leukaemia who have been in remission for at least a year and who have an absolute lymphocyte count of above 700. Vaccination of these children resulted in higher rates of seroconversion (95%) following the administration of two doses of varicella vaccine when compared with single dose administration (82%) (129). Varicella vaccine was also found to be highly protective against chickenpox in several studies undertaken either before or after licence (130, 131). In a large double blind, randomized placebo-controlled trial the vaccine had an efficacy rate of 98% through two chickenpox seasons, with 95% of the vaccine recipients remaining free of chickenpox for the following 7 years (130). Some studies report that chickenpox may still arise in small percentage of previously immunized children and adolescents, but the infection tends to be milder and modified to less than 50 skin lesions with lower incidence of fever in comparison to unvaccinated children (130, 132, 133). In children with acute leukaemia in remission, the vaccine was associated with high degree of protection, reducing the attack rate following household exposure to 13% (129). Fewer studies have evaluated the efficacy of two doses of varicella vaccine. When two doses are administered 3 months apart, the estimated vaccine efficacy over a 10-year observation period for prevention of any varicella disease has been reported as 98.3%, with 100% efficacy for prevention of severe disease (121). Adding varicella to MMR decreases the number as well as the overall burden of injections. MMRV (ProQuad) decreased burden would be expected to enhance compliance and lead to increased rates of immunization. MMRV was found to be highly immunogenic and effective against clinical disease in a number of studies (134, 135). However, MMRV vaccine has had limited availability in the United States since June 2007 because of manufacturing constraints unrelated to vaccine safety or efficacy and is not expected to be widely available before 2009 (136). The live attenuated varicella vaccine was found to be extremely safe in healthy children and adults. Adverse side effects such as pain, tenderness and irritation at the site of injection and rash were minor and transient. Within 1 month of immunization, about 7% of children and 8% of adolescents and adults develop mild vaccineassociated maculopapular rash, which may occur at the vaccine injection site or elsewhere. Although the Oka strain VZV was sometimes isolated from some of these rashes, it is more likely due to the wild type strain causing these rashes in immunized individuals, probably reflecting chickenpox just acquired before immunity is gained from the vaccine (137, 138). It is evident from a number of studies that the incidence of chickenpox has reduced markedly in the United States since the introduction of varicella vaccine in 1995 among all age groups (118, 139). In an active surveillance undertaken within three communities in the United States during the period 1995–2000, varicella
vaccine uptake among children in these areas increased steadily to 80%. This was associated with a fall in the annual incidence of chickenpox in children aged 1 to 4 years, ranging from 83% to 90%. More importantly, the disease incidence fell markedly among infants and adults, which indicates a reduction in the disease transmission among these populations. The overall reduction in the incidence of chickenpox ranged from 76% to 87% (118). Furthermore, an annual hospitalization for chickenpox per 100 000 persons also declined during the period of the surveillance. As the varicella vaccine contains infectious virus, there is a possibility for the virus to establish latency with subsequent reactivation causing shingles. Reactivation of VZV in immunized children with leukaemia indicates that the vaccine virus can indeed remain latent in the dorsal ganglia. However, the attack rate for shingles among these children was significantly lower than it was in leukaemic children with natural VZV infection (140). Very few cases of viral reactivation causing shingles have been reported among healthy children and adults who were involved in clinical trials before vaccine licence. The disease was mild and treatable with antiviral therapy (141). It has been suggested that the use of the live attenuated Oka varicella vaccine in elderly people could boost their cell mediated immunity to VZV and therefore, provide protection against viral reactivation causing shingles and post-herpetic neuralgia (142). A recent randomized, double blind, placebo controlled trial involving 38546 adults aged 60 years or over, was undertaken to evaluate the effect of vaccination on the incidence and severity of shingles and post-herpetic neuralgia. This study showed that the vaccine reduced the burden of illness due to shingles among elderly people by 6.1% and reduced the incidence of postherpetic neuralgia by 66.5%. Moreover, it showed that the vaccine reduces the overall incidence of shingles by 51.3% and significantly reduced pain and discomfort among those who developed shingles. The results reflect the ability of the vaccine to boost immunity to VZV in vaccinated individuals (143).
683
Conclusions Aciclovir has been the drug of choice for many years for the treatment of VZV infections. Recently, other antiviral agents have been developed to over come the low oral bioavailability of ACV as well as to provide a more flattering dosage regime. Chickenpox is a benign mild self-limiting disease in the majority of cases and usually no specific treatment is required. ACV is effective in reducing the severity and duration of chickenpox if given within 24 h following the appearance of the skin lesions; moreover, the benefit of using oral ACV in adolescents and adults is more significant than in children. The American Academy of Paediatrics has recommended that it should be considered for treatment in children 12 years or older, those with chronic cutaneous or pulmonary disease, those being treated with short or intermittent courses of J Oral Pathol Med
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Table 6
Disease VAR
Suggested antiviral therapy of primary and recurrent varicella zoster virus (VZV) infection (based upon best available data) Type of patient Aa Ba
ZOS A B A B A B A B
Dose
Route of administration
Timing
10–20 mg ⁄ kg (max 800 mg) 500 mg ⁄ m2
By mouth Intravenously
Four times daily for 5 days Every 8 h as 1-h infusion for 7 days
800 mg 10–20 mg ⁄ kg
By mouth Intravenously
Five times daily for 7 days Every 8 h as 1-h infusion for 7 days
1000 mg 1000 mg
By mouth By mouth
Three times daily for 7 day Three times daily for 7 day
500 mg 500 mg
By mouth By mouth
Three times daily for 7 day Three times daily for 7–10 day
125 mg
By mouth
Once daily for 7 days
Drug used Aciclovir Suspension – tablets Infusion Aciclovir Tablets Infusion Valaciclovir Tablets Tablets Famciclovir Tablets Tablets Brivudin Tablets Not licensed
VAR: Varicella infection; ZOS, Zoster infection. a A = immunocompetent, B = immunocompromised.
corticosteroids or aerosol corticosteroids and those receiving long-term salicylate therapy. The recommended dose is 20 mg ⁄ kg (maximum single dose of 800 mg) administrated four times a day for 5 days. Intravenous ACV and vidarabine has been used for the treatment of chickenpox in immunocompromised children and adults. Treatment of shingles is indicated to reduce the acute symptoms of pain and malaise, to limit the spread and duration of the skin lesions and to prevent the development of post-herpetic neuralgia and ophthalmological complications in herpes zoster ophthalmicus. Symptomatic treatment of shingles depends upon the patient’s condition, the stage of the rash, the harshness of pain and also upon patient’s response to antiviral therapy. Shingles is usually a self-limiting disease and complete healing occurs when it affects the trunk or the extremities of young individuals without risk factors. Antiviral therapy has the benefit of shortening the healing process and seems to be important when a complicated course of the disease is expected or for selected patients. ACV is effective in an oral dose of 800 mg, 5 times a day for 7 days but has a limited and less predictable effect in preventing the development of post-herpetic neuralgia. Valaciclovir (1000 mg, three times a day for 7 days) was significantly more superior to ACV in shortening the duration of herpes zosterassociated pain and in reducing the prevalence of postherpetic neuralgia as well as the duration of abnormal sensations. Famciclovir can be used for the treatment of shingles in immunocompetent people in a dose of 500 mg orally three times a day for 7 days. Brivudin, given in a single dose orally of 125 mg for 7 days, was confirmed by many clinical studies to be superior to other antiviral agents in the treatment of shingles. Thus, the results of comparative studies of brivudin vs. ACV and famciclovir showed the importance of brivudin with respect to reduced total daily dose and a reduced dosing frequency which provide a more convenient treatment for elderly patients. J Oral Pathol Med
Different classes of drugs have been used for the treatment of post-herpetic neuralgia. The first choice of any of these medications should be guided by the patient’s medical health, the likely adverse effects of the drug and the patient’s preference. Drugs that are currently available for the treatment of post-herpetic neuralgia are rarely associated with complete pain relief, for this reason the pharmacological treatment for patients with post-herpetic neuralgia is considered as a component for a more wide-ranging therapy approach which may include various non-pharmacological therapies. Topical analgesics, anticonvulsants, tricyclic antidepressants and opiods have been found to be of benefict for patiens with post-herpetic neuralgia. The aim of this article was to provide a review of current therapy of VZV infection and Table 6 shows the suggested protocols for its common clinical presentations; however, in view of the availability of newer therapies, there is a need to undertake additional randomized controlled trials to establish the most appropriate (and safe) means of treating and preventing infection in both immunocompetent and immunocompromised individuals.
References 1. Mueller NH, Gilden DH, Cohrs RJ, Mahalingam R, Nagel MA. Varicella zoster virus infection: clinical features, molecular pathogenesis of disease, and latency. Neurol Clin 2008; 26: 675–97. 2. Steiner I, Kennedy PG, Pachner AR. The neurotropic herpes viruses: herpes simplex and varicella-zoster. Lancet Neurol 2007; 6: 1015–28. 3. Elion GB. Mechanism of action and selectivity of acyclovir. Am J Med 1982; 73: 7–13. 4. Snoeck R, Andrei G, De CE. Current pharmacological approaches to the therapy of varicella zoster virus infections: a guide to treatment. Drugs 1999; 57: 187–206.
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Acknowledgements This work was based on a thesis submitted to the postgraduted faculty, Eastman Dental Institute for Oral Health Care Sciences, University of London, in partial fulfilment of the requirements for an MSc degree. A portion of this work was undertaken at UCL/UCLHT, who received a proportion of funding from the Department of Health, NIHR Biomedical Research Centre funding scheme.
