Most Up to Date Article on Post Herpetic Neuralgia and Herpes Zoster in a Respectable Journal:
Journal: Expert Opinion on Pharmacotherapy
Sharon R Kim, Farhan Khan, and Stephen K Tyring
, USA firstname.lastname@example.org
Areas covered: The wide range of treatment and management options for varicella, HZ and PHN are reviewed and discussed. PubMed was the database used for the literature search.
Varicella zoster virus (VZV) causes a primary infection known as varicella (chickenpox) that may reactivate years later to cause herpes zoster (HZ), also known as shingles. Spread by air or direct person to person, VZV is endemic in the general population and is also highly contagious, with a transmission rate of up to 90% for susceptible close contacts [1-3]. For unknown reasons, VZV is epidemic in countries with temperate climate [4,5].
Varicella is a childhood disease with an average of 4 million cases annually, which approximately 90% of the cases were aged < 15 years before the introduction of the vaccine Varivax . Acute varicella presents with self-limiting, diffuse vesicular lesions in different stages. In immunocompetent children, varicella is mild and uncomplicated but is more severe with higher risk of complications in adolescents, adults and immunocompromised patients [1,5]. Starting in 1995, routine immunization of the live, attenuated varicella vaccine was recommended for susceptible children aged 12 months to 13 years in the USA . The mortality rate from varicella declined by 88% compared with the pre-vaccine period . However, varicella-related death continues to occur, especially in immunocompromised patients, foreign-born individuals and infants . Pneumonia, secondary infections and neurologic complications are three most common varicella-related complications .
HZ is a neurocutaneous, unilateral, painful, vesicular eruption along a dermatomal distribution of sensory-nerve roots . Dermatologic, neurologic and ocular complications can occur from HZ. The most common complication is post-herpetic neuralgia (PHN), which is a painful sensation or dysesthesia in the affected area after the dermatomal rash heals. In some studies, PHN is defined as neuropathic pain present at 1, 3 or 6 months [10,11]. However, because pain is subjective and usually felt as a continuum, defining PHN by onset is not practical or recommended, especially in clinical trials .
CDC estimates that 32% of persons in the USA will get HZ or shingles . The main risk factors are increasing age, family history and immunosuppression [13-15]. The HZ vaccine has been available since 2006 for persons > 60 years, and approved for persons 50 – 59 years of age in 2011. However, only 2 – 6.7% of the targeted population had received the vaccine in 2007 and 2008, respectively [16,17].
Because varicella and HZ may have serious morbidity and potential for mortality, antivirals, when indicated, should be initiated as early as possible, especially in patients who are immunosuppressed and/or at the extremes of age. Antivirals are used to lessen the pain, decrease viral shedding, promote healing and prevent complications in varicella and HZ. The efficacy of antivirals are well-demonstrated in patients with HZ over the age of 50 years of age but because the risk of adverse events are low, patients under the age of 50 years old can still benefit from antivirals by hastening the resolution of HZ. Moreover, antivirals may lessen the severity of PHN, a debilitating complication of HZ that is usually defined as neuropathic pain greater than 1 month and requires assiduous pain management. Unfortunately, the available pharmacological interventions are effective in treating PHN in only a subset of patients.
|2. DNA polymerase inhibitors||Section:|
Intravenous (IV) acyclovir has high penetration into tissue and fluids including the cerebrospinal fluid (CSF) because it is highly bound to plasma protein. By contrast, oral acyclovir has approximately 15 – 30% bioavailability of IV acyclovir, which warrants frequent doses to maintain therapeutic, plasma level. The plasma half-life is 2 – 3 h in adult patients with normal kidney function.
Acyclovir is generally well tolerated by patients with minimal toxicities and side effects. However, because acyclovir is renally excreted by both glomerular filtration and tubular secretion, acyclovir may cause nephrotoxicity, especially given as IV at rapid infusion rate to patients who are either dehydrated or have renal issues [19,20]. High serum acyclovir concentrations can cause delirium and other reversible neurologic symptoms in the elderly or renally impaired patients . Patients with genital herpes on long-term oral acyclovir 400 mg twice a day for 10 years showed no evidence of serious adverse drug reactions or cumulative toxicity .
|3. Treatment of varicella||Section:|
In otherwise healthy patients, oral acyclovir is used to treat varicella. If initiated within the 24 h of rash onset, oral acyclovir for 5 – 7 days was shown to decrease the duration and severity of varicella without serious adverse events in otherwise healthy children, adolescents and adults [39-41]. However, administration of acyclovir for healthy children has been controversial because acyclovir showed no significant reduction of varicella-related complications, varicella transmission, pruritus, number of lesions and absence from school . Regarding complications, studies have been limited due to few complications occurring in a healthy cohort or exclusion of subjects with severe complications. American Academy of Pediatrics Committee on Infectious Diseases published a recommended guideline regarding oral acyclovir therapy for healthy children, which they state should not be administered routinely but considered for certain groups at increased risk for moderate to severe varicella (e.g., otherwise healthy, non-pregnant persons > 13 years of age or older, > 12-month-old patients with a chronic cutaneous or pulmonary disorder, and patients receiving long-term salicylate therapy) . Many pediatricians use acyclovir for children with acute primary VZV in order for them to return to school sooner and in doings so allow parents to return to work sooner as well.
Since the 1980s, varicella in immunocompromised pediatric patients has been treated with IV acyclovir 500 mg/m2/dose three times daily for 7 days, which was shown to significantly decrease morbidity, progression and mortality without signs of toxicities . IV acyclovir should be used for disseminated zoster or visceral involvement, such as for varicella pneumonitis, which is the deadliest complication and presents with fever, cough, hypoxia, dyspnea and tachypnea within 1 – 4 days after the rash’s onset . In one retrospective study, all patients but one adult with severe varicella pneumonitis recovered without any sequelae on IV acyclovir 5 – 10 mg/kg every 8 h for at least 7 days . Since VZV replication occurs 1 – 3 days after infection, antivirals should be administered within 72 h. However, some patients may still benefit from antiviral therapy even when initiated after 72 h of the zoster lesion onset .
|4. Treatment of herpes zoster (or shingles)||Section:|
HZ is treated to speed up cutaneous healing, limit progression of the disease, reduce pain and prevent complications, most notably PHN. However, the optimal therapy in preventing PHN remains controversial. Of note, the vesicular rash of HZ does not respond to topical antivirals . Diagnosing zoster early is crucial because systemic antivirals should be given ideally within the first 24 – 72 h of the zoster lesions . However, antivirals given after 3 days may still be effective in treating HZ [47,52]. Systemic antivirals are especially indicated for patients who are more than 50 years old, immunocompromised, with severe eczema, and/or have cranial nerve involvement, such as the first branch of trigeminal nerve (zoster ophthalmicus) . For immunocompetent patients, antivirals should be considered for those with greater age, skin surface area involved with HZ and severity of pain, since these are predictors of pain and prolonged PHN [54,55].
The recommended dose to treat HZ is 800 mg oral acyclovir taken five times daily for immunocompetent individuals. Wood et al. meta-analysis of four double-blind, randomized, placebo-controlled trials of oral acyclovir (800 mg five times daily) given within 72 h of the onset of rash for 7 – 10 days demonstrated acyclovir reduced zoster-associated pain as well as pain associated with PHN at 3 and 6 months in at least 50% of treated, immunocompetent patients . Prolonging acyclovir to 21 days from 7 days or adding prednisolone taper (starting at 40 mg/day) did not show any significant differences in progression, pain and PHN . Compared with placebo, high-dose IV acyclovir given at 10 mg/kg three times daily for 5 days to treat zoster showed no toxicities nor statistical difference in pain or healing in lesions, but only prevented ophthalmic zoster complications . In immunocompetent patients, oral acyclovir is preferred since IV has marginally greater benefit in treating zoster but has higher costs.
Valacyclovir is also approved to treat acute HZ. This drug has similar efficacy as acyclovir in terms of resolution of cutaneous zoster and decreasing pain intensity, but has better oral bioavailability and less dosing frequency than acyclovir [58,59]. In a randomized, double-blind, multicenter study, valacyclovir 1000 mg three times daily for 7 or 14 days compared with acyclovir 800 mg five times daily for 7 days significantly accelerated the resolution of HZ-associated pain (p = 0.001 and p = 0.03, respectively), reduced the median pain durations (38 and 44 days, respectively, vs 51 days for acyclovir; p = 0.001), and resulted in fewer patients with PHN at 6 months (19.3% in the valacyclovir groups, 25.7% in the acyclovir treatment group, p = 0.02) . However, there were no significant differences with pain intensity, qualify of life, the rate of cutaneous healing and adverse events. It is also important to note that in the same study, they found that a 7-day treatment course of valacyclovir had similar benefits as a 14-day course.
In a randomized, double-blind, placebo-controlled trial of 419 immunocompetent patients presenting within 24 h of lesion onset, oral famciclovir (500 or 750 mg three times daily for 7 days) was shown to reduce the duration of viral shedding, lesion formation and even the median duration of PHN from 163 days to 63 days (p = 0.02 and 0.01) . For the treatment of ophthalmic zoster, famciclovir 500 mg three times daily was well tolerated and demonstrated similar efficacy to acyclovir 800 mg five times . In a randomized clinical trial of immunocompetent patients ≥ 50 years of age with HZ, valacyclovir (1 g, three times daily) or famciclovir (500 mg three times daily) for 7 days proved to be therapeutically equivalent in regards to resolution of zoster-associated pain (hazard ratio, 1.02; 95% confidence interval, 0.84 – 1.23; p = 0.84), PHN, cutaneous healing and treatment safety .
Patients with defective cell-mediated immunity such as those with lymphoproliferative malignancies and bone marrow transplant are at risk for developing dissemination and visceral involvement of HZ. IV acyclovir has been shown to decrease complications, stop progression and had more rapid virus clearance . Oral acyclovir, valacyclovir or famciclovir may be used to treat immunosuppressed patients with careful monitoring and follow-ups. In a randomized, double-blind, acyclovir controlled, multicenter study, oral famciclovir 500 mg three times daily for 10 days in the treatment of HZ in immunocompromised patients showed similar efficacy and safety profile to oral acyclovir 800 mg five times daily for 10 days .
Arora et al. conducted a double-blinded study, involving immunocompromised patients with clinically diagnosed HZ who were randomized to receive oral valacyclovir therapy for 7 days, either 1 or 2 g t.i.d. . Patients in both arms of the study demonstrated similar efficacy and safety with both treatment dosages of valacyclovir.
In addition to antivirals to treat acute zoster-associated pain, analgesics, opioids, neuroactive agents and gabapentin have been reported as treatments. Opioid analgesics are the mainstay of treatment for acute pain. In a randomized, placebo-controlled trial of oral oxycodone and oral gabapentin for treating acute pain in patients with HZ, the controlled-release oxycodone was better than placebo in the first 8 days (p = 0.01) and 14 days (p = 0.02) . However, patients on gabapentin did not significantly have greater relief than placebo . However, one clinical trial showed that a single dose of 900 mg gabapentin compared with placebo decreased the severity of acute zoster pain by 54% (placebo 38%, p < 0.05) and allodynia by 42% (placebo 11%, p < 0.05) . Topical lidocaine patch 5% and topical aspirin are other options; both reduced acute herpetic neuralgia in double-blind, placebo-controlled studies .
|5. Prevention of post-herpetic neuralgia with pharmacotherapy||Section:|
PHN occurs in 10 – 20% of patients with HZ who are > 50 years of age, with the risk of PHN and severity of pain increasing with age [10,70]. Because there is currently no treatment that works consistently nor effectively in all patients with PHN, the best approach is to prevent PHN in the first place by preventing HZ with vaccines (discussed in the vaccine section) and/or pharmacologically treating HZ. However, recommending a specific drug regime for clinical practice solely to prevent PHN is still premature, especially since no studies have clearly demonstrated pharmacotherapy in preventing PHN. Currently, investigations are underway but unfortunately, studies regarding PHN do not have the same methodologies, including an uniform, accepted assessment/definition of neuropathic pain in PHN [11,70-75].
Lapolla et al. in 2011 demonstrated the efficacy of gabapentin plus valacyclovir in preventing PHN in patients with acute HZ. This uncontrolled, open-label study enrolled a total of 133 patients with HZ diagnosed within 72 h of vesicle formation. Patients were treated with 1000 mg of valacyclovir three times a day for 7 days plus gabapentin at an initial dose of 300 mg/day, titrated up to a maximum of 3600 mg/day, side effects permitting. The combination of gabapentin and valacyclovir administered acutely in patients with HZ reduced the incidence of PHN to 9.8% at 6 months . The results of this study prompted Green & Stratman 2011 to recommend that dermatologists begin prescribing gabapentin in addition to antivirals to healthy patients with acute HZ who are > 50 years of age that have pain scores ≥ 4 out of 10 . However, the study by Lapolla is an open-label study and did not include a control group.
|6. Management of post-herpetic neuralgia||Section:|
Managing PHN may be difficult and require a multifaceted approach to adequately address the chronic neuropathic pain that may be subjectively rated higher in intensity than labor pain or post-surgical pain . The pain is not proportionate with the size or severity of the rash, and should never be underestimated by the physicians. Patients with PHN also report mechanical allodynia, sleep disturbance, depression, anxiety and loss of appetite [10,69,70]. Primary treatment options for managing pain associated with PHN are numerous and include anticonvulsants (gabapentin and pregabalin), selective tricyclic antidepressants (TCAs), opioids, topical capsaicin, lidocaine patch, sympathetic nerve blocks, transcutaneous electrical stimulation, acupuncture, intrathecal methylprednisolone and gamma knife radiosurgery. Invasive treatments or procedures, such as peripheral and central neural blockade, should only be considered for patients with severe, refractory pain. No one therapy is superior to the other nor completely effective in treating PHN. However, there are not much data on the benefits of combination therapy, which undoubtedly has more side effects than single therapy. Therefore, management of PHN often has to be multimodal and tailored to the patients’ co-morbidities, needs, costs and preferences. It is also important to set realistic goals with the patients because PHN may last for years and have minimal response to therapy.
First-line therapies, all tested with randomized clinical trials, include calcium channel α2-δ ligands (gabapentin and pregabalin), lidocaine patch and TCAs (amitriptyline, nortriptyline and desipramine). A meta-analysis by Collins reported TCA and anticonvulsants decrease the pain of PHN by 50% . A more recent meta-analysis by Hempenstall et al. also support the use of TCAs as well as strong opioids, anticonvulsants, topical lidocaine 5% patches and capsaicin for the treatment of PHN .
Oral gabapentin (300 – 900 mg/day up to 3600 mg/day), which is an anticonvulsant approved to treat epilepsy and restless leg syndrome, demonstrated efficacy in treating PHN. In two large multicenter, randomized, double-blind, placebo-controlled trials, oral gabapentin showed significant reduction in pain [78,79]. Because of the non-linear absorption, gabapentin dosage varies among patients and may have to be titrated up to 3600 mg/day, which means patients have to take up to1200 mg three times per day as tolerated. Common side effects related to oral gabapentin include dizziness, somnolence and headache . In 2011 and 2012, the FDA approved gabapentin AcuForm and gabapentin enacarbil, which are both extended-release forms of gabapentin given as a once-daily medication for the treatment of PHN [80,81].
The anticonvulsant pregabalin, a GABA analog of gabapentin, received FDA-approval for the treatment of PHN, diabetic polyneuropathy and for adjunctive therapy to treat partial seizures in adults [82,83]. Oral pregabalin (150 – 600 mg/day) was shown to decrease the median days of pain and generally well-tolerated in three randomized placebo-controlled clinical trials of 4 – 13 weeks’ duration [83-85]. Pregabalin has better bioavailability and pharmacokinetics than gabapentin such that pregabalin is absorbed more rapidly with a predictable, linear process . Adverse effects are similar to gabapentin.
TCAs, such as amitriptyline and nortriptyline, are antidepressants shown to effectively alleviate pain in PHN by randomized controlled clinical trials; however, they are not FDA-approved for PHN, and amitriptyline is contraindicated in the elderly [87-89]. The use of TCAs may be limited due to their intolerable adverse events including sudden cardiac death . Before starting TCA, it is recommended that patients over the age of 40 years be screened with an echocardiogram. Also, because the adverse effects may be intolerable with its sedative and anticholinergic actions (constipation, urinary retention, dry mouth, etc.), it is recommended to start low at bedtime. Nortriptyline, a noradrenergic metabolite of amitriptyline, was shown to be associated with fewer side effects and is as efficacious with pain relief as amitriptyline .
|7. Treatment of drug-resistant VZV||Section:|
Mechanism of resistance is related to reduced or altered TK, or altered viral DNA polymerase. Acyclovir resistance of VZV is uncommon but has been reported in immunocompromised patients on acyclovir for chronic duration [94,95]. A report by Jacobson et al. described four advanced HIV patients with disseminated cutaneous VZV infection who initially responded to acyclovir but had recurrence even after receiving 1 – 5 months of acyclovir 0.4 – 4 g . Acyclovir-resistant HZ may appear clinically different as there is one report of chronic verrucous lesions .
|8. Prevention of VZV with vaccination||Section:|
Despite the advances in treating VZV infection and PHN, many patients are still refractory to current treatment that makes prevention of varicella and HZ with vaccines even more of an important research focus. The live, attenuated VZV containing vaccines effectively prevent primary varicella and are well-tolerated; two are available in the USA: i) Varivax (Merck) is a single-antigen vaccine for immunocompetent patients over the age of 12 months and ii) Proquad (Merck) is a combination vaccine with the measles, mumps and rubella vaccines for immunocompetent pediatric patients aged 12 months to 12 years. In the pre-vaccine era, the annual incidence of primary varicella was 15 cases per 1000 population . After the initiation of the varicella vaccines, from 2000 to 2010, the incidence declined 79% and in 2010, the incidence was at 9 cases per 100,000 . However, the universal varicella vaccination program has been recently criticized because the varicella vaccination may be less effective than the natural immunity that existed in pre-vaccine communities, which may translate to decrease cost-effectiveness due to increased HZ morbidity . Still, it would be interesting to see how the primary prevention of varicella will affect the incidence and natural history of HZ in the future.
In 2006, a HZ vaccine, Zostavax (Merck), became available to prevent or attenuate HZ by boosting the VZV cell-mediated immunity to decrease the risk of reactivating the latent VZV infection, leading to the reduction of pain associated with HZ and PHN. The HZ vaccine also contains the same live-attenuated strain of VZV as the varicella vaccines. In a double-blinded, randomized, placebo-controlled trial with 38,546 patients over the age of 60 years, the HZ vaccine reduced the burden of illness due to HZ by 61.1% (p < 0.001), and decreased the incidence of HZ by 51% (p < 0.001) and PHN by 66.5% (p < 0.001) . In the multicenter study, Zostavax Efficacy and Safety (ZEST trial), the use of the vaccine decreased the risk of HZ by approximately 70% in adults aged 50 – 59 years . Of note, the efficacy of HZ vaccine declines after each year but the efficacy is still statistically significant for the incidence of HZ and the HZ burden of illness through year 5 .
|10. Expert opinion||Section:|
Both antiviral therapy and immunization have not only improved the management of varicella and shingles, but have also significantly decreased the mortality and morbidly rates. In general, both are efficacious and have low side-effect profile.
Ever since the varicella vaccine became routine for susceptible children aged 12 months to 13 years starting in 1995, the mortality rate have declined substantially. However, the data are rather unknown regarding the natural history of shingles in this generation of children who received the vaccination. Regardless, for those adults who had varicella previously, which is endemic in the worldwide population, it is estimated 32% of them will suffer with shingles and thus at risk for developing PHN. Unfortunately, many adults over the age of 50 are not receiving the vaccination, which effectively can prevent a multitude of morbidities from shingles.
For the otherwise healthy patients with increased risk for moderate to severe varicella, oral acyclovir is recommended. Oral acyclovir for 5 – 7 days should be initiated within the 24 h of rash onset, because this was shown to decrease the duration and severity of varicella. The rule of thumb is that antivirals should be administered within 72 h because VZV replication occurs 1 – 3 days after infection. However, therapy initiated for more than 3 days after the rash may still be beneficial.
Even though acyclovir has minimal toxicities with no serious adverse events in otherwise healthy children, adolescents and adults, nephrotoxicity is a potential side effect. Also, oral acyclovir warrants frequent dosing to maintain therapeutic plasma level, because oral acyclovir has approximately 15 – 30% bioavailability of IV acyclovir. Thus, some patients may prefer oral valacyclovir, which is better absorbed and have decreased dosing regimen.
For the immunocompromised patients and those with disseminated zoster or visceral involvement, IV acyclovir should be used because it has high penetration into tissue and fluids including the CSF. IV acyclovir should not be given at rapid infusion rate to patients who are either dehydrated or have renal issues because it may cause nephrotoxicity and/or delirium.
To treat acute HZ (< 72 h), systemic antivirals should be given ideally within the first 24 – 72 h, but can be given after 3 days because systemic antivirals have shown to limit progression of the disease, reduce pain and possibly prevent PHN. Systemic antivirals are especially indicated for patients who are more than 50 years old, immunocompromised, have severe eczema, cranial nerve involvement, large skin involvement and with severe pain. In immunocompetent patients, oral acyclovir for 7 days is recommended because IV acyclovir has marginally greater benefit in treating shingles but with much greater cost. Prolonging acyclovir to 21 or adding prednisolone taper did not show any significant improvement. Other options include oral valacyclovir (1 g three times daily) or famciclovir (500 mg three times daily) for 7 days, which are both therapeutically equivalent to acyclovir in regards to resolution of pain, rash healing and safety. Patients without contraindications to corticosteroids can take it with their antiviral therapy because concomitant use have shown to improve quality of life and reduce pain, but does not prevent PHN.
Additionally, analgesics, opioids, neuroactive agents and gabapentin can be used to treat acute zoster-associated pain. Opioid analgesics, such as oxycodone, are still the mainstay treatment for acute pain. Other options include oral gabapentin, topical lidocaine patch 5% and topical aspirin, which all may reduce acute pain. Of note, gabapentin when used with antivirals may prevent PHN because of its neuroprotective properties.
The management options for PHN are numerous, allowing for multimodal treatment to be tailored to the patients’ needs and preferences. Gabapentin and topical lidocaine 5% patches should be first line, because both demonstrated efficacy in treating PHN and are relatively safe. The drawback to gabapentin is that the dosage varies among patients and may have to be titrated up to 3600 mg/day. However, now, there are two FDA-approved extended-release forms of gabapentin, gabapentin AcuForm and gabapentin enacarbil, that can be given once daily. Another option is pregabalin, which has better bioavailability and pharmacokinetics than gabapentin but similar adverse effects to gabapentin. TCA is also effective but the adverse effects may be intolerable with its sedative and anticholinergic actions. Opioids can also be used to relieve PHN but should be second line because of its adverse effects and potential for abuse, overdose and dependence. Tramadol may be a better option for patients with a risk for substance abuse or cardiac problems that restrict the use of TCAs.
In conclusion, the prevention and management of varicella and HZ are paramount because the varicella virus is endemic and still cause significant morbidity and mortality. Vaccinations should be encouraged, especially because the HZ vaccine is the most efficacious in preventing PHN. PHN is unfortunately refractory to the available therapeutic options and sometimes require multimodal treatments. The rule of thumb is to initiate antiviral therapy as soon as the patient is diagnosed with shingles, because it shortens the healing time and may prevent PHN. Gabapentin may also be initiated because it decreases the acuity of zoster-associated pain and may prevent PHN with its neuroprotective properties. However, preventing PHN with antivirals and/or gabapentin remains controversial.
Even though major advances have been made in the treatment and prevention of VZV, much research regarding varicella is still necessary, including but not limited to developing better antivirals, inactivated vaccines for immunocompromised patients and effective strategies preventing PHN.
Varicella zoster virus (VZV) can cause three different conditions: varicella (chickenpox), herpes zoster (HZ or shingles, a reactivation of latent VZV in sensory ganglia) and post-herpetic neuralgia (PHN, a painful complication of HZ).
Antivirals are not recommended for treating uncomplicated varicella in otherwise healthy children < 12 years old. Oral antivirals are only recommended for children at risk for moderate to severe varicella, and/or > 13 years old. IV acyclovir should be used for immunosuppressed patients, disseminated zoster or visceral involvement.
Oral antivirals can treat HZ effectively by promoting healing of skin lesions and lessen the severity of pain. Antivirals may reduce the severity of complications but do not reliably prevent PHN.
The goal of treating PHN is to manage the neuropathic pain, which may require multiple and combination therapies. Management should be guided by patient’s age, co-morbidities, preferences and costs. Unfortunately, only a subset of patients responds to the pharmacological interventions.
Prevention is preferable to treatment, which is possible with the use of vaccinations that are generally well-tolerated and effective.
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