The treatment – shingles
Consultant virologist Dr Ken Mutton gives an overview on how to treat shingles in general practice.
Shingles typically manifests as a painful vesicular rash in a dermatomal distribution that does not cross the midline of the body. It is usually preceded by prodromal symptoms ranging from tingling in the nerve area affected to severe pain, followed by redness and then by vesicular lesions, but cases do occur without any rash. Lesions most commonly occur on the trunk, followed by the face, including the ophthalmic area. Admission to hospital is most likely to be required with ophthalmic zoster and in immunocompromised individuals in whom the diseases can be severe and may disseminate widely.3
Ophthalmic zoster accounts for 15% of cases and occurs where the first branch of the trigeminal nerve is involved. It is of particular concern because of its high rate of serious eye complications, including keratitis and uveitis.
Standard current treatment
Without treatment the lesions usually resolve in two to four weeks. Paracetamol can be given for pain relief, and the lesions should be kept dry. There is no place for topical antiviral therapy.
Early systemic treatment with antiviral agents has been shown to improve outcome, reduce the neuritic pain of active shingles, accelerate healing, and lessen the likelihood of complications, most importantly the risk of postherpetic neuralgia. The addition of steroids such as prednisone or prednisolone may improve acute pain and healing, and may be considered for the elderly patient with marked pain who does not have a contraindication to glucocorticoids.1
First choice current treatments for shingles are with oral antiviral drugs, aciclovir, valaciclovir, or famciclovir. Treatment is most effective if begun within 48 to 72 hours of the onset, so GPs should have a low threshold for introducing treatment for presumed zoster in patients with risk factors such as immunosuppression, or older age when there is altered sensation or tingling in a dermatomal distribution. This is especially important where there is a suspicion of the prodromal symptoms of zoster in the ophthalmic nerve distribution. Abdominal shingles, presenting with severe abdominal pain, can be particularly difficult to diagnose as the lesions are confined to the intestines.
In the immunocompetent patient, early initiation of aciclovir treatment is associated with reduced incidence of ocular complications, duration of pain and risk of postherpetic neuralgia. Treatment should ideally begin as soon as possible, and should be considered at all ages unless very mild, and certainly given to those over 50 years. Although ideally started within 48 to 72 hours of the onset of symptoms, treatment should nevertheless be initiated after 72 hours in ophthalmic zoster and in those over 50 years of age who have new vesicles still appearing.
In controlled trials, aciclovir has been shown to reduce the duration of appearance of new lesions by one-and-a-half days and to accelerate healing. For those over 50 years the proportion with persistent pain six months later was reduced from 35% to 15% in one study. Aciclovir given orally is poorly absorbed, so the dose required is high. Aciclovir 800mg five times a day for seven days orally is recommended, but compliance is difficult with this regimen. As oral aciclovir has a relatively low bioavailability, levels of aciclovir may be suboptimal compared with levels achieved after the use of its prodrug valaciclovir. It is important to maintain good hydration when taking oral aciclovir at high doses to prevent kidney damage from the drug crystallising in the renal tubules. The dosage needs to be reduced in renal impairment to lessen the risk of aciclovir toxicity.
Valaciclovir, the prodrug of aciclovir, is much better absorbed. The standard dosage regimen for valaciclovir is 1g three times a day. It is metabolised in the liver to form the active drug aciclovir, so the drug should be used with caution if there is significant impairment of liver function. The dose in renal impairment needs to be reduced. Valaciclovir gives similar improvement in healing to oral aciclovir but further reduces the duration of pain. Valaciclovir levels after a 1000mg dose are similar to those of intravenous aciclovir, so valaciclovir is preferred to oral aciclovir where feasible. It is particularly important to use valaciclovir in ophthalmic zoster, as levels in the eye and cornea are twice as high with valaciclovir as with oral aciclovir.
Famciclovir is another prodrug - the prodrug of penciclovir - an antiviral similar to aciclovir. Its dosage regimen is 500mg three times a day in the immunocompetent, although this needs to be lowered if there is renal impairment. Results are similar to those with valaciclovir.
Treatment with antiviral agents should be continued for seven days in the immunocompetent. In immunocompromised patients treatment should be continued for longer, usually for 10 days or until two days after all the skin lesions have crusted.
Results for healing of lesions, halting development of new lesions and crusting of lesions, are little different with valaciclovir and famciclovir compared with aciclovir. The significant benefits in terms of reduction of pain with valaciclovir and famciclovir, and the improved compliance and higher active drug levels, make these agents preferable to oral aciclovir.5
Varicella zoster immunoglobulin is made available via Public Health England for the prevention of chicken pox in non-immune high-risk individuals after contact with cases of chicken pox and shingles. This is a high titre varicella antibody preparation sourced from outside the UK and is in relatively short supply. There is no evidence of benefit in the treatment of zoster, and it is not available for this indication.
Intravenous immunoglobulin on the other hand has been given as an adjunct to treatment, but there is too little evidence of benefit to recommend its use. In a single German study, addition of IVIG to standard antiviral therapy with aciclovir appeared to lead to reduced risk of postherpetic neuralgia when patients were assessed at 42 days after shingles, but there was no data at later time-points.
Therapy with the oral antiviral agents as above is indicated in the immunocompromised patient, including those infected with HIV. Early initiation of antiviral treatment is effective at reducing risk of potentially life-threatening dissemination of the virus. The duration of therapy should be prolonged, to 10 days or to two days after all lesions have crusted. Steroids should not be given.
Patients should be hospitalised for treatment with intravenous aciclovir at a dose of 10-15mg/kg eight hourly if there is any evidence of dissemination, including new areas of skin involvement, respiratory and central nervous system symptoms. Disseminated varicella zoster infection can be readily confirmed by polymerase chain reaction testing of an EDTA-anticoagulated blood sample, but diagnostic tests must not be allowed to delay the initiation of appropriate antiviral therapy. Highly immunocompromised patients such as recent allogeneic haematological stem cell transplant recipients, and allogeneic haematological stem cell transplant recipients who are receiving immunosuppressive therapy for graft versus host disease, should immediately be hospitalised for intravenous therapy, as should other transplant recipients on highly immunosuppressive regimens.6 Urgent ophthalmological assessment as well as hospitalisation is needed if there is ophthalmic shingles in an immunocompromised individual. If there is a delay in hospital admission oral valaciclovir or famciclovir might reasonably be started.
Shingles can become infected with bacteria, particularly staphylococci and streptococci, which may produce impetigo-like lesions. The frequency with which secondary infection occurs is unclear - figures of 1-2% are often quoted but estimates can be up to 30% in some countries. Serious cellulitis can occur and needs immediate antibiotic treatment with flucloxacillin or other antimicrobial agents such as penicillin V or clindamycin. A number of cases of necrotising fasciitis, mostly associated with group A streptococcal infection, have been reported in zoster. This life threatening condition needs to be recognised as soon as possible so that urgent surgical intervention can be initiated, together with antibiotic treatment. There is a suggestion that use of NSAIDs to control pain in acute shingles may increase the risk of bacterial superinfection.7
Postherpetic neuralgia is especially common in those over 60 years. In most cases it lasts for several months after resolution of the initial shingles lesions, but in 2% of patients it can last for as long as five years. It can be a debilitating condition, with ongoing pain, allodynia, and sleep disturbance. Severe postherpetic neuralgia may require referral to specialist pain services.
A key aim of prompt therapy of shingles with antiviral drugs is to reduce the risk of long-term postherpetic neuralgia pain. As this is caused by nerve damage, it is reasonable to assume that higher levels of antiviral achieved by valaciclovir and famciclovir switching off virus replication earlier leads to a lower risk of postherpetic neuralgia. This result is clear from a number of trials.
Adjunctive steroid therapy does not appear to reduce the rate of postherpetic neuralgia, although it may benefit early acute pain during the episode of shingles at the risk of steroid side-effects.
Management includes a number of options, topical and oral, and combination approaches are often needed.
Anaesthetic patches with 5% lidocaine may be considered for topical pain relief. Local application of capsaicin 0.075% cream may help some patients, although burning from the drug may restrict this approach if there is allodynia, and relief tends to be moderate - even with four applications per day. Self-adhesive 8% capsaicin patches may be considered for a limited area under specialist supervision. They require topical anaesthesia of the skin, for example with lidocaine cream, before application to reduce the burning sensation, but are long-lived.
Opioid analgesics such as oxycodone, morphine and tramadol may be used with appropriate care for severe pain, and are effective agents in controlling postherpetic neuralgia pain.
Pregabalin and gabapentin reduce the pain of postherpetic neuralgia. Pregabalin is initiated at a dose of 150mg a day in divided doses, increasing as necessary. Gabapentin is initiated at a dose of 300mg a day and increased by 300mg a day as required by the response, up to 3.6g, or until limiting side-effects supervene. Controlled trials show substantial reductions in pain compared to placebo.
Tricyclic antidepressants such as amitriptyline and nortriptyline are also beneficial in postherpetic neuralgia. They have been shown to improve pain, but side-effects and pre-existing cardiac disease in older patients may limit their use. One study found that 67% of patients described ‘good to excellent’ pain relief.8 Results are similar to those obtained with gabapentin, but pregabalin may have better outcomes when assessed at eight weeks.8
What is newly available?
Varicella zoster vaccination to prevent shingles in older adults in the UK should lead to changes in the pattern of shingles, with fewer cases in older people. In the US Shingles Prevention Study, a high potency live attenuated zoster vaccine significantly reduced the incidence of shingles - by 51% - and reduced the burden of illness by 61%, and the incidence of postherpetic neuralgia by 65%.6 The shingles vaccine is offered routinely as part of the NHS vaccination programme for people aged 70, 78 or 79. Patients became eligible for the vaccine on the first day of September 2014, after they turned 70, 78 or 79 and remain so until the last day of August this year. Shingles may recur, so vaccination should be given to all individuals in this age group including those who have had previous shingles. It should not be given to a patient currently on antiviral therapy.
In Chinese literature, complementary medicine approaches have been reported to have benefit in the management of pain in acute shingles. These include acupuncture, moxibustion and wet cupping. There are anecdotal reports of benefit from hypnotherapy in some patients with postherpetic neuralgia, but a systematic review of the role of hypnosis has not been reported so far.
Shingles in the pregnant woman does not pose a risk to the foetus, as the pre-existing maternal ‘immunity’ to varicella zoster gives protection. The same considerations with regard to treating the woman, however, pertain whether she is pregnant or not. Considerations about the safety of aciclovir in pregnancy should not deter its use in painful shingles.
Individuals with pre-existing skin conditions such as eczema may develop more severe zoster with a risk of dissemination. Early treatment with oral antivirals should be initiated, with hospitalisation for intravenous therapy if there is evidence of dissemination.
Some individuals develop shingles on a background of long-term aciclovir use, for example for genital herpes simplex suppression or for recurrent episodes of shingles. Many of these patients are at increased risk of shingles because of HIV infection. If lesions do not respond to oral antivirals as expected, aciclovir resistance in the varicella zoster strain should be considered. Parenteral antiviral drugs such as foscarnet or cidofovir will be required.
Dr Ken Mutton is a consultant virologist at Central Manchester University Hospitals
1 Wareham DW, Breuer J. 2007. Herpes zoster. BMJ 334:1211-1215.
2 Forbes HJ, Bhaskaran K, Thomas SL et al. 2014. Quantification of risk factors for herpes zoster: population based case-control study. BMJ 348:g2911.
3 Morgan R, King D. 1998. Characteristics of patients with shingles admitted to a district general hospital. Postgrad Med J 74:101-103.
4 Chaves SS, Haber P, Walton K et al. 2008. Safety of varicella vaccine after licensure in the United States: experience from reports to the vaccine adverse event reporting system, 1995-2005. J Infect Dis 197 Suppl 2:S170-177.
5 McDonald EM, de Kock J, Ram FS. 2012. Antivirals for management of herpes zoster including ophthalmicus: a systematic review of high-quality randomized controlled trials. Antivir Ther 17:255-264.
6 Dworkin RH, Johnson RW, Breuer J et al. 2007. Recommendations for the management of herpes zoster. Clin Infect Dis 44 Suppl 1:S1-26.
7 Mikaeloff Y, Kezouh A, Suissa S. 2008. Nonsteroidal anti-inflammatory drug use and the risk of severe skin and soft tissue complications in patients with varicella or zoster disease. Br J Clin Pharmacol 65:203-209.
8 Khadem T, Stevens V. 2013. Therapeutic options for the treatment of postherpetic neuralgia: a systematic review. J Pain Palliat Care Pharmacother 27:268-283.