K. K. Sra, MD1 and S. K. Tyring, MD, PhD, MBA1,2
1University of Texas, Health Sciences Center, Houston, Texas, USA
2Departments of Dermatology, Microbiology/Immunology, and Internal Medicine, University of Texas, Medical Branch, Houston, Texas, USA
Postherpetic neuralgia (PHN) is a serious complication of herpes zoster that has a predilection for older individuals. PHN is often associated with significant morbidity, and it can cause insomnia, fatigue, depression and interference with daily activities in affected
individuals. Treatment for PHN is initiated with anitvirals during the acute herpes
zoster outbreak. Acyclovir (Zoviraxr®, GlaxoSmithKline), valacyclovir (Valtrex®, GlaxoSmithKline) or famciclovir (Famvir®, Novartis) can be used to treat herpes zoster, and all three have been shown to reduce the duration of the herpetic rash and zoster-associated pain. These antivirals are most effective when used within the first 72 hours of the onset of the rash. Side-effects of these antivirals are low and include nausea, vomiting, abdominal pain and headache. Other treatment options for PHN include topical analgesics, opioid analgesics, tricyclic antidepressants and gabapentin. Because of the complexity of PHN, most patients require a combination of treatment modalities for adequate pain relief.
Key Words: postherpetic neuralgia, herpes zoster
Herpes zoster is initially characterized by a prodromal phase that is associated with pain and paresthesia in the affected dermatome. Hours to days later, a papular rash appears and progresses to vesicles, then pustules and finally crusts and heals 3-4 weeks later. In some patients, the pain persists weeks to months, or years after the rash has healed, hence the term postherpetic neuralgia (PHN). Studies have demonstrated that there are three phases of PHN: acute, subacute, and chronic.1 The acute phase occurs with the onset of the rash and lasts for approximately 30 days, the subacute phase lasts 1-3 months after the onset of the rash, and the chronic phase, or PHN, lasts 3 months or longer after the onset of the rash.2
Risk factors for PHN include prodromal symptoms and severity of pain at the onset of the rash.5 The most significant risk factor for the development of PHN is age, as the incidence of PHN increases with age. While studies have demonstrated the overall incidence ranges from 10% to 27%,6,7 the incidence for individuals over the age of 50 is 40%, and 75% for those over the age of 75.8,9
The persistent pain associated with herpes zoster is variable in nature, and can be characterized as any of the following: (1) burning background pain with fluctuating severity; (2) sudden, sharp shooting pain; (3) mechanical or thermal allodynia (pain produced by non-noxious stimulus).10 As a result of this severe, often debilitating pain, a patient’s quality of life is often adversely affected. In addition to interfering with activities of daily living, PHN may lead to fatigue, insomnia, anxiety, and depression.11 Because of the severity and complexity of the disease, treatment is initiated at the onset of the rash and may be necessary months to years later.
Antivirals and PHN
Acyclovir, valacyclovir, or famciclovir can be used to treat acute herpes zoster and to reduce the severity and duration of viral replication. Through this inhibition of viral replication, acyclovir decreases the appearance of new lesions and accelerates crusting of the lesions.12 Despite this highly therapeutic effect of acyclovir in acute herpes zoster, many previously published studies demonstrated that acyclovir had no benefit in reducing the duration or incidence of PHN. However, more recent meta-analysis studies of all placebo-controlled trials with acyclovir for herpes zoster established that there is a significant reduction in zoster-associated pain in patients who received acyclovir.13,14
Similar results have also been observed with valacyclovir, as it, like acyclovir, minimizes the severity and duration of the acute herpes zoster outbreak.12 In addition, valacyclovir is more effective than acyclovir at reducing the duration of PHN. Studies have shown an average reduction of the duration of pain from 60 days, as seen with acyclovir, to 40 days with valacyclovir. Similar reductions in pain were also noted at 6 months after healing of the rash, as only 19% of patients taking valacyclovir reported pain, compared to the 26% of patients taking acyclovir.15
Famciclovir also promotes cutaneous healing and reduces the duration of acute pain. Patients who receive famciclovir have PHN resolve two times faster than those who receive placebo, resulting in a 3.5 month reduction in the average duration of pain.16 When comparing famciclovir to valacyclovir, both drugs equally hasten the resolution of zoster-associated pain and PHN.17
All three antiviral agents are approved for the treatment of herpes zoster. The most beneficial effects of the drugs are seen if they are used within the first 72 hours of the onset of the rash. Therefore, early clinical diagnosis and treatment of the disease results in faster cutaneous healing and reduced duration of PHN.
Antiviral Drug Profile
Acyclovir, valacyclovir, and famciclovir are highly selective for thymidine kinase (TK), an ezyme encoded by the herpes zoster virus. TK converts acyclovir into acyclovir monophosphate, a substrate that is ultimately modified into acyclovir triphosphate via cellular enzymes. In famciclovir, the active metabolite is penciclovir rather than acyclovir (as in valacyclovir), and it also undergoes phosphorylations via TK and other cellular enzymes to form penciclovir triphosphate. Penciclovir and acyclovir triphosphate inhibit DNA replication of the virus through (1) competitive inhibition and inactivation of viral DNA polymerase; and (2) via incorporation and termination of the growing viral DNA. By inhibiting viral replication, these antivirals reduce viral shedding, hasten cutaneous healing and reduce the severity and duration of pain.
Acyclovir, valacyclovir, and famciclovir share a similar safety profile. All three are considered very safe, with nausea, vomiting, diarrhea, abdominal pain, and headache being the most commonly reported side-effects. Although extremely rare, nephropathy, and neurotoxicity have been reported in acyclovir.
The difference in these antiviral agents lies in the bioavailability and cost. Unlike acyclovir, which has an oral bioavailability of 10%-20%, valacyclovir and famciclovir have an advantage of increased oral bioavailability of 65% and 77%, respectively, over acyclovir.19 As a result of this increased bioavailability, both famciclovir and valacyclovir have a more convenient dosing schedule and both are taken three times daily (see table 1). In addition, since all three antiviral agents reduce the duration of PHN, cost is often a factor when choosing among these drugs. Famciclovir is typically more expensive than valacyclovir, which is more expensive than generic acyclovir.
|Antiviral Agent||Dosage||Adverse Effects|
|Acyclovir||800mg, po, 5 times daily for 7-10 days||Nausea, vomiting, headache, diarrhea, dizziness,|
fatigue, anorexia, edema, and sore throat
|Valacyclovir||1gm, po, t.i.d. for 7 day||Nausea, vomiting, headache, dizziness, and abdominal pain|
|Famciclovir||500mg, po, t.i.d. for 7 days||Nausea, vomiting, headache, dizziness, abdominal pain, and fatigue|
Table 1: Antivirals Approved for Treatment of Herpes Zoster.
Treatment Modalities for PHN
Topical analgesics are commonly used for the short-term relief of PHN. Capsaicin cream, applied 3-4 times daily, is commonly prescribed and functions to reduce pain by depleting substance P via neurogenic vasodilatation. Side-effects include intolerable burning pain.20 A topical 5% lidocaine patch can also provide relief of PHN for approximately 12 hours after application.21 Side-effects are mild and include local skin reactions such as erythema.
Tricyclic antidepressants (TCAs) have been used extensively for the treatment of PHN, as they have been shown to provide moderate-to-excellent pain relief.20 Amitriptyline is the most widely prescribed TCA, but other TCAs such as nortriptyline and desipramine can also be used effectively to treat PHN.22 Despite their widespread use, side-effects are common, and careful consideration is often required prior to prescribing TCAs to older patients. TCAs are associated with dry mouth, constipation, urinary retention, blurred vision, glaucoma, and weight gain. Cardiovascular side-effects have also been associated with TCAs and include orthostatic hypotension, arrhythmias, and EKG abnormalities.
Opioid analgesics are also commonly employed for the treatment of PHN. Short-acting analgesics provide acute relief of pain, but long-acting agents, such as controlled release morphine and oxycodone, can also be used for an extended duration of pain relief.4 Side-effects of these analgesics include drowsiness, nausea, constipation, and loss of appetite. Patients should also be evaluated for a history of substance abuse before they are prescribed these analgesics.
Gabapentin, a second-generation anticonvulsant, has been shown to significantly reduce the duration of PHN.23,24 Patients receiving gabapentin have lower daily pain scores and fewer disturbances in mood and sleep when compared to those recieving placebo. Although there is no standard dosing regimen, recent studies indicate that treatment can be initiated at 900mg/day, and additional titration to 1800mg/day is often necessary for additional efficacy.25 Dosages of up to 3600mg/day may be required in some patients, and it should be noted that doses should be prescribed based on the individual’s tolerance of the medication.25 Gabapentin has a good safety profile, especially among older patients. Side-effects that have been reported include somnolence, dizziness, and gait disturbances such as ataxia. Because both gabapentin and the lidocaine patch are approved by the US FDA for the treatment of PHN and are associated with minimal side-effects, some consider these two agents to be first-line treatments for PHN.4
Although corticosteriods (oral or parenteral) have been used for the prevention of PHN in the past, they are currently not recommended in patients with PHN.26 Recent studies show that while patients treated with corticosteriods, such as prednisone, have a shorter duration of acute pain and faster resolution of the herpes zoster rash, no long-term benefits of PHN have been documented.27 As such, short-term corticosteroid use (i.e., 40-60mg prednisone taper for 15-21 days) can be utilized to reduce the severity of pain and improve quality of life in the acute phase;27,28 however, long-term use of corticosteroids is not recommended as they can facilitate bone loss and impair the host immune system, factors particularly of concern in the elderly.
Postherpetic neuralgia is a debilitating disease, especially in older individuals. The early use of antivirals (i.e., within the first 72 hours of the onset of the rash) not only reduces the duration of rash, but also reduces the duration of PHN. Thus, treatment of PHN begins with early diagnosis and treatment of herpes zoster. Other treatment modalities such as topical analgesics, TCAs, gabapentin, and opioid analgesics are often necessary, as many patients continue to have pain despite the early use of antivirals. A combination of different treatment modalities is usually implemented, as no single therapy is completely effective. Although most of these therapeutic agents are used after the resolution of the rash, the use of one or more of these treatments (i.e., gabapentin, opioid analgesics, or TCAs) with antivirals during the acute herpes zoster infection may help not only to alleviate acute pain, but also to prevent and reduce the duration of PHN.
- Arani RB, Soong SJ, Weiss HL, et al. Phase specific analysis of herpes zoster associated pain data: a new statistical approach. Stat Med 20(16):2429-39 (2001 Aug).
- Dworkin RH, Portenoy RK. Proposed classification of herpes zoster pain. Lancet 343(8913):1648 (1994 Jun).
- Desmond RA, Weiss HL, Arani RB, et al. Clinical applications for change-point analysis of herpes zoster pain. J Pain Symptom Manage 23(6):510-6 (2002 Jun).
- Dworkin RH, Schmader KE. Treatment and prevention of postherpetic neuralgia. Clin Infect Dis 36(7):877-82 (2003 Apr).
- Whitley RJ, Weiss HL, Soong SJ, Gnann JW. Herpes zoster: risk categories for persistent pain. J Infect Dis 179(1):9-15 (1999 Jan).
- Donahue JG, Choo PW, Manson JE, Platt R. The incidence of herpes zoster. Arch Intern Med 155(15):1605-9 (1995 Aug).
- Scott FT, Leedham-Green ME, Barrett-Muir WY, et al. A study of shingles and the development of postherpetic neuralgia in East London. J Med Virol 70(Suppl 1):S24-30 (2003).
- Lancaster T, Silagy C, Gray S. Primary care management of acute herpes zoster: systematic review of evidence from randomized controlled trials. Br J Gen Pract 45(390):39-45 (1995 Jan).
- Portenoy RK, Duma C, Foley KM. Acute herpetic and postherpetic neuralgia: clinical review and current management. Ann Neurol 20(6):651-64 (1986 Dec).
- Bowsher D. Factors influencing the features of postherpetic neuralgia and outcome when treated with tricyclics. Eur J Pain 7(1):1-7 (2003).
- Schmader KE. Epidemiology and impact on quality of life of postherpetic neuralgia and painful diabetic neuropathy. Clin J Pain 18(6):350-4 (2002 Nov-Dec).
- Beutner KR, Friedman DJ, Forszpaniak C, Andersen PL, Wood MJ. Valaciclovir compared with acyclovir for improved therapy for herpes zoster in immunocompetent adults. Antimicrob Agents Chemother 39(7):1546-53 (1995 Jul).
- Wood MJ, Kay R, Dworkin RH, Soong SJ, Whitley RJ. Oral acyclovir therapy accelerates pain resolution in patients with herpes zoster: a meta-analysis of placebo-controlled trials. Clin Infect Dis 22(2):341-7 (1996 Feb).
- Jackson JL, Gibbons R, Meyer G, Inouye, L. The effect of treating herpes zoster with oral acyclovir in preventing postherpetic neuralgia. A meta-analysis. Arch Intern Med 157(8):909-12 (1997 Apr).
- Beutner KR. Antivirals in the treatment of pain. J Geriatr Dermatol 6(2 suppl):23A-28A (1994).
- Tyring SK. Efficacy of famciclovir in the treatment of herpes zoster. Semin Dermatol 15(2 Suppl 1):27-31 (1996 Jun).
- Tyring SK, Beutner KR, Tucker BA, Anderson WC, Crooks RJ. Antiviral therapy for herpes zoster: randomized, controlled clinical trial of valacyclovir and famciclovir therapy in immunocompetent patients 50 years and older. Arch Fam Med 9(9):863-9 (2000 Sep-Oct).
- Burnette TC, de Miranda P. Metabolic disposition of the acyclovir prodrug valaciclovir in the rat. Drug Metab Dispos 22(1):60-4 (1994 Jan-Feb).
- Pue MA, Pratt SK, Fairless AJ, et al. Linear pharmacokinetics of penciclovir following administration of single oral doses of famciclovir 125, 250, 500 and 750 mg to healthy volunteers. J Antimicrob Chemother 33(1):119-27 (1994 Jan).
- Kost RG, Straus SE. Postherpetic neuralgia–pathogenesis, treatment, and prevention. N Engl J Med 335(1):32-42 (1996 Jul).
- Rowbotham MC, Davies PS, Verkempinck C, Galer BS. Lidocaine patch: double-blind controlled study of a new treatment method for post-herpetic neuralgia. Pain 65(1):39-44 (1996 Apr).
- Watson CP, Vernich L, Chipman M, Reed K. Nortriptyline versus amitriptyline in postherpetic neuralgia: a randomized trial. Neurology 51(4):1166-71 (1998 Oct).
- Rowbotham M, Harden N, Stacey B, Bernstein P, Magnus-Miller L. Gabapentin for the treatment of postherpetic neuralgia: a randomized controlled trial. JAMA 280(21):1837-42 (1998 Dec).
- Rice AS, Maton S. Postherpetic Neuralgia Study Group. Gabapentin in postherpetic neuralgia: a randomised, double blind, placebo controlled study. Pain 94(2):215-24 (2001 Nov).
- Backonja M, Glanzman RL. Gabapentin dosing for neuropathic pain: evidence from randomized, placebo-controlled clinical trials. Clin Ther 25(1):81-104 (2003 Jan).
- Ernst ME, Santee JA, Klepser TB. Oral corticosteroids for pain associated with herpes zoster. Ann Pharmacother 32(10):1099-103 (1998 Oct).
- Whitley RJ, Weiss H, Gnann JW Jr, et al. Acyclovir with and without prednisone for the treatment of herpes zoster. A randomized, placebo-controlled trial. The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. Ann Intern Med 125(5):376-83 (1996 Sep).
- Wood MJ, Johnson RW, McKendrick MW, Taylor J, Mandal BK, Crooks J. A randomized trial of acyclovir for 7 days or 21 days with and without prednisolone for treatment of acute herpes zoster. N Engl J Med 330(13):896-900 (1994 Mar).