Secondary Prevention of Postherpetic Neuralgia

Abstract & Commentary

By Allan J. Wilke, MD, Professor, Department of Introduction to Clinical Medicine, Ross University School of Medicine, Commonwealth of Dominica. Dr. Wilke reports no financial relationship to this field of study.

Synopsis: Adding gabapentin to valacyclovir early in the treatment of acute herpes zoster may reduce the incidence of postherpetic neuralgia.

Source: Lapolla W, et al. Incidence of postherpetic neuralgia after combination treatment with gabapentin and valacyclovir in patients with acute herpes zoster: Open-label study. Arch Dermatol 2011;147:901-907.

Postherpetic neuralgia (phn), pain persisting longer than 3 months after development of a rash, is the most common complication of herpes zoster (HZ). It can be severe, especially in the elderly, with age being the most important factor in predicting its development. The worst cases are very difficult to treat and can sometimes last for months to years. This group of researchers from Texas report on an uncontrolled, open-labeled study performed in a private dermatology clinic that tested the hypothesis that treatment of acute HZ with a combination of gabapentin and valacyclovir would prevent PHN.

Between February 2002 and October 2007, they approached consecutive adults who presented to their office with acute HZ. Their inclusion criteria included age ≥ 50 years, a clinical diagnosis of uncomplicated HZ presenting within the first 72 hours of vesicles, and an average pain score ≥ 4 on the 10-point Likert scale. Moderate pain was defined as 4-6, and severe pain as 7-10. They had a large number of exclusion criteria including: women who had even the slightest chance of becoming pregnant or were already pregnant or nursing; patients with immune dysfunction or who were receiving immunosuppressive therapy; patients treated with medications directed against the herpesvirus; patients currently receiving gabapentin or a tricyclic antidepressant; patients with liver or renal problems; and patients with ocular involvement of HZ. The investigators recruited 133 subjects, with an average age of 65. Most were white. Two-thirds were female. On presentation, 62% rated the pain ≥ 7. Patients accepted into the study received 1000 mg caplets of valacyclovir, which they took three times a day for 7 days. They were also started on gabapentin 300 mg per day, which was increased weekly to a goal of 3600 mg per day in three divided doses, based on patient tolerance and side effects. At 4 weeks, pain was reassessed. If it was < 4, then gabapentin was stopped. Otherwise, it was continued for another 4 weeks. In either case, discontinuing it was accomplished by tapering it over 1 week. Patients were allowed to continue other pain medication. The subjects had frequent follow-up, at which time pain, sleep disturbance, use of analgesics, and any abnormal sensations were recorded. In addition, quality-of-life questionnaires were collected at each visit.

The endpoint of interest was the presence of pain at 3, 4, and 6 months. Thirty-seven (37) subjects were lost to follow-up; almost half of them reported no pain at their last visit. At 6 months, 9.8% of subjects still reported some pain; 6.8% rated pain > 3. Patients who presented with severe pain were more likely than patients with moderate pain to have pain at the study's end, although this did not achieve statistical significance. There was a trend for patients older than 70 to have persistent pain compared to younger subjects, but again, this was not statistically significant. There was no gender difference. Quality-of-life scores improved for all participants during the course of the study.

Commentary

The main weakness of this study is its design. It was neither blinded nor randomized. Secondly, the site of this study was a private dermatology clinic; these patients may differ from those who present to a primary care office.

The reported prevalence of PHN varies wildly, depending on where the study was conducted. For instance, a study in an Icelandic general practice reported a prevalence < 7% in patients older than 60 at 3 months.1 A meta-analysis of studies that evaluated the efficacy of acyclovir in treating acute HZ estimated a prevalence of 21%.2 A population-based study from the Mayo Clinic reported 33% in subjects ≥ 79 years of age.3 The discrepancy probably relates to the methods of patient recruitment to drug trials, the referral of more severely afflicted patients to specialty clinics (as may have occurred in the current study), the rigor of recording data, and how patients are questioned about pain (quantitative vs qualitative assessment).

The prevention of PHN recalls the phrase, "The best defense is a good offense." Preventing HZ is possible through vaccination.4 Varicella-zoster vaccine (Zostavax) for the prevention of shingles reduces the incidence of HZ by 51%. Subjects who received the vaccine and went on to develop HZ had a 39% reduction in PHN.5 Unfortunately, the vaccine has not been widely used for reasons that are both economic and operational; only 2-7% of eligible people have been vaccinated.6 Merck sells the vaccine to the federal government for about $160, making it the most expensive adult vaccine,7 but the good news is that Medicare Part D covers it. It needs to be stored in a freezer. In March of this year, the Food and Drug Administration (FDA) lowered the age for the use of zostavax to 50 years. The vaccine is not 100% effective, and there will always be people who go unvaccinated, so having an effective treatment to prevent PHN would be welcomed.

Currently, valacyclovir and famciclovir are recommended for the treatment of HZ. Twenty years ago, before we had those medications, Whitley and colleagues used acyclovir with prednisone to treat HZ.8 Although they were able to show quicker healing, earlier resolution of acute pain, and improved quality of life, the resolution of pain at 6 months was not statistically different than placebo. Recommendations for treating PHN include analgesics, gabapentin (starting much later in the disease course than in this study), amitriptyline, carbamazepine, topical lidocaine, topical capsaicin (over-the-counter), and topical triethanolamine salicylate. The FDA recently approved a topical 8% patch formulation of capsaicin (Qutenza) for local treatment of PHN. It is available only by prescription.

Intervention should always balance benefit and harms. Although valacyclovir is FDA-approved for the treatment of HZ and gabapentin for the treatment of PHN, I cannot recommend the early use of both to prevent PHN, based on this study. On the other hand, what harm might befall your patient? Elderly patients are more likely to suffer central nervous system adverse effects (dizziness and drowsiness) from these drugs. If you can reduce that risk, it may be worth a month's trial.

References

1. Helgason S, et al. Prevalence of postherpetic neuralgia after a first episode of herpes zoster: Prospective study with long term follow-up. BMJ 2000;321:794-796.

2. Wood MJ, et al. Oral acyclovir therapy accelerates pain resolution in patients with herpes zoster: A meta-analysis of placebo-controlled trials. Clin Infect Dis 1996; 22:341-347.

3. Yawn BP, et al. A population-based study of the incidence and complication rates of herpes zoster before zoster vaccine introduction. Mayo Clin Proc 2007;82: 1341-1349.

4. Chen N, et al. Vaccination for preventing postherpetic neuralgia. Cochrane Database Syst Rev 2011 Mar 16;(3):CD007795.

5. Oxman MN, et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med 2005;352:2271-2284.

6. Hurley LP, et al. Barriers to the use of herpes zoster vaccine. Ann Intern Med 2010;152:555-560.

7. http://www.cdc.gov/vaccines/programs/vfc/cdc-vac- price-list.htm. Accessed August 28, 2011.

8. Whitley RJ, 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 1996;125:376-383.