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A New Age In Prevention & Treatment

The varicella-zoster virus (VZV) first strikes as chickenpox or varicella, now preventable through vaccination, but which is still regarded by many as a mild childhood illness. However, according to the CDC, chickenpox-related complications result in 10,000 hospitalizations and nearly 100 deaths in the U.S. each year. Following an episode of chickenpox, the virus lies dormant in nerve tissues. However, in nearly one million Americans annually, it strikes a second time as shingles or herpes zoster. Shingles is an often painful outbreak of a rash or blisters on the skin, usually occurring in a band on one side of the body, or clustered on one side of the face. It may disappear in two to four weeks. But the risk of complications from shingles, such as post-herpetic neuralgia (PHN), increases with age, weakened immunity and delay or lack of treatment. PHN can cause piercing or stabbing pain persisting for months or even years.

The opinions expressed in this three-part article reflect the respective opinions of the featured scientists and authors, and not the VZV Research Foundation, which is not licensed to practice medicine.

The Varicella Vaccine

"The suffering or death of even one child from a vaccine-preventable disease is an unnecessary tragedy."

With these words, Walter A. Orenstein, M.D., director of the Centers for Disease Control and Prevention's (CDC) National Immunization Program, joined his colleagues in announcing, on July 6, 2000, that America's childhood immunization coverage rates for 1999 are the highest ever recorded. While the overall immunization rate for preschool children remains at 80 percent, coverage rates for four individual vaccines increased from 1998 to 1999, including varicella (chickenpox) vaccine, which increased more than 16 percent to 59.4 percent. This marks the first time that over half the children surveyed were immunized for chickenpox.

The CDC's goal, by 2010, is to reach a varicella vaccination coverage rate of 90 percent among children aged 19-35 months, and more than 95 percent of children at school entry. This goal is extremely important, but reaching it will be "quite challenging," according to Philip LaRussa, M.D., Professor of Clinical Pediatrics at Columbia University College of Physicians and Surgeons in New York City.

Dr. LaRussa, who, in 1979, became the first adult to be vaccinated with the varicella vaccine in the U.S., backs up his assertion with the fact that some physicians do not regard chickenpox as a serious health problem. Others remain resistant to the vaccine.

"When any kind of change to clinical procedure is introduced, you can convince roughly two-thirds of practitioners to comply," said Dr. LaRussa. "The remaining one-third of physicians do not actively promote vaccine usage among their patients, many of whom, in turn, adopt the same anti-vaccine stance. These doctors will only use the vaccine if their states require it."

Dr. LaRussa believes discussion of chickenpox eradication is unrealistic at this point. "Ten to 15 percent of vaccinated individuals will develop breakthrough infections and remain a source of the virus, as will elderly individuals who develop shingles and are able to transmit chickenpox to susceptible individuals. Our best approach is to keep vaccination rates high, thereby reducing the number of these susceptible individuals."

Looking to the future, Dr. LaRussa notes that current research into the combination of the varicella vaccine with the measles, mumps and rubella vaccine, or MMR-V, is promising. "But we do not know how long it will take to develop a combined vaccine that will offer the same degree of efficacy to all four of these diseases as the MMR vaccine and varicella vaccine currently achieve separately. Therefore, we cannot delay varicella immunization of susceptible children and adults until a combined vaccine arrives. The varicella vaccine must be used on its own merits, now."

Dr. LaRussa noted a secondary, major benefit of vaccinating children. "Besides having a greater chance of not developing chickenpox, these children will also be at much lower risk for shingles. And for those adults who have had chickenpox in childhood, I am hopeful the Shingles Prevention Study will find that shingles vaccination will reduce their chances of develop shingles."

The Shingles Prevention Study

"As physicians, we are often powerless to help make life better for our patients who suffer from the misery of acute shingles pain and PHN. An enormous sense of frustration over this fact motivated us to undertake this study. It was our obligation as doctors."

Michael N. Oxman, M.D., a staff physician at the San Diego VA Medical Center and professor of Medicine and Pathology at the University of California, San Diego, is National Chairman of the Shingles Prevention Study. He began laying the groundwork for the study in 1991, when he applied to the Department of Veterans Affairs Cooperative Studies Program for a planning grant.

Eight years later, the study was launched and enrollment recently exceeded the 50 percent mark, with the participation of more than 20,000 individuals, age 60 or older, who have not yet had shingles. Ultimately, 37,500 subjects will be involved in the study, which is being conducted at 22 sites throughout the country by the Department of Veterans Affairs Cooperative Studies Program, with the collaboration of the National Institute of Allergy and Infectious Diseases and Merck & Co., Inc., the vaccine's manufacturer.

The primary objective of this double-blind, placebo-controlled trial is to determine whether vaccination with live attenuated Oka/Merck varicella-zoster vaccine can decrease the incidence and/or severity of shingles and its complications in older adults. A secondary objective is to ascertain if vaccination can protect against post-herpetic neuralgia (PHN).

According to Dr. Oxman, the two hypotheses being tested are based on three key observations. "First, there is a marked increase in the incidence and severity of shingles and PHN in older persons, and this increase is correlated with an age-dependent decline in their cellular immunity to the varicella-zoster virus. Second, individuals with normal immune systems rarely experience more than one episode of shingles, and we think that this is because an episode of shingles generates a substantial and prolonged increase in cellular immunity to VZV. It seems as if one episode of shingles immunizes against another attack. Third, several studies carried out by Dr. Myron Levin and others have demonstrated that live attenuated Oka/Merck varicella-zoster vaccine can induce a substantial and prolonged boost in cellular immunity to VZV that is similar to that produced by an episode of shingles."

Based on these observations, he is hopeful the vaccine will be shown to protect individuals in the same manner in which an episode of shingles does, but without the associated pain and suffering caused by shingles.

When asked why he thought an increasing number of individuals were participating in the study, Dr. Oxman noted a degree of altruism in enrollees. "Many participants have indicated they have relatives or friends whose experiences with shingles and PHN were devastating. They cite people they know whose lives were literally destroyed by the pain of PHN and the accompanying allodynia, the medical term for pain produced by a normally painless stimulus, such as the touch of clothing or a soft breeze. Sure, they don't want this to happen to them, but many express the hope that their involvement will help their children and their children's children avoid the suffering."

Still, there remains an overall lack of awareness or interest in shingles and PHN, in Dr. Oxman's view. "Shingles doesn't affect everyone, nor is it a deadly disease, so we really do not pay much attention to it as a society. Another important reason why shingles and its complications are largely ignored is that they affect primarily older Americans. We live in a youth-oriented culture that tends to turn its back on anything having to do with old age. What we don't realize is that, if we're lucky, we'll all live to a ripe old age. And the longer you live, the greater your chances of developing shingles."

If current projections are accurate, the results of the study should be available in 2004. Dr. Oxman believes if the vaccine is proven effective, it should be available within one year of the study's conclusion.

But until there is a vaccine, Dr. Oxman and his colleagues will continue to look for methods of providing relief to patients suffering from acute shingles pain.

"A 71-year-old patient of mine, who is very typical of patients I see, just rated his shingles pain as a '10' on a scale of '0 to 10.' He is in the early phase of zoster pain, and morphine and Percocet have worked fairly well for him. But the degree of pain he is already experiencing in the early phase of shingles doesn't auger well for him. It suggests he may develop PHN. With PHN, he will still be in pain, but, unfortunately, his PHN may not respond as well to the pain-relieving medicines that are working now. "

Nevertheless, Dr. Oxman is very encouraged by recent, significant advances in the management of PHN.

For more information on the Shingles Prevention Study, please contact National Study Coordinator Heather Williams, MSN, RN, at (858) 552-8595, extension 4638. To reach a Shingles Study Prevention Site near you, dial, toll-free, (877) 841-6251.

Emerging Treatments for PHN

"PHN treatment is very subjective. What provides pain relief for one person may have no impact on another. I do wish we could come up with a single treatment approach or algorithm for PHN, but that will not be possible, at least in the short-term. The good news is clinicians now have an array of evidence-based approaches to managing PHN that have emerged only recently."

Since the mid-1980s, Kenneth E. Schmader, M.D., associate professor of Medicine at Duke University, has witnessed firsthand the devastating impact of PHN on many of his elderly patients. "The search for effective pain relief is far from over, but the long wait for evidence from randomized, controlled trials of several pain therapies is over. And with the emergence of four, significant treatment options, a new age in PHN pain management has begun."

Dr. Schmader cites a paper published in the May 2000 edition of the journal Drugs, entitled, "Treatment of Postherpetic Neuralgia: An Update," 1 authors Ghassan E. Kanazi, M.D., Robert W. Johnson, MB, BS, FRCA, and Robert H. Dworkin, Ph.D., reviewed the findings of recent studies:

  • Lidocaine Patch: Michael Rowbotham, M.D. of the University of California, San Francisco and his colleagues "recently presented the results of several double-blind...studies in which topical lidocaine in either gel or patch form relieved pain in patients suffering from PHN with allodynia. A majority of patients treated with the...(lidocaine) patch have reported moderate or greater pain relief." Based on this data, the U.S. Food and Drug Administration granted approval to a lidocaine patch for the treatment of PHN in 1999. 1; 2-4
  • Nortriptyline: C. Peter N. Watson, M.D., F.R.C.P. of the University of Toronto and his colleagues "conducted a double-blind crossover trial comparing (the tricyclic antidepressants, or TCAs) amitriptyline and nortriptyline in a sample of patients with PHN. The results demonstrated that these two TCAs had equivalent analgesic effects in PHN, but...nortriptyline was better tolerated by patients." Nortriptyline was shown to have fewer side effects than amitriptyline, which "has been the most widely used antidepressant in the treatment of PHN...(but) is one of the TCAs with the greatest number of adverse effects." 1; 5
  • Gabapentin: Dr. Rowbotham and his colleagues also conducted "the largest clinical trial ...to date in PHN...a double-blind study (involving the anticonvulsant gabapentin). Treatment with gabapentin was associated with a significant reduction in average daily pain ratings as well as improvements in sleep, mood and quality of life. The safety and efficacy of gabapentin treatment in patients with PHN appeared to be at least as favorable as that reported for antidepressant treatment...(These findings) suggest gabapentin should be considered a first-line treatment in patients with PHN, especially among those without depressive symptoms requiring antidepressant treatment." 1; 6
  • Oxycodone: Dr. Watson and Najib Babul, PharmD "...(directed) a placebo-controlled crossover trial...of controlled release oxycodone. Patients treated with oxycodone had significantly greater pain relief, reduction of allodynia, decreased disability...than patients receiving placebo. These results not only establish that opioid analgesics have an important role in the treatment of PHN; they also provide compelling evidence that neuropathic pain responds to opioids."

According to Dr. Schmader, the immediate, next steps in research into PHN treatments include additional, controlled trials to determine the efficacy of these four therapies used in combination and the development of newer agents that attack neuropathic pain. He also believes the Shingles Prevention Trial, which is attempting to ascertain if immunization with varicella-zoster vaccine can protect against PHN, will help scientists determine whether PHN prevention is a valid strategy.

1 Kanazi, G.E., Johnson, R.W., and Dworkin, R.H. Treatment of postherpetic neuralgia: an update. Drugs 2000 May; 59; 1113-1126

2 Rowbotham, M.C., Davies, P.S., Fields, H.L. Topical lidocaine gel relieves post-herpetic neuralgia. Ann Neurol 1995; 37; 246-53

3 Rowbotham, M.C., Davies, P.S., Verkempinck, C., et al. Lidocaine patch: double-blind controlled study of a new treatment method for postherpetic neuralgia. Pain 1996; 65; 39-44

4 Galer, B.S., Rowbotham, M.C., Perander, J., and Friedman, E. Topical lidocaine patch relieves post-herpetic neuralgia more effectively than a vehicle topical patch: results of an enriched enrollment study. Pain 1999: 80: 533-8

5 Watson, C.P.N., Vernich, L., Chipman, M., et al. Nortriptyline versus amitriptyline in post-herpetic neuralgia: a randomized trial. Neurology 1998; 51; 1166-71

6 Rowbotham, M.C., Harden, N., Stacey, B., et al. Gabapentin for the treatment of postherpetic neuralgia: a randomized controlled trial. JAMA 1998; 280; 1837-42

7 Watson, C.P.N. and Babul, N. Efficacy of oxycodone in neuropathic pain: a randomized trial in postherpetic neuralgia. Neurology 1998; 50; 1837-41