Such interventions would have the potential to reduce the prevalence of chronic pain in the population .
Although certain risk factors can identify individuals who are most likely to develop chronic pain , few interventions to prevent chronic pain have been identified .
To facilitate the identification of preventive interventions , an IMMPACT meeting was convened to discuss research design considerations for clinical trials investigating the prevention of chronic pain .
We present general design considerations for prevention trials in population s that are at relatively high risk for developing chronic pain .
Famciclovir for the Treatment of Acute Herpes Zoster: Effects on Acute Disease and Postherpetic Neuralgia: A Randomized, Double-Blind, Placebo-Controlled Trial
Herpes zoster ( shingles ) develops in as many as 20 % of all persons [ 1 ] . The characteristic zoster rash is often accompanied by substantial pain , dysesthesias , and skin hypersensitivity . The unmet challenge in the management of patients with acute zoster is the alleviation of chronic pain . In many patients , pain resolves once the affected area of skin returns to normal . However , some patients continue to experience pain long after the lesions have healed ; this pain is commonly called postherpetic neuralgia . Postherpetic neuralgia is by far the most common complication of herpes zoster and is one of the most intractable pain disorders [ 2 , 3 ] . The incidence of postherpetic neuralgia increases sharply with increasing age [ 4 , 5 ] ; nearly half of patients older than 60 years have this complication [ 2 , 5 ] . Postherpetic neuralgia is also more severe and persists longer in older than in younger patients [ 3 ] . The disorder is clearly the most distressing component of the disease process for both the patient and the physician . Although for many years acyclovir has been the only oral antiviral agent approved for the treatment of patients with acute herpes zoster  , its effect on postherpetic neuralgia remains controversial [ 6 - 10 ] . Famciclovir , a new antiviral agent , was approved for marketing by the Food and Drug Administration in June 1994 for the management of acute herpes zoster . Famciclovir is the well-absorbed ( 77 % bioavailable ) [ 11 ] oral form of penciclovir , with activity against varicella-zoster virus , herpes simplex virus types 1 and 2 , and Epstein-Barr virus [ 12 - 15 ] . Penciclovir is selectively activated in virus-infected cells through phosphorylation to the antiviral compound penciclovir triphosphate . Viral thymidine kinase converts penciclovir to penciclovir monophosphate , which is converted by cellular enzymes to penciclovir triphosphate [ 12 , 16 , 17 ] . Penciclovir triphosphate inhibits viral DNA polymerase , thereby halting DNA synthesis and viral replication [ 16 - 19 ] . The in vitro potencies of penciclovir and acyclovir depend on the tissue culture cell line and assay method used but are generally similar [ 14 , 15 , 20].The 50 % plaque inhibitory concentrations in human lung fibroblasts infected with varicella-zoster virus were 4.0 1.5 g/mL for penciclovir and 4.0 1.1 g/mL for acyclovir [ 14 ] . A potentially clinical ly important characteristic of penciclovir triphosphate is that it persists in virus-infected host cells longer than acyclovir triphosphate [ 19 ] . For cells infected with varicella-zoster virus , the intracellular half-life of penciclovir triphosphate is 9.1 hours ; in contrast , the half-life for acyclovir triphosphate is 0.8 hours [ 19 , 21 ] . Thus , penciclovir triphosphate has the potential to continue to inhibit viral replication even if serum concentrations are below the inhibitory level . Consistent oral bioavailability linked to a favorable intracellular half-life of penciclovir triphosphate in cells infected with varicella-zoster virus suggested that famciclovir could offer clinical ly important advantages in the management of herpes zoster over currently available therapy . These advantages include a reduced total daily dose and a reduced dosing frequency . Because persistent antiviral activity throughout each day of dosing was expected to lead to improved clinical efficacy , especially with regard to postherpetic neuralgia , we examined the effects of famciclovir on acute herpes zoster and postherpetic neuralgia . Methods Study Design In our r and omized , double-blind , placebo-controlled , multicenter trial , we compared the efficacy and safety of famciclovir , 500 mg or 750 mg , given three times daily for 7 days , with that of placebo in the treatment of patients with uncomplicated acute herpes zoster . Eligible participants were immunocompetent patients 18 years or older with clinical ly diagnosed uncomplicated herpes zoster who gave written informed consent . Exclusion criteria included zoster rash that had been present for more than 72 hours ; complications of herpes zoster ( for example , ocular or visceral involvement , disseminated herpes zoster ) ; presence of crusts at enrollment ; other serious underlying disease ( such as immune disorders or human immunodeficiency virus [ HIV ] infection ) ; or pregnancy or lactation . Patients were prohibited from receiving any concomitant antiviral or immunomodifying therapy and any topical medication that would be applied to zoster lesions during the study . Patient Assessment s Patients were instructed to return to the clinic for evaluation of lesions and pain on each of the 7 therapy days and every day for the 7 days after therapy . Patients with lesions that were fully crusted by day 7 were examined every other day during the week after therapy . After day 14 , weekly visits were required of all patients until all lesions had lost their crusts . After the lesions had healed , patients were assessed for the presence of postherpetic neuralgia ( defined as pain after healing ) at monthly intervals for an additional 5 months . These monthly pain assessment s continued for all patients , even if postherpetic neuralgia had resolved before completion of the study period . Patients attending the clinic for fewer than 80 % of required visits were deemed noncompliant . The number of papules , vesicles , ulcers , and crusts within the primary dermatome was classified as none , mild ( < 25 lesions ) , moderate ( 25 to 50 lesions ) , or severe ( > 50 lesions ) . A specimen for viral culture was obtained at baseline and daily thereafter while vesicles were present . Patients were asked to rate the intensity of their pain as none , mild , moderate , or severe . Definitions for mild , moderate , and severe pain were not prospect ively provided . Adverse events were assessed at each visit according to the time of onset , duration , severity , and investigator-defined relation to the study medication . Blood sample s were obtained for chemical and hematologic assessment , and urine sample s were obtained for dipstick analysis before initiation of therapy and at the last therapy visit . Statistical Analysis Efficacy end points were analyzed by st and ard survival methods . We used the Cox proportional-hazards regression model in our analyses [ 22 ] . Time-dependent covariates were modeled to evaluate the proportional hazards assumption , and a model that included the main effects of treatment was used to examine efficacy . Statistical conclusions were based on the significance of estimated hazard ratios . Hazard ratios greater than 1 indicated a faster rate of event occurrence in patients receiving famciclovir than in those receiving placebo . An estimated hazard ratio of 2 indicated that the event of interest occurred twice as rapidly in patients receiving famciclovir as it did in placebo recipients . Two comparisons were made for each end point : 500-mg famciclovir compared with placebo and 750-mg famciclovir compared with placebo . We also used Kaplan-Meier estimates of the cumulative proportion of patients achieving an event to graphically illustrate the trial results . We used the Fisher exact test ( two-tailed ) to analyze proportion data . The primary efficacy variable was the time to full crusting of the lesions . Secondary variables included duration of viral shedding ; time to resolution of vesicles , ulcers , crusts , and acute pain ; and duration of postherpetic neuralgia ( that is , the time to resolution of pain after the lesions had healed ) . Healing was defined as the first time in which a patient had no papules , vesicles , ulcers , or crusts and after which did not develop them at any later visit . Similarly , the time to the resolution of a clinical variable was the time to the complete cessation of that variable with no further occurrence at any later date . Duration of viral shedding was measured as the number of days from the first dose of the study medication to the last positive culture . The enrollment objective before the study was 400 patients ; this number was selected to ensure a target of 300 evaluable patients ( 100 per group ) . The sample provided an 80 % power to detect a significant difference from placebo , assuming a true hazard ratio of 1.5 and exponential time to full crusting ( or time to event ) . We analyzed data from both the intention-to-treat group ( patients receiving at least one dose of study medication ) and the efficacy-evaluable group ( patients complying with the protocol ) . We prospect ively defined the efficacy-evaluable group before unblinding the r and omization code . Because the results of both analyses were generally similar , we present data for the intention-to-treat group , unless otherwise specified . We also examined prospect ively defined subgroups with respect to age , duration of rash at enrollment , and severity of rash at enrollment . The safety analysis included all patients who had received at least one dose of the study medication . Each analysis included all patients who provided information for the respective end point . For example , the analysis for the time to resolution of crusts included all patients who presented with crusts during the study . Therefore , the number of patients in each analysis of the time to resolution of a condition may vary because only patients experiencing the specific condition were included in the analysis . Results Demographic Characteristics Characteristics of patients in the intention-to-treat group ( n = 419 ) , including sex , age , duration of rash , location of rash , severity of rash , and severity of pain , are shown in Table 1 . Of the 419 patients enrolled , 138 received 500 mg of famciclovir , 135 received 750 mg of famciclovir , and 146 received placebo . Approximately half of the patients were female , and the mean age was 50 years . More than half of the patients had severe rash ( > 50 lesions ) at enrollment , and more than 60 % had moderate or severe zoster pain  at enrollment . Table 1 . Patient Characteristics at Study Enrollment The intention-to-treat group and the efficacy-evaluable group ( n = 323 ) had similar
Such interventions would have the potential to reduce the prevalence of chronic pain in the population .
Although certain risk factors can identify individuals who are most likely to develop chronic pain , few interventions to prevent chronic pain have been identified .
To facilitate the identification of preventive interventions , an IMMPACT meeting was convened to discuss research design considerations for clinical trials investigating the prevention of chronic pain .
We present general design considerations for prevention trials in population s that are at relatively high risk for developing chronic pain .