Designing Randomized Controlled Trials of Oral Analgesics for Chronic Postherpetic Neuralgia

  • Ian GilronEmail author
  • C. Peter N. Watson


Postherpetic neuralgia (PHN) – pain persisting for more than 3 months after the resolution and healing of a varicella zoster eruption – is an important cause of chronic neuropathic pain and likely one of the most dreaded complications of the varicella zoster virus [31]. Recent estimates suggest a prevalence of PHN ranging from 3.9 to 42.0/100,000 person-years [61]. The prevalence of PHN may be expected to diminish with the development of a zoster vaccine [43] although widespread implementation of vaccination programs and long-term efficacy of this vaccine may be less than previously expected [41]. In addition to relative ease of documenting the diagnosis (e.g., acute onset, photograph, and follow-up of characteristic dermatomal zoster eruption), the unilateral nature and characteristic neuropathic features of burning or shock-like pain, allodynia, and sensory loss [35] make PHN one of the most frequently studied conditions for the development of new treatments for neuropathic pain [18]. Following earlier clinical observations and open-label studies, Watson and colleagues, in [63], conducted the first reported randomized controlled trial (RCT) of an oral agent (the antidepressant amitriptyline) to treat chronic pain associated with postherpetic neuralgia [63]. Since then, many dozens of RCTs have been reported involving many thousands of patients with PHN. Given the continuing prevalence of PHN and the potential for PHN trial results to be extrapolated to other neuropathic pain conditions [10], improvements in RCT design may facilitate the development of new and improved treatments for chronic PHN in particular and neuropathic pain in general.Ensuring internal validity of an RCT,evaluating the effects of a study treatment for PHN – in comparison with placebo or other treatment comparators – requires minimization of various sources of bias (systematic deviation from the true result), which can be largely accomplished through random allocation of each RCT participant to the different study treatments and effectively blinding trial participants and research personnel to treatment allocation [30]. Other potential risks of bias (Fig. 21.1) may persist despite randomization and blinding [25], and some of these may be mitigated by other trial design features (e.g., efforts to minimize trial dropouts and missing data). Another important feature of internal validity of a trial is assay sensitivity – defined as “the ability of an RCT to distinguish an effective treatment from a less effective or ineffective treatment” [14]. Several trial features that maximize internal validity (e.g.,selection of motivated, compliant participants with a clear-cut diagnosis of PHN and no other comorbidities) can often conflict with the external validity or generalizability of the trial, and failure to balance internal vs. external validity runs the risk that the trial results have limited relevance in“real-world” practice [47]. This chapter will review the fundamental elements of clinical trials that should be considered in efforts to meet the trial goals and obtain an optimal balance between internal and external trial validity. Current challenges and future directions for trial designs of RCTs of treatments for chronic PHN will be discussed.


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© Springer International Publishing Switzerland 2017

Authors and Affiliations

  1. 1.Department of Anesthesiology and Perioperative MedicineQueen’s UniversityKingstonCanada
  2. 2.Department of MedicineUniversity of TorontoTorontoCanada

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