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 populations that are at relatively high risk for developing chronic pain. Specific design considerations included subject identification, timing and duration of treatment, outcomes, timing of assessment, and adjusting for risk factors in the analyses. We provide a detailed examination of 4 models of chronic pain prevention (i.e., chronic post-surgical pain, postherpetic neuralgia, chronic low back pain, and painful chemotherapy-induced peripheral neuropathy). The issues discussed can, in many instances, be extrapolated to other chronic pain conditions. These examples were selected because they are representative models of primary and secondary prevention, reflect persistent pain resulting from multiple insults (i.e., surgery, viral infection, injury, and toxic/noxious element exposure), and are chronically painful conditions that are treated with a range of interventions. Improvements in the design of chronic pain prevention trials could improve assay sensitivity and thus accelerate the identification of efficacious interventions. Such interventions would have the potential to reduce the prevalence of chronic pain in the population. Additionally, standardization of outcomes in prevention clinical trials will facilitate meta-analyses and systematic reviews and improve detection of preventive strategies emerging from clinical trials.

Chemotherapy-induced peripheral neuropathy (CIPN) occurs in approximately 68% of patients who receive neurotoxic chemotherapy and lasts at least 6 months post-chemotherapy in approximately 30% of individuals. CIPN is associated with decreased quality of life and functional impairments. Evidence suggests that CIPN symptoms are caused, in part, by enhanced excitability and impaired inhibition in the central nervous system. Transcutaneous electrical nerve stimulation (TENS) decreases pain by counteracting both of these mechanisms and is efficacious in other conditions associated with neuropathic pain. This single-arm study (n = 29) assessed the feasibility of investigating TENS for CIPN after chemotherapy completion using a wireless, home-based TENS device. Eighty-one percent of eligible patients who were approached enrolled, and 85% of participants who received the TENS device completed the primary (6-week) study term. Qualitative interview data suggest that use of the device on the continuous setting that automatically alternates between 1-h stimulation and rest periods for 5 h/day would be acceptable to most participants. Significant (i.e., p < 0.05) improvements were observed with the EORTC-CIPN20 (percent change from baseline: 13%), SF-MPQ-2 (52%), numeric rating scale of pain (38%), tingling (30%), numbness (20%), and cramping (53%), and UENS large fiber sensation subscore (48%). Preliminary data that support the reliability and construct validity of the UENS for CIPN in cancer survivors are also provided. Together these data suggest that it is feasible to evaluate TENS for CIPN using a wireless, home-based device and that further evaluation of TENS for CIPN in a randomized clinical trial is warranted.

These data identify reporting practices that could be improved in order to enhance readers' ability to critically evaluate RCTs of CIPN treatments and use the findings to inform the design of future studies and clinical practice. Reporting recommendations are provided.

ObjectivesInterpretation of CIs in randomised clinical trials (RCTs) with treatment effects that are not statistically significant can distinguish between results that are ‘negative’ (the data are not consistent with a clinically meaningful treatment effect) or ‘inconclusive’ (the data remain consistent with the possibility of a clinically meaningful treatment effect). This interpretation is important to ensure that potentially beneficial treatments are not prematurely abandoned in future research or clinical practice based on invalid conclusions.DesignSystematic review of RCT reports published in 2014 in Annals of Internal Medicine, New England Journal of Medicine, JAMA, JAMA Internal Medicine and The Lancet (n=247).Results85 of 99 articles with statistically non-significant results reported CIs for the treatment effect. Only 17 of those 99 articles interpreted the CI. Of the 22 articles in which CIs indicated an inconclusive result, only four acknowledged that the study could not rule out a clinically meaningful treatment effect.ConclusionsInterpretation of CIs is important but occurs infrequently in study reports of trials with treatment effects that are not statistically significant. Increased author interpretation of CIs could improve application of RCT results. Reporting recommendations are provided.

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