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Clinical outcome assessments (COAs) measure outcomes that are meaningful to patients in clinical trials and are critical for determining whether a treatment is effective. The objectives of this study are to (1) describe the different types of COAs and provide an overview of key considerations for evaluating COAs, (2) review COAs and other outcome measures for chronic pain treatments that are recommended by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) or other expert groups, and (3) review advances in understanding pain-related COAs that are relevant to clinical trials. The authors reviewed relevant articles, chapters, and guidance documents from the European Medicines Agency and U.S. Food and Drug Administration. Since the original core set of outcome measures were recommended by IMMPACT 14 years ago, several new advancements and publications relevant to the measurement or interpretation of COAs for chronic pain trials have emerged, presenting new research opportunities. Despite progress in the quality of measurement of several outcome domains for clinical trials of chronic pain, there remain some measurement challenges that require further methodological investigation.

Supplemental Digital Content is Available in the Text., 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 (ie, chronic postsurgical 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 (ie, surgery, viral infection, injury, and toxic or 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.

Fundamental statistical considerations relevant to phase 2 proof of concept and phase 3 confirmatory randomized trials investigating the efficacy and safety of pain treatments are reviewed., This article presents an overview of fundamental statistical principles of clinical trials of pain treatments. Statistical considerations relevant to phase 2 proof of concept and phase 3 confirmatory randomized trials investigating efficacy and safety are discussed, including (1) research design; (2) endpoints and analyses; (3) sample size determination and statistical power; (4) missing data and trial estimands; (5) data monitoring and interim analyses; and (6) interpretation of results. Although clinical trials of pharmacologic treatments are emphasized, the key issues raised by these trials are also directly applicable to clinical trials of other types of treatments, including biologics, devices, nonpharmacologic therapies (eg, physical therapy and cognitive-behavior therapy), and complementary and integrative health interventions.

This article reviews current methods and challenges and provides recommendations for future design and conduct of clinical trials of interventions to treat acute pain., Introduction: The clinical setting of acute pain has provided some of the first approaches for the development of analgesic clinical trial methods. Objectives: This article reviews current methods and challenges and provides recommendations for future design and conduct of clinical trials of interventions to treat acute pain. Conclusion: Growing knowledge about important diverse patient factors as well as varying pain responses to different acute pain conditions and surgical procedures has highlighted several emerging needs for acute pain trials. These include development of early-phase trial designs that minimize variability and thereby enhance assay sensitivity, minimization of bias through blinding and randomization to treatment allocation, and measurement of clinically relevant outcomes such as movement-evoked pain. However, further improvements are needed, in particular for the development of trial methods that focus on treating complex patients at high risk of severe acute pain.

This review explores foundational content relevant to the careers of junior investigators in pain clinical trails., Introduction: Clinical investigation serves a vital role to advance treatment and management strategies for patients with pain. For those new to clinical investigation, key advice for both the novice clinical investigator and the experienced researcher expanding to translational work may accelerate research efforts. Objective: To review foundational material relevant to junior investigators focusing on pain clinical trials, with an emphasis on randomized controlled trials. Methods: We reviewed recent publications and resources relevant to clinical investigators, with a particular emphasis on pain research. Results: Understanding the approaches and barriers to clinical pain research is a first step to building a successful investigative portfolio. Key components of professional development include motivation, mentorship, and collaborative approaches to research. Many junior clinical investigators face challenges in pursing research careers and sparking iterative progress toward success in clinical trials. Pain-specific research metrics and goals—including hypothesis development, study design considerations, and regulatory concerns—are also important considerations to junior investigators who pursue clinical trails. Approaches to build toward collaborative and independent funding are essential for investigators. Conclusion: This work provides a foundation for understanding the clinical research process and helps inform the goals and plans of clinical investigators.

Introduction:. The evolution of pain treatment is dependent on successful development and testing of interventions. Proof-of-concept (POC) studies bridge the gap between identification of a novel target and evaluation of the candidate intervention's efficacy within a pain model or the intended clinical pain population. Methods:. This narrative review describes and evaluates clinical trial phases, specific POC pain trials, and approaches to patient profiling. Results:. We describe common POC trial designs and their value and challenges, a mechanism-based approach, and statistical issues for consideration. Conclusion:. Proof-of-concept trials provide initial evidence for target use in a specific population, the most appropriate dosing strategy, and duration of treatment. A significant goal in designing an informative and efficient POC study is to ensure that the study is safe and sufficiently sensitive to detect a preliminary efficacy signal (ie, a potentially valuable therapy). Proof-of-concept studies help avoid resources wasted on targets/molecules that are not likely to succeed. As such, the design of a successful POC trial requires careful consideration of the research objective, patient population, the particular intervention, and outcome(s) of interest. These trials provide the basis for future, larger-scale studies confirming efficacy, tolerability, side effects, and other associated risks.

Summaries of the articles included in part II of the ACTTION Guide to Clinical Trials of Pain Treatments are followed by brief overviews of methodologic considerations involving precision pain medicine, pragmatic clinical trials, real world evidence, and patient engagement in clinical trials.

This article provides a set of practical, evidence-based suggestions for designing and executing chronic pain clinical trials in a manner that minimizes measurement error., The purpose of this article is to provide readers with a basis for understanding the emerging science of clinical trials and to provide a set of practical, evidence-based suggestions for designing and executing confirmatory clinical trials in a manner that minimizes measurement error. The most important step in creating a mindset of quality clinical research is to abandon the antiquated concept that clinical trials are a method for capturing data from clinical practice and shifting to a concept of the clinical trial as a measurement system, consisting of an interconnected set of processes, each of which must be in calibration for the trial to generate an accurate and reliable estimate of the efficacy (and safety) of a given treatment. The status quo of inaccurate, unreliable, and protracted clinical trials is unacceptable and unsustainable. This article gathers aspects of study design and conduct under a single broad umbrella of techniques available to improve the accuracy and reliability of confirmatory clinical trials across traditional domain boundaries.

Introduction:. A growing number and type of nonpharmacological approaches for the management of chronic pain have demonstrated at least modest evidence of efficacy, and for some, there is emerging evidence of their effectiveness in relatively large scale trials. Behavioral approaches are those that generally seek to promote adaptive behavioral change in the service of reducing pain and improving physical and emotional functioning and quality of life. Despite a substantial empirical literature supporting the clinical utility of these approaches, a large number of unanswered questions remain and clinical trials to answer some of these questions are needed. Although considerations for development and enactment of data-analytic plans are generally similar to those in pharmacological trials (eg, intent-to-treat, prespecifying outcomes and time points, and handling of missing data), there may be some important differences to consider when planning and conducting clinical trials examining these behavioral approaches. Objectives:. The primary objective of this article is to describe some aspects of clinical trials for behavioral approaches for the management of chronic pain that requires special consideration. Methods:. Important topics discussed include: (1) intervention development, (2) research design considerations (adequate and appropriate control and comparison conditions), (3) appropriate outcomes, (4) recruitment and sampling biases and blinding, (5) intervention fidelity and adherence, and (6) demographic and cultural considerations. Results and Conclusions:. A number of methodological recommendations are made in the service of encouraging the conduct of high-quality research comparable with that performed for pharmacological and other medical interventions.

Introduction:. Disabling chronic pain is a common experience for children and adolescents. However, the evidence base for chronic pain interventions for youth is extremely limited, which has hindered the development of evidence-based practice guidelines for most pediatric chronic pain conditions. Objectives:. To review and provide recommendations on clinical trial design and evaluation in children and adolescents with chronic pain. Methods:. In this article, we summarize key issues and provide recommendations for addressing them in clinical trials of chronic pain interventions in children and adolescents and their families. Results:. To stimulate high-quality trials of pediatric chronic pain management interventions, attention to key issues including sample characterization, trial design and treatment administration, outcome measurement, and the ethics of intervening with children and adolescents, as opposed to adults with chronic pain, is needed. Conclusion:. Future research to develop interventions to reduce or prevent childhood chronic pain is an important priority area, and requires special considerations in implementation and evaluation in clinical trials.

Use of this checklist by authors and reviewers will improve quality and transparency in reporting randomized clinical trials of pain treatments., Introduction: Randomized clinical trials (RCTs) are considered the gold standard when assessing the efficacy of interventions because randomization of treatment assignment minimizes bias in treatment effect estimates. However, if RCTs are not performed with methodological rigor, many opportunities for bias in treatment effect estimates remain. Clear and transparent reporting of RCTs is essential to allow the reader to consider the opportunities for bias when critically evaluating the results. To promote such transparent reporting, the Consolidated Standards of Reporting Trials (CONSORT) group has published a series of recommendations starting in 1996. However, a decade after the publication of the first CONSORT guidelines, systematic reviews of clinical trials in the pain field identified a number of common deficiencies in reporting (eg, failure to identify primary outcome measures and analyses, indicate clearly the numbers of participants who completed the trial and were included in the analyses, or report harms adequately). Objectives: To provide a reporting checklist specific to pain clinical trials that can be used in conjunction with the CONSORT guidelines to optimize RCT reporting. Methods: Qualitative review of a diverse set of published recommendations and systematic reviews that addressed the reporting of clinical trials, including those related to all therapeutic indications (eg, CONSORT) and those specific to pain clinical trials. Results: A checklist designed to supplement the content covered in the CONSORT checklist with added details relating to challenges specific to pain trials or found to be poorly reported in recent pain trials was developed. Conclusion: Authors and reviewers of analgesic RCTs should consult the CONSORT guidelines and this checklist to ensure that the issues most pertinent to pain RCTs are reported with transparency.

Nearly all who review the literature conclude that the role of invasive procedures to treat chronic pain is poorly characterized because of the lack of “definitive” studies. The overt nature of invasive treatments, along with the risks, technical skills, and costs involved create challenges to study them. However, these challenges do not completely preclude evaluating invasive procedure effectiveness and safety using well-designed methods. This article reviews the challenges of studying outcomes of invasive therapies to treat pain and discuss possible solutions. Although the following discussion can apply to most invasive therapies to treat chronic pain, it is beyond the scope of the article to individually cover every invasive therapy used. Therefore, most of the examples focus on injection therapies to treat spine pain, spinal cord stimulation, and intrathecal drug therapies.