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Unique aspects of clinical trials of invasive therapies for chronic pain

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.
This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Corresponding author. Address: 9500 Gilman Drive, MC 0898, La Jolla, CA 92093-0898. Tel.: 858-822-0776; fax: 858-534-7080. E-mail address: mswallace@ucsd.edu (M. Wallace).
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
Received May 07, 2018
Accepted August 07, 2018
© 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.

Unique aspects of clinical trials of invasive therapies for chronic pain


Orginally Published At: PAIN Reports

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Considerations of trial design and conduct in behavioral interventions for the management of chronic pain in adults

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.
This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Corresponding author. Address: Pain Research, Informatics, Multimorbidities, and Education (PRIME) Center, VA Connecticut Healthcare System, 950 Campbell Ave, 116B5, West Haven, CT 06516. Tel.: (203) 932-5711. E-mail address: sara.edmond@yale.edu (S.N. Edmond).
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
Received September 06, 2017
Received in revised form March 17, 2018
Accepted March 21, 2018
© 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.

Considerations of trial design and conduct in behavioral interventions for the management of chronic pain in adults


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Opportunities and challenges for junior investigators conducting pain clinical trials

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.
This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike License 4.0 (CC BY-NC-SA) which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.
Corresponding author. Address: Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins School of Medicine, 600 N. Wolfe St, Baltimore, MD 21287. Tel.: 410-955-1822. E-mail address: bicket@jhmi.edu (M. Bicket).
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
Received November 13, 2017
Received in revised form December 05, 2017
Accepted January 16, 2018
© 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.

Opportunities and challenges for junior investigators conducting pain clinical trials


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Current methods and challenges for acute pain clinical trials

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 is an open access article distributed under the Creative Commons Attribution-NoDerivatives License 4.0 (CC BY-ND) which allows for redistribution, commercial and non-commercial, as long as it is passed along unchanged and in whole, with credit to the author.
Corresponding author. Address: Department of Anesthesiology, Queen’s University, 76 Stuart St, Kingston, ON K7L 2V7, Canada. Tel.: 613-548-7827; fax: 613-548-1375. E-mail address: gilroni@queensu.ca (I. Gilron).
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
Received August 28, 2017
Received in revised form January 16, 2018
Accepted January 31, 2018
© 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.

Current methods and challenges for acute pain clinical trials


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Special considerations in conducting clinical trials of chronic pain management interventions in children and adolescents and their families

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.
This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Corresponding author. Address: Seattle Children’s Research Institute, M/S CW8-6, PO Box 5371, Seattle, WA 98145-5005. Tel.: 1-206-884-4208; fax: 206-985-3262. E-mail address: tonya.palermo@seattlechildrens.org (T.M. Palermo).
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
Received November 30, 2017
Received in revised form February 21, 2018
Accepted March 03, 2018
© 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.

Special considerations in conducting clinical trials of chronic pain management interventions in children and adolescents and their families


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Ethical considerations in the design, execution, and analysis of clinical trials of chronic pain treatments

Introduction:
In the field of
pain research, clinical trials may randomize over 500 subjects and include more than 150 sites spanning over a dozen countries.
Methods:
This review examines the ethical considerations affecting clinical trial design, execution, and analysis of trials for chronic pain. The Belmont Report has been the touchstone for human studies protection efforts since 1979. Commissioned by the U.S. government in response to ethical failures in medical research, such as the Tuskegee Syphilis Study, the report emphasizes 3 basic principles: respect for persons, beneficence, and justice. Trial design and sample size have important ethical implications.
Conclusions:
Measures to enhance trial transparency and combat publication and many other types of bias should be implemented.
This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Corresponding author. Address: California Pacific Medical Center Research Institute, 475 Brannan St, Suite 130 San Francisco, CA 94107. Tel.: 415-600-1750; fax: 415-600-1725. E-mail address: mcrowbotham@gmail.com (M.C. Rowbotham).
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
Received August 10, 2017
Received in revised form February 18, 2018
Accepted February 24, 2018
© 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.

Ethical considerations in the design, execution, and analysis of clinical trials of chronic pain treatments


Orginally Published At: PAIN Reports