Toward a Mechanism-Based Approach to Pain Diagnosis Daniel Vardeh,* Richard J. Mannion, y and Clifford J. Woolf z *Division of Pain Neurology, Department of Neurology and Anesthesia, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts. y Department of Academic Neurosurgery, Cambridge University Hospitals NHS Trust, Cambridge, United Kingdom. z FM Kirby Neurobiology Center, Boston Children’s Hospital and Harvard Medical School, Boston, Massachusetts. Abstract: The past few decades have witnessed a huge leap forward in our understanding of the mechanistic underpinnings of pain, in normal states where it helps protect from injury, and also in path- ological states where pain evolves from a symptom reflecting tissue injury to become the disease itself. However, despite these scientific advances, chronic pain remains extremely challenging to manage clin- ically. Although the number of potential treatment targets has grown substantially and a strong case has been made for a mechanism-based and individualized approach to pain therapy, arguably clinicians are not much more advanced now than 20 years ago, in their capacity to either diagnose or effectively treat their patients. The gulf between pain research and pain management is as wide as ever. We are still currently unable to apply an evidence-based approach to chronic pain management that reflects mech- anistic understanding, and instead, clinical practice remains an empirical and often unsatisfactory journey for patients, whose individual response to treatment cannot be predicted. In this article we take a common and difficult to treat pain condition, chronic low back pain, and use its presentation in clinical practice as a framework to highlight what is known about pathophysiological pain mecha- nisms and how we could potentially detect these to drive rational treatment choice. We discuss how present methods of assessment and management still fall well short, however, of any mechanism- based or precision medicine approach. Nevertheless, substantial improvements in chronic pain manage- ment could be possible if a more strategic and coordinated approach were to evolve, one designed to identify the specific mechanisms driving the presenting pain phenotype. We present an analysis of such an approach, highlighting the major problems in identifying mechanisms in patients, and develop a framework for a pain diagnostic ladder that may prove useful in the future, consisting of successive identification of 3 steps: pain state, pain mechanism, and molecular target. Such an approach could serve as the foundation for a new era of individualized/precision pain medicine. The Analgesic, Anes- thetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION)- American Pain Society (APS) Pain Taxonomy (AAPT) includes pain mechanisms as 1 of the 5 dimensions that need to be considered when making a diagnostic classification. The diagnostic ladder proposed in this article is consistent with and an extension of the AAPT. Perspective: We discuss how identifying the specific mechanisms that operate in the nervous sys- tem to produce chronic pain in individual patients could provide the basis for a targeted and rational precision medicine approach to controlling pain, using chronic low back pain as our example. ª 2016 by the American Pain Society Key words: Diagnosis, low back pain, mechanism, target. A mechanistic approach to address chronic pain has been actively promoted over the past few decades in an attempt to exploit the growing un- derstanding of underlying pathological processes as a means to improve patient management. 51,157,158 Medicine is obviously most impactful when defined The views expressed in this article are those of the authors, none of whom has financial conflicts of interest relevant to the specific issues discussed. No official endorsement by the U.S. Food and Drug Administration (FDA) or the pharmaceutical and device companies that have provided unre- stricted grants to support the activities of the ACTTION public-private partnership with the FDA should be inferred. Financial support for this supplement and for the development of the AAPT has been provided by the ACTTION public-private partnership, which has received research contracts, grants, or other revenue from the FDA, multiple pharmaceu- tical and device companies, and other sources. A complete list of current ACTTION sponsors is available at: http://www.acttion.org/partners. Clifford J. Woolf was supported by the National Institutes of Health (RO1DE022912; RO1NS038253; R37NS039518; PO1NS072040-01A). Address reprint requests to Clifford J. Woolf, MD, PhD, FM Kirby Neuro- biology Center, Boston Children’s Hospital, 300 Longwood Ave, Boston, MA 02115. E-mail: clifford.woolf@childrens.harvard.edu 1526-5900/$36.00 ª 2016 by the American Pain Society http://dx.doi.org/10.1016/j.jpain.2016.03.001 T50 The Journal of Pain, Vol 17, No 9 (September), Suppl. 2, 2016: pp T50-T69 Available online at www.jpain.org and www.sciencedirect.com Downloaded from ClinicalKey.com at Maimonides Medical Center - JC September 22, 2016. For personal use only. No other uses without permission. Copyright ©2016. Elsevier Inc. All rights reserved.