Addiction Clinical Trial Translations, Innovations, Opportunities, And Networks Research Articles

Research objectives and general considerations for pragmatic clinical trials of pain treatments: IMMPACT statement.

Many questions regarding the clinical management of people experiencing pain and related health policy decision-making may best be answered by pragmatic controlled trials. To generate clinically relevant and widely applicable findings, such trials aim to reproduce elements of routine clinical care or are embedded within clinical workflows. In contrast with traditional efficacy trials, pragmatic trials are intended to address a broader set of external validity questions critical for stakeholders (clinicians, healthcare leaders, policymakers, insurers, and patients) in considering the adoption and use of evidence-based treatments in daily clinical care. This article summarizes methodological considerations for pragmatic trials, mainly concerning methods of fundamental importance to the internal validity of trials. The relationship between these methods and common pragmatic trials methods and goals is considered, recognizing that the resulting trial designs are highly dependent on the specific research question under investigation. The basis of this statement was an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) systematic review of methods and a consensus meeting. The meeting was organized by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership. The consensus process was informed by expert presentations, panel and consensus discussions, and a preparatory systematic review. In the context of pragmatic trials of pain treatments, we present fundamental considerations for the planning phase of pragmatic trials, including the specification of trial objectives, the selection of adequate designs, and methods to enhance internal validity while maintaining the ability to answer pragmatic research questions.

Consider new options for treating OUD in designing trials

Although there are already three approved medications to treat opioid use disorder (OUD) — methadone, buprenorphine, and naltrexone — “novel treatments” are needed, according to a review published this month in JAMA Psychiatry. Partly because of long‐standing barriers to treatment with methadone and buprenorphine, the review looked at possible treatments that go “beyond the endogenous mu‐opioid receptor [MOR] system. For the review, a public–private partnership including members of the federal Food and Drug Administration (FDA) and the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) group met to look at potential treatments for OUD, including cannabinoids, psychedelics, sedative‐hypnotics and vaccines. The consensus recommendations for clinical trial design included targeting the stage of treatment (e.g., seeking treatment, early abstinence, long‐term recovery), looking at the role of treatment, looking at primary outcomes informed by patient preferences, and considering adverse events, including the potential for relapse or overdose in the case of relapse. The study, “Clinical Trial Design Challenges and Opportunities for Emerging Treatments for Opioid Use Disorder,” is by Brian D. Kulik, Ph.D., and colleagues, and funded by the ACTTION public–private partnership with the FDA.

AAAPT: Assessment of the Acute Pain Trajectory.

ObjectiveDefine and contrast acute pain trajectories vs. the aggregate pain measurements, summarize appropriate linear and nonlinear statistical analyses for pain trajectories at the patient level, and present methods to classify individual pain trajectories. Clinical applications of acute pain trajectories are also discussed.SettingIn 2016, an expert panel involving the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION), American Pain Society (APS), and American Academy of Pain Medicine (AAPM) established an initiative to create a pain taxonomy, named the ACTTION-APS-AAPM Pain Taxonomy (AAAPT), for the multidimensional classification of acute pain. The AAAPT panel commissioned the present report to provide further details on analysis of the individual acute pain trajectory as an important component of comprehensive pain assessment.MethodsLinear mixed models and nonlinear models (e.g., regression splines and polynomial models) can be applied to analyze the acute pain trajectory. Alternatively, methods for classifying individual pain trajectories (e.g., using the 50% confidence interval of the random slope approach or using latent class analyses) can be applied in the clinical context to identify different trajectories of resolving pain (e.g., rapid reduction or slow reduction) or persisting pain. Each approach has advantages and disadvantages that may guide selection. Assessment of the acute pain trajectory may guide treatment and tailoring to anticipated symptom recovery. The acute pain trajectory can also serve as a treatment outcome measure, informing further management.ConclusionsApplication of trajectory approaches to acute pain assessments enables more comprehensive measurement of acute pain, which forms the cornerstone of accurate classification and treatment of pain.

AAAPT Diagnostic Criteria for Acute Neuropathic Pain.

Acute neuropathic pain is a significant diagnostic challenge, and it is closely related to our understanding of both acute pain and neuropathic pain. Diagnostic criteria for acute neuropathic pain should reflect our mechanistic understanding and provide a framework for research on and treatment of these complex pain conditions. The Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership with the U.S. Food and Drug Administration (FDA), the American Pain Society (APS), and the American Academy of Pain Medicine (AAPM) collaborated to develop the ACTTION-APS-AAPM Pain Taxonomy (AAAPT) for acute pain. A working group of experts in research and clinical management of neuropathic pain was convened. Group members used literature review and expert opinion to develop diagnostic criteria for acute neuropathic pain, as well as three specific examples of acute neuropathic pain conditions, using the five dimensions of the AAAPT classification of acute pain. AAAPT diagnostic criteria for acute neuropathic pain are presented. Application of these criteria to three specific conditions (pain related to herpes zoster, chemotherapy, and limb amputation) illustrates the spectrum of acute neuropathic pain and highlights unique features of each condition. The proposed AAAPT diagnostic criteria for acute neuropathic pain can be applied to various acute neuropathic pain conditions. Both the general and condition-specific criteria may guide future research, assessment, and management of acute neuropathic pain.

Idiopathic distal sensory polyneuropathy: ACTTION diagnostic criteria.

To present standardized diagnostic criteria for idiopathic distal sensory polyneuropathy (iDSP) and its subtypes: idiopathic mixed fiber sensory neuropathy (iMFN), idiopathic small fiber sensory neuropathy (iSFN), and idiopathic large fiber sensory neuropathy (iLFN) for use in research. The Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities and Networks (ACTTION) public-private partnership with the Food and Drug Administration convened a meeting to develop consensus diagnostic criteria for iMFN, iSFN, and iLFN. After background presentations, a collaborative, iterative approach was used to develop expert consensus for new criteria. An iDSP diagnosis requires at least 1 small fiber (SF) or large fiber (LF) symptom, at least 1 SF or LF sign, abnormalities in sensory nerve conduction studies (NCS) or distal intraepidermal nerve fiber density (IENFD), and exclusion of known etiologies. An iMFN diagnosis requires that at least 1 of the above clinical features is SF and 1 clinical feature is LF with abnormalities in sensory NCS or IENFD. Diagnostic criteria for iSFN require at least 1 SF symptom and at least 1 SF sign with abnormal IENFD, normal sensory NCS, and the absence of LF symptoms and signs. Diagnostic criteria for iLFN require at least 1 LF symptom and at least 1 LF sign with normal IENFD, abnormal sensory NCS, and absence of SF symptoms and signs. Adoption of these standardized diagnostic criteria will advance research and clinical trials and spur development of novel therapies for iDSPs.

Comment on: Diagnosis of fibromyalgia: comparison of the 2011/2016 ACR and AAPT criteria and validation of the modified Fibromyalgia Assessment Status: reply.

OBJECTIVE To compare the concordance of the three diagnostic criteria, respectively the 2011 ACR criteria (ACR 2011 Cr), the ACR 2016 criteria (ACR 2016 Cr) and the Analgesic, Anesthetic, and Addiction Clinical Trial Translations Innovations Opportunities and Networks (ACTTION)-APS Pain Taxonomy criteria (AAPT Cr), and to explore the performance of an additional set of criteria, the modified Fibromyalgia Assessment Status (FAS 2019 modCr), in the diagnosis of FM syndrome. METHODS Consecutive patients with chronic widespread pain, referred by the primary care setting, underwent rheumatologic assessment that established the presence or not of FM and were investigated through the four sets of proposed criteria. For the FAS 2019 modCr, discriminant validity to distinguish patients with FM and non-FM was assessed with receiver operating characteristic curve analysis. RESULTS A total of 732 (405 with FM and 327 with other common chronic pain problems) patients were evaluated. Against the clinical diagnosis of FM, the sensitivity, specificity and correct classification were, respectively: 79.8, 91.7 and 85.1% for ACR 2011 Cr; 78, 90.5 and 83.6% for the ACR 2016 Cr; and 73.8, 91.7 and 81.8% for the AAPT Cr. The alternative set, proposed on the FAS 2019 modCr, provided a maximal diagnostic accuracy with a score ≥20 (Youden's index), with a sensitivity of 84.2%, specificity 89.0% and positive likelihood ratio 7.65. CONCLUSION There is a considerable agreement between criteria-based diagnoses of FM, although the AAPT Cr perform least well in terms of percentage of correct classification. The FAS 2019 modCr had comparable characteristics.

AAPT Diagnostic Criteria for Chronic Low Back Pain

Chronic low back pain (CLBP) conditions are highly prevalent and constitute the leading cause of disability worldwide. The Analgesic, Anesthetic, and Addiction Clinical Trial Translations Innovations Opportunities and Networks (ACTTION) public-private partnership with the US Food and Drug Administration and the American Pain Society (APS), have combined to create the ACTTION-APS Pain Taxonomy (AAPT). The AAPT initiative convened a working group to develop diagnostic criteria for CLBP. The working group identified 3 distinct low back pain conditions which result in a vast public health burden across the lifespan. This article focuses on: 1) the axial predominant syndrome of chronic musculoskeletal low back pain, 2) the lateralized, distally-radiating syndrome of chronic lumbosacral radicular pain 3) and neurogenic claudication associated with lumbar spinal stenosis. This classification of CLBP is organized according to the AAPT multidimensional framework, specifically 1) core diagnostic criteria; 2) common features; 3) common medical and psychiatric comorbidities; 4) neurobiological, psychosocial, and functional consequences; and 5) putative neurobiological and psychosocial mechanisms, risk factors, and protective factors. PerspectiveAn evidence-based classification of CLBP conditions was constructed for the AAPT initiative. This multidimensional diagnostic framework includes: 1) core diagnostic criteria; 2) common features; 3) medical and psychiatric comorbidities; 4) neurobiological, psychosocial, and functional consequences; and 5) putative neurobiological and psychosocial mechanisms, risk factors, and protective factors.

AAAPT Diagnostic Criteria for Acute Knee Arthroplasty Pain.

The relationship between preexisting osteoarthritic pain and subsequent post-total knee arthroplasty (TKA) pain is not well defined. This knowledge gap makes diagnosis of post-TKA pain and development of management plans difficult and may impair future investigations on personalized care. Therefore, a set of diagnostic criteria for identification of acute post-TKA pain would inform standardized management and facilitate future research. The Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership with the US Food and Drug Administration (FDA), the American Pain Society (APS), and the American Academy of Pain Medicine (AAPM) formed the ACTTION-APS-AAPM Pain Taxonomy (AAAPT) initiative to address this goal. A multidisciplinary work group of pain experts was invited to conceive diagnostic criteria and dimensions of acute post-TKA pain. The working group used contemporary literature combined with expert opinion to generate a five-dimensional taxonomical structure based upon the AAAPT framework (i.e., core diagnostic criteria, common features, modulating factors, impact/functional consequences, and putative mechanisms) that characterizes acute post-TKA pain. The diagnostic criteria created are proposed to define the nature of acute pain observed in patients following TKA.

The ACTTION Guide to Clinical Trials of Pain Treatments: standing on the shoulders of giants.

The ACTTION Guide to Clinical Trials of Pain Treatments: standing on the shoulders of giants.

AAPT Diagnostic Criteria for Peripheral Neuropathic Pain: Focal and Segmental Disorders

Peripheral neuropathic pain is among the most prevalent types of neuropathic pain. No comprehensive peripheral neuropathic pain classification system that incorporates contemporary clinical, diagnostic, biological, and psychological information exists. To address this need, this article covers the taxonomy for 4 focal or segmental peripheral neuropathic pain disorders, as part of the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership and the American Pain Society (APS) collaborative to develop a standardized, evidence-based taxonomy initiative: the ACTTION-APS Pain Taxonomy (AAPT). The disorders—postherpetic neuralgia, persistent posttraumatic neuropathic pain, complex regional pain disorder, and trigeminal neuralgia—were selected because of their clinical and clinical research relevance. The multidimensional features of the taxonomy are suitable for clinical trials and can also facilitate hypothesis-driven case-control and cohort epidemiologic studies. PerspectiveThe AAPT peripheral neuropathic pain taxonomy subdivides the peripheral neuropathic pain disorders into those that are generalized and symmetric and those that are focal or segmental and asymmetric. In this article, we cover the focal and segmental disorders: postherpetic neuralgia, persistent posttraumatic neuropathic pain, complex regional pain disorder, and trigeminal neuralgia. The taxonomy is evidence-based and multidimensional, with the following dimensions: 1) core diagnostic criteria; 2) common features; 3) common medical and psychiatric comorbidities; 4) neurobiological, psychosocial, and functional consequences; and 5) putative neurobiological and psychosocial mechanisms, risk factors, and protective factors.

Trial designs for chemotherapy-induced peripheral neuropathy prevention

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and potentially dose-limiting side effect of neurotoxic chemotherapies. No therapies are available to prevent CIPN. The small number of positive randomized clinical trials (RCTs) evaluating preventive therapies for CIPN provide little guidance to inform the design of future trials. Moreover, the lack of consensus regarding major design features in this area poses challenges to development of new therapies. An Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities and Networks (ACTTION)-Consortium on Clinical Endpoints and Procedures for Peripheral Neuropathy Trials (CONCEPPT) meeting attended by neurologists, oncologists, pharmacists, clinical trialists, statisticians, and regulatory experts was convened to discuss design considerations and provide recommendations for CIPN prevention trials. This article outlines considerations related to design of RCTs that evaluate preventive therapies for CIPN including (1) selection of eligibility criteria (e.g., cancer types, chemotherapy types, inclusion of preexisting neuropathy); (2) selection of outcome measures and endpoints, including those that incorporate alterations in chemotherapy dosing, which may affect the rate of CIPN development and its severity; (3) potential effects of the investigational therapy on the efficacy of chemotherapy; and (4) sample size estimation. Our hope is that attention to the design considerations and recommendations outlined in this article will improve the quality and assay sensitivity of CIPN prevention trials and thereby accelerate the identification of efficacious therapies.

Clinical trial designs and models for analgesic medications for acute pain in neonates, infants, toddlers, children, and adolescents: ACTTION recommendations.

Clinical trials to test the safety and efficacy of analgesics across all pediatric age cohorts are needed to avoid inappropriate extrapolation of adult data to children. However, the selection of acute pain models and trial design attributes to maximize assay sensitivity, by pediatric age cohort, remains problematic. Acute pain models used for drug treatment trials in adults are not directly applicable to the pediatric age cohorts-neonates, infants, toddlers, children, and adolescents. Developmental maturation of metabolic enzymes in infants and children must be taken into consideration when designing trials to test analgesic treatments for acute pain. Assessment tools based on the levels of cognitive maturation and behavioral repertoire must be selected as outcome measures. Models and designs of clinical trials of analgesic medications used in the treatment of acute pain in neonates, infants, toddlers, children, and adolescents were reviewed and discussed at an Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) Pediatric Pain Research Consortium consensus meeting. Based on extensive reviews and continuing discussions, the authors recommend a number of acute pain clinical trial models and design attributes that have the potential to improve the study of analgesic medications in pediatric populations. Recommendations are also provided regarding additional research needed to support the use of other acute pain models across pediatric age cohorts.

The ACTTION-APS-AAPM Pain Taxonomy (AAAPT) Multidimensional Approach to Classifying Acute Pain Conditions.

With the increasing societal awareness of the prevalence and impact of acute pain, there is a need to develop an acute pain classification system that both reflects contemporary mechanistic insights and helps guide future research and treatment. Existing classifications of acute pain conditions are limiting, with a predominant focus on the sensory experience (eg, pain intensity) and pharmacologic consumption. Consequently, there is a need to more broadly characterize and classify the multidimensional experience of acute pain. Consensus report following expert panel involving the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION), American Pain Society (APS), and American Academy of Pain Medicine (AAPM). As a complement to a taxonomy recently developed for chronic pain, the ACTTION public-private partnership with the US Food and Drug Administration, the APS, and the AAPM convened a consensus meeting of experts to develop an acute pain taxonomy using prevailing evidence. Key issues pertaining to the distinct nature of acute pain are presented followed by the agreed-upon taxonomy. The ACTTION-APS-AAPM Acute Pain Taxonomy will include the following dimensions: 1) core criteria, 2) common features, 3) modulating factors, 4) impact/functional consequences, and 5) putative pathophysiologic pain mechanisms. Future efforts will consist of working groups utilizing this taxonomy to develop diagnostic criteria for a comprehensive set of acute pain conditions. The ACTTION-APS-AAPM Acute Pain Taxonomy (AAAPT) is a multidimensional acute pain classification system designed to classify acute pain along the following dimensions: 1) core criteria, 2) common features, 3) modulating factors, 4) impact/functional consequences, and 5) putative pathophysiologic pain mechanisms. Significant numbers of patients still suffer from significant acute pain, despite the advent of modern multimodal analgesic strategies. Mismanaged acute pain has a broad societal impact as significant numbers of patients may progress to suffer from chronic pain. An acute pain taxonomy provides a much-needed standardization of clinical diagnostic criteria, which benefits clinical care, research, education, and public policy. For the purposes of the present taxonomy, acute pain is considered to last up to seven days, with prolongation to 30days being common. The current understanding of acute pain mechanisms poorly differentiates between acute and chronic pain and is often insufficient to distinguish among many types of acute pain conditions. Given the usefulness of the AAPT multidimensional framework, the AAAPT undertook a similar approach to organizing various acute pain conditions.

The ACTTION-APS-AAPM Pain Taxonomy (AAAPT) Multidimensional Approach to Classifying Acute Pain Conditions.

Objective. With the increasing societal awareness of the prevalence and impact of acute pain, there is a need to develop an acute pain classification system that both reflects contemporary mechanistic insights and helps guide future research and treatment. Existing classifications of acute pain conditions are limiting, with a predominant focus on the sensory experience (e.g., pain intensity) and pharmacologic consumption. Consequently, there is a need to more broadly characterize and classify the multidimensional experience of acute pain. Setting. Consensus report following expert panel involving the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION), American Pain Society (APS), and American Academy of Pain Medicine (AAPM). Methods. As a complement to a taxonomy recently developed for chronic pain, the ACTTION public-private partnership with the US Food and Drug Administration, the APS, and the AAPM convened a consensus meeting of experts to develop an acute pain taxonomy using prevailing evidence. Key issues pertaining to the distinct nature of acute pain are presented followed by the agreed-upon taxonomy. The ACTTION-APS-AAPM Acute Pain Taxonomy will include the following dimensions: 1) core criteria, 2) common features, 3) modulating factors, 4) impact/functional consequences, and 5) putative pathophysiologic pain mechanisms. Future efforts will consist of working groups utilizing this taxonomy to develop diagnostic criteria for a comprehensive set of acute pain conditions. Perspective. The ACTTION-APS-AAPM Acute Pain Taxonomy (AAAPT) is a multidimensional acute pain classification system designed to classify acute pain along the following dimensions: 1) core criteria, 2) common features, 3) modulating factors, 4) impact/functional consequences, and 5) putative pathophysiologic pain mechanisms. Conclusions. Significant numbers of patients still suffer from significant acute pain, despite the advent of modern multimodal analgesic strategies. Mismanaged acute pain has a broad societal impact as significant numbers of patients may progress to suffer from chronic pain. An acute pain taxonomy provides a much-needed standardization of clinical diagnostic criteria, which benefits clinical care, research, education, and public policy. For the purposes of the present taxonomy, acute pain is considered to last up to seven days, with prolongation to 30 days being common. The current understanding of acute pain mechanisms poorly differentiates between acute and chronic pain and is often insufficient to distinguish among many types of acute pain conditions. Given the usefulness of the AAPT multidimensional framework, the AAAPT undertook a similar approach to organizing various acute pain conditions.

Mechanisms for Research Support.

During the second day of the Pediatric Anesthesia NeuroDevelopment Assessment (PANDA) symposium 2016, 3 invited speakers focused on future directions for the PANDA group. This session, entitled "The Way Forward," included 3 talks on how other groups have organized through public-private partnerships (ACTTION), obtained NIH funding, and how to better communicate a research message. Dr Robert H. Dworkin spoke on the mission of the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities and Networks (ACTTION), which is a public-private partnership with the United States Food and Drug Administration that pushes forward research related to pain and analgesics. Dr Tracy King discussed National Institute of Health funding for future studies in neurocognitive development after exposure to anesthetics. Dr Sharon Hertz discussed how the PANDA group might better craft their message to the public regarding effects of analgesics on neurocognitive development. Through their talks, the above speakers provided a clear route for the way forward in regard to research, funding, and messaging for the PANDA group.

The Role of Psychosocial Processes in the Development and Maintenance of Chronic Pain.

The recently proposed Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION)-American Pain Society (APS) Pain Taxonomy (AAPT) provides an evidence-based, multidimensional, chronic pain classification system. Psychosocial factors play a crucial role within several dimensions of the taxonomy. In this article, we discuss the evaluation of psychosocial factors that influence the diagnosis and trajectory of chronic pain disorders. We review studies in individuals with a variety of persistent pain conditions, and describe evidence that psychosocial variables play key roles in conferring risk for the development of pain, in shaping long-term pain-related adjustment, and in modulating pain treatment outcomes. We consider "general" psychosocial variables such as negative affect, childhood trauma, and social support, as well as "pain-specific" psychosocial variables that include pain-related catastrophizing, self-efficacy for managing pain, and pain-related coping. Collectively, the complexity and profound variability in chronic pain highlights the need to better understand the multidimensional array of interacting forces that determine the trajectory of chronic pain conditions. The AAPT is an evidence-based chronic pain classification system in which psychosocial concepts and processes are essential in understanding the development of chronic pain and its effects. In this article we review psychosocial processes that influence the onset, exacerbation, and maintenance of chronic pain disorders.

Assessment of Psychosocial and Functional Impact of Chronic Pain.

The psychosocial and functional consequences of chronic pain disorders have been well documented as having significant effects on the experience of pain, presentation to health care providers, responsiveness to and participation in treatment, disability, and health-related quality of life. Thus, psychosocial and functional consequences have been incorporated as 1 of the 5 dimensions within the integrated Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION)-American Pain Society (APS) Pain Taxonomy (AAPT): 1) core diagnostic criteria; 2) common features; 3)common medical comorbidities; 4) neurobiological, psychosocial, and functional consequences; and 5) putative neurobiological and psychosocial mechanisms, risk factors, and protective factors. In this article we review the rationale for a biopsychosocial perspective, on the basis of current evidence, and describe a set of key psychosocial and behavioral factors (eg, mood/affect, coping resources, expectations, sleep quality, physical function, and pain-related interference with daily activities) that are important consequences of persistent pain and that should be considered when classifying patients within the comprehensive AAPT chronic pain structure. We include an overview of measures and procedures that have been developed to assess this set of factors and that can be used as part of the comprehensive assessment and classification of pain and to address specific research questions. Psychosocial and functional consequences are important considerations in the classification of individuals with chronic pain. A set of key psychosocial and behavioral factors (eg,mood/affect, coping resources, expectations, sleep quality, physical function, and pain-related interference with daily activities) that should be considered when classifying patients within the comprehensive classification of chronic pain disorders developed by the AAPT are outlined and examples of assessment methods for each are described.

Toward a Mechanism-Based Approach to Pain Diagnosis.

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 pathological 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 clinically. 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 20years 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 mechanistic 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 mechanisms 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 management 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, Anesthetic, 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. We discuss how identifying the specific mechanisms that operate in the nervous system 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.

Multidimensional Diagnostic Criteria for Chronic Pain: Introduction to the ACTTION-American Pain Society Pain Taxonomy (AAPT).

A variety of approaches have been used to develop diagnostic criteria for chronic pain. The published evidence of the reliability and validity of existing diagnostic criteria is limited, and these criteria have typically not been used in clinical practice. The availability of a widely accepted, consistently applied, and evidence-based taxonomy of diagnostic criteria would improve the quality of clinical research on chronic pain and would be of great value in clinical practice. To address the need for evidence-based diagnostic criteria for the major chronic pain conditions, the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership with the US Food and Drug Administration and the American Pain Society (APS) have collaborated on the development of the ACTTION-APS Pain Taxonomy (AAPT). AAPT provides a multidimensional framework that is applied systematically in the development of diagnostic criteria. This article (1) describes the background and rationale for AAPT; (2) presents the AAPT taxonomy and the specific conditions for which diagnostic criteria have been developed (to be published separately); (3) briefly reviews the 5 dimensions that constitute the AAPT multidimensional framework and describes the 7 accompanying articles that discuss these dimensions and other important issues involving AAPT; and (4) provides an overview of next steps, specifically, the general processes by which the initial set of diagnostic criteria (for which the evidence base has been drawn from the literature, systematic reviews, and secondary analyses of existing databases) will undergo additional assessments of reliability and validity. To address the need for evidence-based diagnostic criteria for the major chronic pain conditions, the AAPT provides a multidimensional framework that is applied systematically in the development of diagnostic criteria. The long-term objective of AAPT is to advance the scientific understanding of chronic pain and its treatment.

Adverse Event Reporting in Clinical Trials of Intravenous and Invasive Pain Treatments: An ACTTION Systematic Review.

This systematic review of AE reporting in intravenous and invasive pain treatment trials shows that little improvement has been made since the 2004 CONSORT harms reporting guidelines. Better assessment and reporting of treatment AEs is necessary to understand the full clinical effect of intravenous and invasive treatments.