Methods for pragmatic randomized clinical trials of pain therapies: IMMPACT statement.

ABSTRACT: Pragmatic, randomized, controlled trials hold the potential to directly inform clinical decision making and health policy regarding the treatment of people experiencing pain. Pragmatic trials are designed to replicate or are embedded within routine clinical care and are increasingly valued to bridge the gap between trial research and clinical practice, especially in multidimensional conditions, such as pain and in nonpharmacological intervention research. To maximize the potential of pragmatic trials in pain research, the careful consideration of each methodological decision is required. Trials aligned with routine practice pose several challenges, such as determining and enrolling appropriate study participants, deciding on the appropriate level of flexibility in treatment delivery, integrating information on concomitant treatments and adherence, and choosing comparator conditions and outcome measures. Ensuring data quality in real-world clinical settings is another challenging goal. Furthermore, current trials in the field would benefit from analysis methods that allow for a differentiated understanding of effects across patient subgroups and improved reporting of methods and context, which is required to assess the generalizability of findings. At the same time, a range of novel methodological approaches provide opportunities for enhanced efficiency and relevance of pragmatic trials to stakeholders and clinical decision making. In this study, best-practice considerations for these and other concerns in pragmatic trials of pain treatments are offered and a number of promising solutions discussed. The basis of these recommendations was an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) meeting organized by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks.

Pains Revisited.

OBJECTIVES: The management of pain patients has not evolved as rapidly as envisioned when IASP was founded almost 50 years ago. We sought to identify factors that could contribute to this situation, with a focus on concepts of pain and the education of pain physicians. METHODS: Relevant literature describing new strategies for diagnosing and managing patients with high-impact chronic pain was reviewed. RESULTS: It appears that the acute-chronic dichotomy has outlived its usefulness and pains should be identified as of peripheral origin or due to central processing errors. Pains of peripheral origin and those of central processing errors require different diagnostic and therapeutic strategies. DISCUSSION: Peripheral treatments and opioids are not effective for central pains. When the cause of the pain lies in the central nervous system, a more centrally focused approach is needed to minimize wasteful pursuit of peripheral causes. The education and training of pain physicians should reflect the skills needed to address these 2 very different clinical problems.

Moving forward with pain: an interview with John D Loeser.

John D Loeser speaks to Thomas York, Journal Development Editor of Pain Management. John D Loeser is Professor, emeritus, of Neurological Surgery and Anesthesiology and Pain Medicine at the University of Washington where he has been a faculty member since 1969. He was the Director of the Multidisciplinary Pain Center at the University of Washington from 1983 to 1997. He has been active in research, teaching and patient care in the field of Pain Management for over 45 years. He was a founding member and served as president of the American Pain Society and the International Association for the Study of Pain. He has authored or co-authored over 400 peer-reviewed articles, 129 book chapters and 8 books. He is particularly interested in multidisciplinary pain management and the development of rational strategies for the treatment of patients with chronic pain.

Future perspectives: the next fifty years of the International Association for the Study of Pain.

ABSTRACT: The International Association for the Study of Pain (IASP) has become the leading professional association dedicated to promoting pain research and management. Through its many activities, including research funding, educational programs, advocacy initiatives, and global collaborations, the Association has significantly contributed to the understanding and treatment of pain. Looking into the future, the IASP is determined to continue its mission of reducing the burden of pain on individuals and societies worldwide. Here, we explore how current and past activities of the IASP will shape the future of pain research, treatment, education, and advocacy as well as provide a valuable service to its members across the world.

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

ABSTRACT: 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.

Multidisciplinary Pain Management: A Tale of Two Outcomes.

Economic implications of pain management. By Loeser JD. Acta Anaesthesiol Scand 1999; 43:957-95. Reprinted with permission. Multidisciplinary pain management was an invention of John J. Bonica, M.D. He started the Multidisciplinary Pain Clinic at the University of Washington in 1960. This clinical service evolved over the years, and when John Loeser, M.D., became its director in 1982, he collaborated with Bill Fordyce, Ph.D., to create what was known as "the structured program." The program has served as the model for pain treatment programs throughout the world, many of which have fared better than that at the University of Washington. The migration of Stephen Butler, M.D., to Uppsala, Sweden, in 2000 has given us the opportunity to contrast multidisciplinary pain management in the Nordic countries with that in the United States.

A new way of thinking about pains.

ABSTRACT: The traditional construct of acute pain vs chronic pain is arbitrary and obscures fundamental differences in clinical pain phenomena. A more powerful dichotomy between peripherally generated pain and centrally maintained pains can facilitate advances in both pain research and clinical care. We should abandon the temporally based pain classification scheme because it does not accurately reflect the underlying principles inherent in the phenomena of pain.

What are the Origins of Chronic Back Pain of "Obscure Origins"? Turning Toward Family and Workplace Social Contexts.

Chronic back pain (CBP) is a common symptom throughout the world, and those undergoing it often experience a profound degradation of life. Despite extensive research, it remains an elusive symptom. In most cases, CBP is "non-specific," since bio-mechanisms examined in the clinic do not account for it; another way of saying this is that it is "of obscure origins." This paper re-directs attention towards origins that are distal and usually out of sight from the vantage point of the clinic. CBP as considered here is non-specific, persists ≥ 3 months, and, additionally, interferes with activities of daily life, such as family interaction or work. A theory proposed in the paper draws upon Durkheim's Suicide to explain why exposures in the distal social contexts of family and workplace are fundamentally implicated in CBP. The theory is formed out of previously published studies on family and workplace social contexts of CBP and, in effect, provides a theoretical framework with which to review them. After treatment of CBP in the clinic, patients return to family and workplace contexts. Unless exposures in these contexts are addressed, they serve as continually renewing sources of CBP that remain unabated regardless of mechanism-based treatment in the clinic.

Persistent Spinal Pain Syndrome: A Proposal for Failed Back Surgery Syndrome and ICD-11.

OBJECTIVE: For many medical professionals dealing with patients with persistent pain following spine surgery, the term Failed back surgery syndrome (FBSS) as a diagnostic label is inadequate, misleading, and potentially troublesome. It misrepresents causation. Alternative terms have been suggested, but none has replaced FBSS. The International Association for the Study of Pain (IASP) published a revised classification of chronic pain, as part of the new International Classification of Diseases (ICD-11), which has been accepted by the World Health Organization (WHO). This includes the term Chronic pain after spinal surgery (CPSS), which is suggested as a replacement for FBSS. METHODS: This article provides arguments and rationale for a replacement definition. In order to propose a broadly applicable yet more precise and clinically informative term, an international group of experts was established. RESULTS: 14 candidate replacement terms were considered and ranked. The application of agreed criteria reduced this to a shortlist of four. A preferred option-Persistent spinal pain syndrome-was selected by a structured workshop and Delphi process. We provide rationale for using Persistent spinal pain syndrome and a schema for its incorporation into ICD-11. We propose the adoption of this term would strengthen the new ICD-11 classification. CONCLUSIONS: This project is important to those in the fields of pain management, spine surgery, and neuromodulation, as well as patients labeled with FBSS. Through a shift in perspective, it could facilitate the application of the new ICD-11 classification and allow clearer discussion among medical professionals, industry, funding organizations, academia, and the legal profession.

Research design considerations for randomized controlled trials of spinal cord stimulation for pain: Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials/Institute of Neuromodulation/International Neuromodulation Society recommendations.

ABSTRACT: Spinal cord stimulation (SCS) is an interventional nonpharmacologic treatment used for chronic pain and other indications. Methods for evaluating the safety and efficacy of SCS have evolved from uncontrolled and retrospective studies to prospective randomized controlled trials (RCTs). Although randomization overcomes certain types of bias, additional challenges to the validity of RCTs of SCS include blinding, choice of control groups, nonspecific effects of treatment variables (eg, paresthesia, device programming and recharging, psychological support, and rehabilitative techniques), and safety considerations. To address these challenges, 3 professional societies (Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials, Institute of Neuromodulation, and International Neuromodulation Society) convened a meeting to develop consensus recommendations on the design, conduct, analysis, and interpretation of RCTs of SCS for chronic pain. This article summarizes the results of this meeting. Highlights of our recommendations include disclosing all funding source and potential conflicts; incorporating mechanistic objectives when possible; avoiding noninferiority designs without internal demonstration of assay sensitivity; achieving and documenting double-blinding whenever possible; documenting investigator and site experience; keeping all information provided to patients balanced with respect to expectation of benefit; disclosing all information provided to patients, including verbal scripts; using placebo/sham controls when possible; capturing a complete set of outcome assessments; accounting for ancillary pharmacologic and nonpharmacologic treatments in a clear manner; providing a complete description of intended and actual programming interactions; making a prospective ascertainment of SCS-specific safety outcomes; training patients and researchers on appropriate expectations, outcome assessments, and other key aspects of study performance; and providing transparent and complete reporting of results according to applicable reporting guidelines.

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. PERSPECTIVE: An 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.

Evaluation of the Impact of an Online Opioid Education Program for Acute Pain Management.

OBJECTIVE: The University of Washington instituted a policy requiring all credentialed clinicians who prescribe opioids to complete a one-time education activity about safe and responsible opioid prescribing. A scenario-based, interactive online learning module was developed for opioid management of acute pain in hospitalized adults. This study examined the impact of the education module on learners' knowledge, perceived competence, and use of guideline-adherent practices. METHODS: Clinicians who completed the education module participated in a voluntary de-identified online survey approximately six months after the learning activity. Survey questions were related to 1) the perception of improved knowledge; 2) impact on learner's use of three guideline-adherent practices; and 3) perceived competence in managing opioids for acute pain. Descriptive statistics were generated, and multiple linear regression models were used for analysis. RESULTS: Clinicians (N = 167) reported improvement in knowledge and perceived competence. Controlling for other aspects of knowledge evaluated, learning to construct a safe opioid taper plan for acute pain, distinguishing between short- and long-acting opioids, and safely initiating opioids for acute pain were significantly associated with increased self-reported likelihood of incorporating the Washington state Prescription Monitoring Program (P = 0.003), using multimodal analgesia (P = 0.022), and reducing the duration of opioids prescribed (P = 0.016). Only improvement in knowledge of how to construct a safe opioid taper plan was significantly associated with increased perceived competence (P = 0.002). CONCLUSIONS: Our findings suggest that this online education module about safe opioid prescribing for acute pain management was effective at improving knowledge, increasing the likelihood of using guideline-adherent clinical practices, and increasing perceived competence.

Intense Focused Ultrasound Preferentially Stimulates Transected Nerves Within Residual Limbs: Pilot Study.

Objective: Identifying pain generators in tissue deep in the skin can require uncomfortable, complicated, and invasive tests. We describe pilot studies testing the hypothesis that ultrasound image-guided, intense focused ultrasound (ig-iFU) can noninvasively and differentially stimulate the end of transected nerves in the residual limbs of amputee patients. Design: We applied iFU to the transected nerve ending as individual pulses with a length of 0.1 seconds using a carrier frequency of 2.0 MHz. After targeting, we gradually increased the iFU intensity to reach consistent patient-reported stimulation of the transected nerve ending. We also stimulated the proximal nerve, tissue near the nerve ending, and the intact contralateral nerve. We described the resulting sensations and correlated the results of the study participant's pre-iFU study responses to phantom and residual limb pain questionnaires. Results: iFU spatial and temporal average intensity values between 16 W/cm2 and 433 W/cm2 that were applied to the transected nerve ending and proximal nerve elicited sensations, including phantom limb sensations, while the same intensity applied to control tissue centimeters away from the nerve ending, or to the intact nerve on the contralateral limb, did not. Two out of 11 study participants reported only mild and transient pain created by iFU stimulation. Successful iFU intensity values correlated with neither phantom nor residual limb pain scores. Conclusions: Transected nerves had greater sensitivity to iFU stimulation than ipsilateral and contralateral control tissue, including intact nerve. These results support the view that ig-iFU may one day help physicians identify deep, tender tissue in patients who report experiencing pain.

Exploring Unorthodox Dimensions for Two-Electron Atoms.

Melding quantum and classical mechanics is an abiding quest of physical chemists who strive for heuristic insights and useful tools. We present a surprisingly simple and accurate treatment of ground-state two-electron atoms. It makes use of only the dimensional dependence of a hydrogen atom, together with the exactly known first-order perturbation value of the electron-electron interaction, both quintessentially quantum, and the D → ∞ limit, entirely classical. The result is an analytic formula for D-dimensional two-electron atoms with Z ≥ 2. For D = 3 helium, it gives accuracy better than 2 millihartrees, which is better than current density functional theory. A kindred explicit formula for correlation energy exploits interpolation between D → ∞ and D = 1 or 2; when added to the Hartree-Fock energy, it improves accuracy for D = 3 helium to better than 0.1 millihartrees.

AAPT Diagnostic Criteria for Central Neuropathic Pain.

Central neuropathic pain, which is pain caused by a lesion or disease of the central somatosensory nervous system, is a serious consequence of spinal cord injury, stroke, multiple sclerosis, and other conditions affecting the central nervous system. A collaborative effort between the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks public-private partnership and the American Pain Society, the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks-American Pain Society Pain Taxonomy (AAPT) initiative, invited a working group to develop diagnostic criteria for central neuropathic pain. The criteria for central neuropathic pain that were developed expand upon existing criteria for neuropathic pain and the International Classification of Diseases 11th Revision draft criteria to ensure consistency. This article focuses on central neuropathic pain associated with spinal cord injury, stroke, and multiple sclerosis, but the AAPT framework can be extended to central pain due to other causes such as traumatic brain injury. The classification of central neuropathic pain 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. PERSPECTIVE: The AAPT chronic central neuropathic pain taxonomy provides a classification for central pain associated with spinal cord injury, stroke, and multiple sclerosis. The diagnostic criteria are 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.