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Classification of musculoskeletal pain based on underlying pain mechanisms (nociceptive, neuropathic, and nociplastic pain) is challenging. In the absence of a gold standard, verification of features that could aid in discrimination between these mechanisms in clinical practice and research depends on expert consensus. This Delphi expert consensus study aimed to: (1) identify features and assessment findings that are unique to a pain mechanism category or shared between no more than 2 categories and (2) develop a ranked list of candidate features that could potentially discriminate between pain mechanisms. A group of international experts were recruited based on their expertise in the field of pain. The Delphi process involved 2 rounds: round 1 assessed expert opinion on features that are unique to a pain mechanism category or shared between 2 (based on a 40% agreement threshold); and round 2 reviewed features that failed to reach consensus, evaluated additional features, and considered wording changes. Forty-nine international experts representing a wide range of disciplines participated. Consensus was reached for 196 of 292 features presented to the panel (clinical examination-134 features, quantitative sensory testing-34, imaging and diagnostic testing-14, and pain-type questionnaires-14). From the 196 features, consensus was reached for 76 features as unique to nociceptive (17), neuropathic (37), or nociplastic (22) pain mechanisms and 120 features as shared between pairs of pain mechanism categories (78 for neuropathic and nociplastic pain). This consensus study generated a list of potential candidate features that are likely to aid in discrimination between types of musculoskeletal pain.

We conducted a literature search to identify and compare definitions of the experiential dimension of spiritual pain. Key databases were searched, up to the year 2021 inclusive, for papers with a definition of "spiritual" or "existential" pain/distress in a clinical setting. Of 144 hits, seven papers provided theoretical definitions/descriptions; none incorporated clinical observations or underlying pathophysiological constructs. Based on these findings, we propose a new definition for "spiritual pain" as a "self-identified experience of personal discomfort, or actual or potential harm, triggered by a threat to a person's relationship with God or a higher power." Our updated definition can inform future studies in pain assessment and management.

The current International Association for the Study of Pain (IASP) definition of pain as "An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage" was recommended by the Subcommittee on Taxonomy and adopted by the IASP Council in 1979. This definition has become accepted widely by health care professionals and researchers in the pain field and adopted by several professional, governmental, and nongovernmental organizations, including the World Health Organization. In recent years, some in the field have reasoned that advances in our understanding of pain warrant a reevaluation of the definition and have proposed modifications. Therefore, in 2018, the IASP formed a 14-member, multinational Presidential Task Force comprising individuals with broad expertise in clinical and basic science related to pain, to evaluate the current definition and accompanying note and recommend whether they should be retained or changed. This review provides a synopsis of the critical concepts, the analysis of comments from the IASP membership and public, and the committee's final recommendations for revisions to the definition and notes, which were discussed over a 2-year period. The task force ultimately recommended that the definition of pain be revised to "An unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage," and that the accompanying notes be updated to a bulleted list that included the etymology. The revised definition and notes were unanimously accepted by the IASP Council early this year.

The estimated probability of progressing from phase 3 analgesic clinical trials to regulatory approval is approximately 57%, suggesting that a considerable number of treatments with phase 2 trial results deemed sufficiently successful to progress to phase 3 do not yield positive phase 3 results. Deficiencies in the quality of clinical trial conduct could account for some of this failure. An Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials meeting was convened to identify potential areas for improvement in trial conduct in order to improve assay sensitivity (ie, ability of trials to detect a true treatment effect). We present recommendations based on presentations and discussions at the meeting, literature reviews, and iterative revisions of this article. The recommendations relate to the following areas: 1) study design (ie, to promote feasibility), 2) site selection and staff training, 3) participant selection and training, 4) treatment adherence, 5) data collection, and 6) data and study monitoring. Implementation of these recommendations may improve the quality of clinical trial data and thus the validity and assay sensitivity of clinical trials. Future research regarding the effects of these strategies will help identify the most efficient use of resources for conducting high quality clinical trials. PERSPECTIVE: Every effort should be made to optimize the quality of clinical trial data. This manuscript discusses considerations to improve conduct of pain clinical trials based on research in multiple medical fields and the expert consensus of pain researchers and stakeholders from academia, regulatory agencies, and industry.

Background: Uncontrolled cancer pain is a significant problem in palliative medicine. Opioids are often first-line treatment that increase risks of analgesic tolerance and hyperalgesia. Topical ketamine with other adjuvant pain medications is an often-overlooked treatment, yet may be most effective in difficult-to-treat cancer pain. Objective: We report a case series of hospice patients with uncontrolled cancer pain who were suboptimally treated with opioids and nerve blocks, whose symptoms responded to topical ketamine with other adjuvants. We review the pronociceptive properties of opioids and how topical multimodal treatment of cancer pain can be more effective than standard opioids, other topical adjuvant medications, and nerve blocks. We discuss the shortcomings of the World Health Organization (WHO) stepladder for the treatment of cancer pain and suggest an adjuvant treatment algorithm, directing physicians to appropriate adjuvant pain agents based on pain type and distinct receptor actions. Design: This is a retrospective case series of patients who responded to topical multimodal pain treatment with implementation of findings into an addendum to the WHO stepladder. Subjects: Subjects were from a case series of community-based hospice patients with previously uncontrolled cancer pain. Measurement: Measurement was made by self-report of pain levels using the 10-point numeric pain rating scale. Results: Patients' pain was controlled with topical adjuvant medications with return to previously lost function and prevention of otherwise escalating opioid dosing. Conclusions: These patient cases reveal how ketamine-based topical treatment for cancer pain can be more effective than standard opioids, other topical adjuvant medications, and nerve blocks with no noted side effects and observed reduction in opioid consumption.

Large variability in the individual response to even the most-efficacious pain treatments is observed clinically, which has led to calls for a more personalized, tailored approach to treating patients with pain (i.e., "precision pain medicine"). Precision pain medicine, currently an aspirational goal, would consist of empirically-based algorithms that determine the optimal treatments, or treatment combinations, for specific patients (i.e., targeting the right treatment, in the right dose, to the right patient, at the right time). Answering this question of "what works for whom" will certainly improve the clinical care of patients with pain. It may also support the success of novel drug development in pain, making it easier to identify novel treatments that work for certain patients and more accurately identify the magnitude of the treatment effect for those subgroups. Significant preliminary work has been done in this area, and analgesic trials are beginning to utilize precision pain medicine approaches such as stratified allocation on the basis of pre-specified patient phenotypes using assessment methodologies such as quantitative sensory testing. Current major challenges within the field include: (1) identifying optimal measurement approaches to assessing patient characteristics that are most robustly and consistently predictive of inter-patient variation in specific analgesic treatment outcomes, (2) designing clinical trials that can identify treatment-by-phenotype interactions, and (3) selecting the most promising therapeutics to be tested in this way. This review surveys the current state of precision pain medicine, with a focus on drug treatments (which have been most-studied in a precision pain medicine context). It further presents a set of evidence-based recommendations for accelerating the application of precision pain methods in chronic pain research. PERSPECTIVE: : Given the considerable variability in treatment outcomes for chronic pain, progress in precision pain treatment is critical for the field. An array of phenotypes and mechanisms contribute to chronic pain; this review summarizes current knowledge regarding which treatments are most effective for patients with specific biopsychosocial characteristics.

To guide clinicians in balancing the risks and benefits of opioids when treating pain, we conducted two systematic reviews: 1) the impact of pain on cognitive function, and 2) the impact of opioids on cognitive function.Part one addressed the impact of pain on cognitive impairment; Part two considered the impact of opioids on cognitive impairment. PubMed was used to search for eligible articles. For part one, 1786 articles were identified, of which 23 met our eligibility criteria. For part two, among 584 articles, 18 were found eligible.For part one, 16 studies concluded that patients with chronic pain showed impaired cognitive function; six studies found that chronic pain does not worsen cognitive function; one study concluded that the impact of pain on cognitive function differs based on the underlying cognitive status. For part two, 15 studies found that using opioids to control pain did not cause significant cognitive impairment, while three studies concluded the opposite. Studies evaluating older subjects did not observe different results from those in the whole population for both reviews.The published literature indicates that moderate to severe pain can impair cognitive function, and that careful use of opioid analgesics in such subjects does not necessarily worsen cognition. Although our results are insufficient to support clear guidance due to heterogeneity of cohorts and outcomes, this study may assist primary care providers by rendering explicitly the factors to be considered by providers caring for this population with pain when opioids are considered.

ObjectiveFor 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.MethodsThis 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.Results14 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.ConclusionsThis 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.

Purpose Scoping reviews address the nature of the literature per se rather than inferring evidence-based treatment guidelines. Scoping reviews of the published literature are intended to describe the aggregated nature of the evidence surrounding some agent or intervention, in contrast to systematic reviews that seek when possible to guide clinical practice. We conducted a scoping review to identify reports of potential clinical utility of off-label topical analgesics and adjuvants when FDA-approved treatments have proven inadequate. Methods We performed a comprehensive search of three databases (PubMed, Web of Science and Embase) for articles dating from 1947 to the present. Mindful that FDA-approved and WHO-recommended analgesic medications often prove inadequate for individual patients in extremis with palliative, hospice or cancer pain, we used broad, structured inclusion criteria to retrieve articles. Results We retrieved 12,100 articles; after screening, we had 39 reports addressing 19 different topical agents out of the 32 chemical entities. Our scoping review disclosed evidence about agents that might not have met inclusion criteria for clinical practice guidelines. Discussion Although generally considered lower quality evidence, case reports or series present suggestions for diverse topical medications to manage pain in challenging circumstances when high-quality evidence for agents and routes of administration is lacking. Conclusion Patients with the greatest need for evidence to identify and guide lesser-used agents during aggressive pain management are the most difficult to enroll and follow in standardized, controlled and/or blinded clinical trials. This scoping review identifies medications, dosages, and routes of topical agents reported to be effective in these often-challenging circumstances. Until larger and higher quality studies are completed, we must rely on the best available evidence even if of lower quality.

Objective 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. Methods 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. Results 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. Conclusions 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.

There is tremendous interpatient variability in the response to analgesic therapy (even for efficacious treatments), which can be the source of great frustration in clinical practice. This has led to calls for “precision medicine” or personalized pain therapeutics (ie, empirically based algorithms that determine the optimal treatments, or treatment combinations, for individual patients) that would presumably improve both the clinical care of patients with pain and the success rates for putative analgesic drugs in phase 2 and 3 clinical trials. However, before implementing this approach, the characteristics of individual patients or subgroups of patients that increase or decrease the response to a specific treatment need to be identified. The challenge is to identify the measurable phenotypic characteristics of patients that are most predictive of individual variation in analgesic treatment outcomes, and the measurement tools that are best suited to evaluate these characteristics. In this article, we present evidence on the most promising of these phenotypic characteristics for use in future research, including psychosocial factors, symptom characteristics, sleep patterns, responses to noxious stimulation, endogenous pain-modulatory processes, and response to pharmacologic challenge. We provide evidence-based recommendations for core phenotyping domains and recommend measures of each domain.

Background Opioid-related harms are increasing among older adults. Until we better understand the factors contributing to this trend, we will be unable to design and implement effective interventions to optimally manage opioid use and its potential harms among older adults. Although considerable research has been done in younger or mixed-age populations, the degree to which it is directly applicable to older adults is uncertain. Objectives To provide a framework for understanding how to reduce adverse outcomes of opioid use among older adults, and to describe the evidence available for different factors associated with and interventions to reduce adverse outcomes related to opioid use in this population. Approach With input from a diverse panel of content experts and other stakeholders, we developed a conceptual framework and evidence map to characterize empirical studies of factors associated with opioid-related outcomes and interventions to reduce opioid-related harms in older adults. We identified relevant literature among older adults (age ≥60 years) for an evidence map by systematically searching PubMed, PsycINFO, and CINAHL for studies published in English between 2000 and May 6, 2020. Findings We identified 5,933 citations, from which we identified 41 studies with multivariable models of factors associated with opioid-related outcomes and 16 studies of interventions in older adults. More than half (22/41) of the multivariable analysis studies evaluated factors associated with long-term opioid use (which, though not a harm per se, may increase the risk of harms if not appropriately managed). Prior or early postoperative opioid use, or greater amounts of prescribed opioids (high number of opioid prescriptions or higher opioid dose), were consistently (100% agreement) and strongly (measure of association ≥2.0) associated with long-term opioid use. Back pain, depression, concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs), and fibromyalgia also had consistent, but weaker, associations with long-term opioid use. Several factors were mostly associated (>75% agreement) with long-term opioid use, including benzodiazepine use, comorbidity scores, (generally undefined) substance misuse, tobacco use, and low income. However, studies were mostly consistent that alcohol abuse and healthcare utilization were not associated with long-term opioid use. Gender, age among older adults, Black race, dementia, rural/nonurban residence, prescription of long-acting opioids, unmarried status, and use of muscle relaxants were variably associated ( Six studies examined factors associated with opioid-related disorders, although only one study evaluated factors associated with opioid use disorder. Alcohol misuse and gender were variably associated with opioid misuse (examined by three studies each). All other evaluations of specific pairs of associated factors and outcomes of interest were evaluated by only one or two studies each. These included analyses of factors associated with multiple opioid prescribers, mental health outcomes, physical health outcomes, all-cause hospitalization, opioid-related hospitalization, nonopioid-specific hospitalization, emergency department visits, opioid overdose, all-cause death, opioid-related death, and nonopioid-related death. The evidence on interventions directed at older adults is sparse. Of the 16 studies of opioid-related interventions in older adults, six examined screening tools to predict opioid-related harms, but none of these tools was tested in clinical practice to assess real-world results. Two studies found that prescription drug monitoring programs are associated with less opioid use in communities. Other studied interventions include multidisciplinary pain education for patients, an educational pamphlet for patients, implementation of an opioid safety initiative, provision of patient information and pain management training for clinicians, a bundle of educational modalities for clinicians, free prescription acetaminophen, a nationally mandated tamper-resistant opioid formulation, and motivational interview training for nursing students. Few intervention studies evaluated pain or other patient-centered outcomes such as disability and functioning. Conclusions The evidence base that is directly applicable to older adults who are prescribed opioids or have opioid-related disorders is limited. Fundamental research is necessary to determine which factors may predict clinically important, patient-centered, opioid-related outcomes. Studies to date have identified numerous possible factors associated with long-term opioid use (whether appropriate or not), but analyses of other opioid-related outcomes in older adults are relatively sparse. Research is also needed to identify interventions to reduce opioid prescribing where harms outweigh benefits (including screening tools), reduce opioid-related harms and disorders, and treat existing misuse or opioid use disorder among older adults.

Author(s): Fishman, Scott M; Carr, Daniel B; Hogans, Beth; Cheatle, Martin; Gallagher, Rollin M; Katzman, Joanna; Mackey, Sean; Polomano, Rosemary; Popescu, Adrian; Rathmell, James P; Rosenquist, Richard W; Tauben, David; Beckett, Laurel; Li, Yueju; Mongoven, Jennifer M; Young, Heather M | Abstract: Background:"The ongoing opioid crisis lies at the intersection of two substantial public health challenges-reducing the burden of suffering from pain and containing the rising toll of the harms that can result from the use of opioid medications" [1]. Improved pain education for health care providers is an essential component of the multidimensional response to both still-unmet challenges [2,3]. Despite the importance of licensing examinations in assuring competency in health care providers, there has been no prior appraisal of pain and related content within the United States Medical Licensing Examination (USMLE). Methods:An expert panel developed a novel methodology for characterizing USMLE questions based on pain core competencies and topical and public health relevance. Results:Under secure conditions, raters used this methodology to score 1,506 questions, with 28.7% (432) identified as including the word "pain." Of these, 232 questions (15.4% of the 1,506 USMLE questions reviewed) were assessed as being fully or partially related to pain, rather than just mentioning pain but not testing knowledge of its mechanisms and their implications for treatment. The large majority of questions related to pain (88%) focused on assessment rather than safe and effective pain management, or the context of pain. Conclusions:This emphasis on assessment misses other important aspects of safe and effective pain management, including those specific to opioid safety. Our findings inform ways to improve the long-term education of our medical and other graduates, thereby improving the health care of the populations they serve.

Given their established analgesic properties, nonsteroidal anti‐inflammatory drugs (NSAIDs) represent an important postoperative pain management option. This study investigated: (1) the effects of mild or moderate renal insufficiency and mild hepatic impairment on the pharmacokinetics (PK) of diclofenac and hydroxypropyl‐β‐cyclodextrin (HPβCD) following administration of the injectable NSAID HPβCD‐diclofenac; and (2) the PK of HPβCD following administration of HPβCD‐diclofenac and intravenous itraconazole formulated with HPβCD in healthy adults. Diclofenac clearance (CL) and volume of distribution (Vz) tended to increase with decreasing renal function (moderate insufficiency versus mild insufficiency or healthy controls). Regression analysis demonstrated a significant relationship between Vz (but not CL or elimination half‐life, t½) and renal function. HPβCD CL was significantly decreased in subjects with renal insufficiency, with a corresponding increase in t½. There were no significant differences in diclofenac or HPβCD PK in subjects with mild hepatic impairment versus healthy subjects. Exposure to HPβCD in healthy subjects following HPβCD‐diclofenac administration was ∼12% of that with intravenous itraconazole, after adjusting for dosing schedule and predicted accumulation (

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.

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 (eg, 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.

This chapter describes two major payment models relevant to the diagnosis and treatment of spine pain. The first is the assessment of the actual outcomes of care delivered, with emphasis on patient-reported outcomes such as pain and functional capacity (“outcomes-based”). The second comprises aggregated past observations in patient groups comparable to the current patient scheduled to receive a treatment (“evidence-based”). Payment decisions are then based upon whether differences were observed in the outcomes of treatment and control groups in the prior studies, preferably conducted as prospective randomized controlled trials. In practice, these two approaches are linked: evidence is typically gathered to assess specific outcomes, and findings of effects upon outcomes contribute to selecting one among many possible treatments and strategies to monitor that treatment’s effectiveness. We further describe a widely used computerized adaptive testing instrument (the Patient-Reported Outcomes Information System, “PROMIS”). We note actions underway by the US Federal insurance system to apply financial, merit-based performance incentives (“MIPS”) to encourage systematic collection and comparisons of treatment outcomes in a range of patient care settings. We conclude by touching on blockchain technology, an innovation that may grow in importance in health care by virtue of its facilitation of collection and pooling of individual patients’ detailed characteristics, care received, and outcomes achieved while maintaining their anonymity.

Tong J Gan,1 Neil Singla,2 Stephen E Daniels,3 Douglas A Hamilton,4,5 Peter G Lacouture,6,7 Christian RD Reyes,8 Daniel B Carr4,9 1Department of Anesthesiology, Stony Brook University, NY, 2Lotus Clinical Research, LLC, Pasadena, CA, 3Premier Research, Austin, TX, 4Javelin Pharmaceuticals, Inc., Cambridge, MA, 5New Biology Ventures, LLC, San Mateo, CA, 6Magidom Discovery, LLC, St Augustine, FL, 7Department of Emergency Medicine, Brown University School of Medicine, Providence, RI, 8Hospira Inc., Lake Forest, IL, 9Department of Anesthesiology, Tufts Medical Center, Boston, MA, USA Purpose: Use of nonopioid analgesics (including nonsteroidal anti-inflammatory drugs) for postoperative pain management can reduce opioid consumption and potentially prevent opioid-related adverse events. This study examined the postoperative opioid-sparing effect of repeated-dose injectable diclofenac formulated with hydroxypropyl-β-cyclodextrin (HPβCD)-diclofenac. Patients and methods: Pooled data from two double-blind, randomized, placebo- and active comparator-controlled Phase III trials were analyzed. Patients received HPβCD-diclofenac, placebo, or ketorolac by intravenous injection every 6 hours for up to 5 days following abdominal/pelvic or orthopedic surgery. Rescue opioid use was evaluated from the time of first study drug administration to up to 120 hours following the first dose in the overall study population and in subgroups defined by baseline pain severity, age, and HPβCD-diclofenac dose. Results: Overall, 608 patients received ≥1 dose of study medication and were included in the analysis. While 93.2% of patients receiving placebo required opioids, the proportion of patients requiring opioids was significantly lower for patients receiving HPβCD-diclofenac (18.75, 37.5, or 50 mg) or ketorolac (P

Summary Aneuploidy and aging are correlated; however, a causal link between these two phenomena has remained elusive. Here, we show that yeast disomic for a single native yeast chromosome generally have a decreased replicative lifespan. In addition, the extent of this lifespan deficit correlates with the size of the extra chromosome. We identified a mutation in BUL1 that rescues both the lifespan deficit and a protein trafficking defect in yeast disomic for chromosome 5. Bul1 is an E4 ubiquitin ligase adaptor involved in a protein quality control pathway that targets membrane proteins for endocytosis and destruction in the lysosomal vacuole, thereby maintaining protein homeostasis. Concurrent suppression of the aging and trafficking phenotypes suggests that disrupted membrane protein homeostasis in aneuploid yeast may contribute to their accelerated aging. The data reported here demonstrate that aneuploidy can impair protein homeostasis, shorten lifespan, and may contribute to age‐associated phenotypes.

Background Consensus indicates that a comprehensive, multimodal, holistic approach is foundational to the practice of acute pain medicine (APM), but lack of uniform, evidence-based clinical pathways leads to undesirable variability throughout U. S. healthcare systems. Acute pain studies are inconsistently synthesized to guide educational programs. Advanced practice techniques involving regional anesthesia assume the presence of a physician-led, multidisciplinary acute pain service, which is often unavailable or inconsistently applied. This heterogeneity of educational and organizational standards may result in unnecessary patient pain and escalation of healthcare costs. Methods A multidisciplinary panel was nominated through the APM Shared Interest Group of the American Academy of Pain Medicine. The panel met in Chicago, IL, in July 2014, to identify gaps and set priorities in APM research and education. Results The panel identified three areas of critical need: 1) an open-source acute pain data registry and clinical support tool to inform clinical decision making and resource allocation and to enhance research efforts; 2) a strong professional APM identity as an accredited subspecialty; and 3) educational goals targeted toward third-party payers, hospital administrators, and other key stakeholders to convey the importance of APM. Conclusion This report is the first step in a 3-year initiative aimed at creating conditions and incentives for the optimal provision of APM services to facilitate and enhance the quality of patient recovery after surgery, illness, or trauma. The ultimate goal is to reduce the conversion of acute pain to the debilitating disease of chronic pain.

Recognizing that electrically stimulating the motor cortex could relieve chronic pain sparked development of noninvasive technologies. In transcranial magnetic stimulation (TMS), electromagnetic coils held against the scalp influence underlying cortical firing. Multiday repetitive transcranial magnetic stimulation (rTMS) can induce long-lasting, potentially therapeutic brain plasticity. Nearby ferromagnetic or electronic implants are contraindications. Adverse effects are minimal, primarily headaches. Single provoked seizures are very rare. Transcranial magnetic stimulation devices are marketed for depression and migraine in the United States and for various indications elsewhere. Although multiple studies report that high-frequency rTMS of the motor cortex reduces neuropathic pain, their quality has been insufficient to support Food and Drug Administration application. Harvard's Radcliffe Institute therefore sponsored a workshop to solicit advice from experts in TMS, pain research, and clinical trials. They recommended that researchers standardize and document all TMS parameters and improve strategies for sham and double blinding. Subjects should have common well-characterized pain conditions amenable to motor cortex rTMS and studies should be adequately powered. They recommended standardized assessment tools (eg, NIH's PROMIS) plus validated condition-specific instruments and consensus-recommended metrics (eg, IMMPACT). Outcomes should include pain intensity and qualities, patient and clinician impression of change, and proportions achieving 30% and 50% pain relief. Secondary outcomes could include function, mood, sleep, and/or quality of life. Minimum required elements include sample sources, sizes, and demographics, recruitment methods, inclusion and exclusion criteria, baseline and posttreatment means and SD, adverse effects, safety concerns, discontinuations, and medication-usage records. Outcomes should be monitored for at least 3 months after initiation with prespecified statistical analyses. Multigroup collaborations or registry studies may be needed for pivotal trials.

Objective The purpose of this article is 1) to present the historical context and rationale for competency-based pain management education; and 2) to suggest learning tools that faculty might apply into their teachings and their institutions' pre-licensure curricula for promoting conceptual learning based on competency-based pain management education. Design Based on the well-documented need to improve the competency of health care professionals in pain assessment and management, an interprofessional group of health care providers collaborated and then convened in August 2012 to develop core competencies for pain management for the pre-licensure programs of study across health care disciplines. This interprofessional group of pain educators achieved consensus on a common set of pain-related competencies intended to be implemented across a variety of pre-licensure professional programs. Setting A group of the interprofessional faculty, who participated in the development of the core competencies for pain management, provides a follow-up of how to implement learning tools within teaching and curricula, based on competency education in pre-licensure health care. Results Broad questions about how to incorporate competencies into pre-licensure curricula, for all health provider pre-licensure programs, including how to assess competency across individuals and how to teach in ways that emphasize the demonstration of conceptual learning, remain unanswered. This article reviews how the use of competencies creates historical context for a shift from teaching to learning and concludes with suggestions and exemplars in applying core competencies for pain management in pre-licensure programs.

Proteins often undergo slow structural rearrangements that involve several angstroms and surpass the nanosecond timescale. These spatiotemporal scales challenge physics-based simulations and open the way to sample-based models of structural dynamics. This article improves an understanding of current capabilities and limitations of sample-based models of dynamics. Borrowing from widely used concepts in evolutionary computation, this article introduces two conflicting aspects of sampling capability and quantifies them via statistical (and graphical) analysis tools. This allows not only conducting a principled comparison of different sample-based algorithms but also understanding which algorithmic ingredients to use as knobs via which to control sampling and, in turn, the accuracy and detail of modeled structural rearrangements. We demonstrate the latter by proposing two powerful variants of a recently published sample-based algorithm. We believe that this work will advance the adoption of sample-based models as reliable tools for modeling slow protein structural rearrangements.

Objective This manuscript reviews medical literature published pertaining to the management of chronic pain with medical marijuana therapy (MMJ), with an emphasis on the social, medical, and legal aspects of therapy. Design Narrative review of peer-reviewed literature. Methods The 3rd Symposium on Controlled Substances and Their Alternatives for the Treatment of Pain was held in Boston on February 27, 2016, with a focus on MMJ for the treatment of chronic pain. Invited speakers had diverse backgrounds, including pain management, addiction psychiatry, neurology, and legal authorities. The purpose of this conference and this subsequent narrative review is to provide a medical, legal, and logistical framework for physicians and other health care providers to refer to when considering the initiation of medical marijuana therapy. Results The invited speakers each covered a unique aspect of MMJ therapy for the treatment of chronic pain. These presentations highlighted the current data for and against the use of MMJ as a pain therapy. Optimal patient selection and screening, in addition to policy developments, were discussed. Conclusions Increasing interest in MMJ for chronic pain underscores a need for primary care and pain physicians to better understand the indications and evidence for its use free from cultural bias. Given a lack of full conclusive clinical utility, continued research is needed to better understand how to best utilize MMJ therapy for the treatment of chronic pain. Policy initiatives, such as enumerated indications, should follow medical science in order to prevent another abused substance epidemic.

Background Pain is a common symptom with cancer, and 30% to 50% of all people with cancer will experience moderate to severe pain that can have a major negative impact on their quality of life. Non-opioid drugs are commonly used to treat mild to moderate cancer pain, and are recommended for this purpose in the WHO cancer pain treatment ladder, either alone or in combination with opioids. A previous Cochrane review that examined the evidence for nonsteroidal anti-inflammatory drugs (NSAIDs) or paracetamol, alone or combined with opioids, for cancer pain was withdrawn in 2015 because it was out of date; the date of the last search was 2005. This review, and another on NSAIDs, updates the evidence. Objectives To assess the efficacy of oral paracetamol (acetaminophen) for cancer pain in adults and children, and the adverse events reported during its use in clinical trials. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase from inception to March 2017, together with reference lists of retrieved papers and reviews, and two online study registries. Selection criteria We included randomised, double-blind, studies of five days' duration or longer, comparing paracetamol alone with placebo, or paracetamol in combination with an opioid compared with the same dose of the opioid alone, for cancer pain of any intensity. Single-blind and open studies were also eligible for inclusion. The minimum study size was 25 participants per treatment arm at the initial randomisation. Data collection and analysis Two review authors independently searched for studies, extracted efficacy and adverse event data, and examined issues of study quality and potential bias. We did not carry out any pooled analyses. We assessed the quality of the evidence using GRADE and created a 'Summary of findings' table. Main results Three studies in adults satisfied the inclusion criteria, lasting up to one week; 122 participants were randomised initially, and 95 completed treatment. We found no studies in children. One study was parallel-group, and two had a cross-over design. All used paracetamol as an add-on to established treatment with strong opioids (median daily morphine equivalent doses of 60 mg, 70 mg, and 225 mg, with some participants taking several hundred mg of oral morphine equivalents daily). Other non-paracetamol medication included non-steroidal anti-inflammatory drugs (NSAIDs), tricyclic antidepressants, or neuroleptics. All studies were at high risk of bias for incomplete outcome data and small size; none was unequivocally at low risk of bias. None of the studies reported any of our primary outcomes: participants with pain reduction of at least 50%, and at least 30%, from baseline; participants with pain no worse than mild at the end of the treatment period; participants with Patient Global Impression of Change (PGIC) of much improved or very much improved (or equivalent wording). What pain reports there were indicated no difference between paracetamol and placebo when added to another treatment. There was no convincing evidence of paracetamol being different from placebo with regards to quality of life, use of rescue medication, or participant satisfaction or preference. Measures of harm (serious adverse events, other adverse events, and withdrawal due to lack of efficacy) were inconsistently reported and provided no clear evidence of difference. Our GRADE assessment of evidence quality was very low for all outcomes, because studies were at high risk of bias from several sources. Authors' conclusions There is no high-quality evidence to support or refute the use of paracetamol alone or in combination with opioids for the first two steps of the three-step WHO cancer pain ladder. It is not clear whether any additional analgesic benefit of paracetamol could be detected in the available studies, in view of the doses of opioids used.

Background Pain is a common symptom with cancer, and 30% to 50% of all people with cancer will experience moderate to severe pain that can have a major negative impact on their quality of life. Non-opioid drugs are commonly used to treat cancer pain, and are recommended for this purpose in theWorld Health Organization (WHO) cancer pain treatment ladder, either alone or in combination with opioids. A previous Cochrane review that examined the evidence for nonsteroidal anti-inflammatory drugs (NSAIDs) or paracetamol, alone or combined with opioids, for cancer pain was withdrawn in 2015 because it was out of date; the date of the last search was 2005. This review, and another on paracetamol, updates the evidence. Objectives To assess the efficacy of oral NSAIDs for cancer pain in adults, and the adverse events reported during their use in clinical trials. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL),MEDLINE, and Embase from inception to April 2017, together with reference lists of retrieved papers and reviews, and two online study registries. Selection criteria We included randomised, double-blind, single-blind, or open-label studies of five days’ duration or longer, comparing any oral NSAID alone with placebo or another NSAID, or a combination of NSAID plus opioid with the same dose of the opioid alone, for cancer pain of any pain intensity. The minimum study size was 25 participants per treatment arm at the initial randomisation. Data collection and analysis Two review authors independently searched for studies, extracted efficacy and adverse event data, and examined issues of study quality and potential bias. We did not carry out any pooled analyses. We assessed the quality of the evidence using GRADE and created a ’Summary of findings’ table. Main results Eleven studies satisfied inclusion criteria, lasting one week or longer; 949 participants with mostly moderate or severe pain were randomised initially, but fewer completed treatment or had results of treatment. Eight studies were double-blind, two single-blind, and one open-label. None had a placebo only control; eight compared different NSAIDs, three an NSAID with opioid or opioid combination, and one both. None compared an NSAID plus opioid with the same dose of opioid alone. Most studies were at high risk of bias for blinding, incomplete outcome data, or small size; none was unequivocally at low risk of bias. It was not possible to compare NSAIDs as a group with another treatment, or one NSAIDwith another NSAID. Results for allNSAIDs are reported as a randomised cohort. We judged results for all outcomes as very low-quality evidence. None of the studies reported our primary outcomes of participants with pain reduction of at least 50%, and at least 30%, from baseline; participants with Patient Global Impression of Change (PGIC) of much improved or very much improved (or equivalent wording). With NSAID, initially moderate or severe pain was reduced to no worse than mild pain after one or two weeks in four studies (415 participants in total), with a range of estimates between 26% and 51% in individual studies. Adverse event and withdrawal reporting was inconsistent. Two serious adverse events were reported with NSAIDs, and 22 deaths, but these were not clearly related to any pain treatment. Common adverse events were thirst/dry mouth (15%), loss of appetite (14%), somnolence (11%), and dyspepsia (11%).Withdrawals were common, mostly because of lack of efficacy (24%) or adverse events (5%). Authors’ conclusions There is no high-quality evidence to support or refute the use of NSAIDs alone or in combination with opioids for the three steps of the three-step WHO cancer pain ladder. There is very low-quality evidence that some people with moderate or severe cancer pain can obtain substantial levels of benefit within one or two weeks.

Objective To reshape medical education about pain to present it as a population-based public health process as well as a neuron-centered phenomenon. Design Collaborate with students to apply a recent inventory of pain-related preclinical curricular content and clinical training in order to modify the current multiyear presentation and offer a broadened social perspective on pain. Appraise fourth-year medical students' pain-related educational needs by surveying their knowledge, attitudes, experience with the curriculum, and self-reported assessment of pain-related competencies. Setting and subjects University-affiliated medical school and its fourth-year medical students. Methods Analysis of a detailed inventory of first- and second-year curricula. Survey of graduating medical students assessing attitudes, skills, and confidence. Construction of a fourth-year pain education elective and collaboration with enrollees to better integrate pain throughout the four-year curriculum. Results This student-faculty collaboration produced an evidence-guided proposal to reorganize pain-related content across the longitudinal medical curriculum. An attitudes/skills/confidence survey of graduating medical students (104 respondents of 200 polled) found that 70% believed chances for successful outcomes treating chronic pain were low. Self-evaluated competency was high for evaluating (82%) and managing (69%) acute pain; for chronic pain, both were lower (evaluating = 38%; managing = 6%). Self-evaluated knowledge of pain physiology and neurobiology was poor (14%), fair (54%), or good (30%), but rarely excellent (2%). Conclusions To meet graduating students' desire for increased competency in pain, pain-related curricula can and should be reorganized to include pain as a disease state and a widespread public health burden, not merely a symptom.

Background Neuropathic pain, which is caused by a lesion or disease affecting the somatosensory system, may be central or peripheral in origin. Neuropathic pain often includes symptoms such as burning or shooting sensations, abnormal sensitivity to normally painless stimuli, or an increased sensitivity to normally painful stimuli. Neuropathic pain is a common symptom in many diseases of the nervous system. Opioid drugs, including morphine, are commonly used to treat neuropathic pain. Most reviews have examined all opioids together. This review sought evidence specifically for morphine; other opioids are considered in separate reviews. Objectives To assess the analgesic efficacy and adverse events of morphine for chronic neuropathic pain in adults. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase for randomised controlled trials from inception to February 2017. We also searched the reference lists of retrieved studies and reviews, and online clinical trial registries. Selection criteria We included randomised, double-blind trials of two weeks' duration or longer, comparing morphine (any route of administration) with placebo or another active treatment for neuropathic pain, with participant-reported pain assessment. Data collection and analysis Two review authors independently extracted data and assessed trial quality and potential bias. Primary outcomes were participants with substantial pain relief (at least 50% pain relief over baseline or very much improved on Patient Global Impression of Change scale (PGIC)), or moderate pain relief (at least 30% pain relief over baseline or much or very much improved on PGIC). Where pooled analysis was possible, we used dichotomous data to calculate risk ratio (RR) and number needed to treat for an additional beneficial outcome (NNT) or harmful outcome (NNH). We assessed the quality of the evidence using GRADE and created 'Summary of findings' tables. Main results We identified five randomised, double-blind, cross-over studies with treatment periods of four to seven weeks, involving 236 participants in suitably characterised neuropathic pain; 152 (64%) participants completed all treatment periods. Oral morphine was titrated to maximum daily doses of 90 mg to 180 mg or the maximum tolerated dose, and then maintained for the remainder of the study. Participants had experienced moderate or severe neuropathic pain for at least three months. Included studies involved people with painful diabetic neuropathy, chemotherapy-induced peripheral neuropathy, postherpetic neuralgia criteria, phantom limb or postamputation pain, and lumbar radiculopathy. Exclusions were typically people with other significant comorbidity or pain from other causes. Overall, we judged the studies to be at low risk of bias, but there were concerns over small study size and the imputation method used for participants who withdrew from the studies, both of which could lead to overestimation of treatment benefits and underestimation of harm. There was insufficient or no evidence for the primary outcomes of interest for efficacy or harm. Four studies reported an approximation of moderate pain improvement (any pain-related outcome indicating some improvement) comparing morphine with placebo in different types of neuropathic pain. We pooled these data in an exploratory analysis. Moderate improvement was experienced by 63% (87/138) of participants with morphine and 36% (45/125) with placebo; the risk difference (RD) was 0.27 (95% confidence interval (CI) 0.16 to 0.38, fixed-effects analysis) and the NNT 3.7 (2.6 to 6.5). We assessed the quality of the evidence as very low because of the small number of events; available information did not provide a reliable indication of the likely effect, and the likelihood that the effect will be substantially different was very high. A similar exploratory analysis for substantial pain relief on three studies (177 participants) showed no difference between morphine and placebo. All-cause withdrawals in four studies occurred in 16% (24/152) of participants with morphine and 12% (16/137) with placebo. The RD was 0.04 (-0.04 to 0.12, random-effects analysis). Adverse events were inconsistently reported, more common with morphine than with placebo, and typical of opioids. There were two serious adverse events, one with morphine, and one with a combination of morphine and nortriptyline. No deaths were reported. These outcomes were assessed as very low quality because of the limited number of participants and events. Authors' conclusions There was insufficient evidence to support or refute the suggestion that morphine has any efficacy in any neuropathic pain condition.