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Currently-used assessments for fibromyalgia require clinicians to suspect a fibromyalgia diagnosis, a process susceptible to unintentional bias. Automated assessments of standard patient-reported outcomes (PROs) could be used to prompt formal assessments, potentially reducing bias. We sought to determine whether hierarchical clustering of patient-reported pain distribution on digital body map drawings predicted fibromyalgia diagnosis. Using an observational cohort from the University of Pittsburgh's Patient Outcomes Repository for Treatment registry, which contains PROs and electronic medical record data from 21,423 patients (March 17, 2016-June 25, 2019) presenting to pain management clinics, we tested the hypothesis that hierarchical clustering subgroup was associated with fibromyalgia diagnosis, as determined by ICD-10 code. Logistic regression revealed a significant relationship between the body map cluster subgroup and fibromyalgia diagnosis. The cluster subgroup with the most body areas selected was the most likely to receive a diagnosis of fibromyalgia when controlling for age, gender, anxiety, and depression. Despite this, more than two-thirds of patients in this cluster lacked a clinical fibromyalgia diagnosis. In an exploratory analysis to better understand this apparent underdiagnosis, we developed and applied proxies of fibromyalgia diagnostic criteria. We found that proxy diagnoses were more common than ICD-10 diagnoses, which may be due to less frequent clinical fibromyalgia diagnosis in men. Overall, we find evidence of fibromyalgia underdiagnosis, likely due to gender bias. Coupling PROs that take seconds to complete, such as a digital pain body map, with machine learning is a promising strategy to reduce bias in fibromyalgia diagnosis and improve patient outcomes. PERSPECTIVE: This investigation applies hierarchical clustering to patient-reported, digital pain body maps, finding an association between body map responses and clinical fibromyalgia diagnosis. Rapid, computer-assisted interpretation of pain body maps would be clinically useful in prompting more detailed assessments for fibromyalgia, potentially reducing gender bias., (Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Objective: Fibromyalgia (FM) is characterized by pervasive pain-related symptomatology and high levels of negative affect. Mind-body treatments such as cognitive behavioral therapy (CBT) appear to foster improvement in FM via reductions in pain-related catastrophizing, a set of negative, pain-amplifying cognitive and emotional processes. However, the neural underpinnings of CBT's catastrophizing-reducing effects remain uncertain. This randomized controlled mechanistic trial was designed to assess CBT's effects on pain catastrophizing and its underlying brain circuitry., Methods: Of 114 enrolled participants, 98 underwent a baseline neuroimaging assessment and were randomized to 8 weeks of individual CBT or a matched FM education control (EDU) condition., Results: Compared with EDU, CBT produced larger decreases in pain catastrophizing post treatment (P < 0.05) and larger reductions in pain interference and symptom impact. Decreases in pain catastrophizing played a significant role in mediating those functional improvements in the CBT group. At baseline, brain functional connectivity between the ventral posterior cingulate cortex (vPCC), a key node of the default mode network (DMN), and somatomotor and salience network regions was increased during catastrophizing thoughts. Following CBT, vPCC connectivity to somatomotor and salience network areas was reduced., Conclusion: Our results suggest clinically important and CBT-specific associations between somatosensory/motor- and salience-processing brain regions and the DMN in chronic pain. These patterns of connectivity may contribute to individual differences (and treatment-related changes) in somatic self-awareness. CBT appears to provide clinical benefits at least partially by reducing pain-related catastrophizing and producing adaptive alterations in DMN functional connectivity., (© 2023 American College of Rheumatology.)

In 2019, the National Health Interview survey found that nearly 59% of adults reported pain some, most, or every day in the past 3 months, with 39% reporting back pain, making back pain the most prevalent source of pain, and a significant issue among adults. Often, identifying a direct, treatable cause for back pain is challenging, especially as it is often attributed to complex, multifaceted issues involving biological, psychological, and social components. Due to the difficulty in treating the true cause of chronic low back pain (cLBP), an over-reliance on opioid pain medications among cLBP patients has developed, which is associated with increased prevalence of opioid use disorder and increased risk of death. To combat the rise of opioid-related deaths, the National Institutes of Health (NIH) initiated the Helping to End Addiction Long-TermSM (HEAL) initiative, whose goal is to address the causes and treatment of opioid use disorder while also seeking to better understand, diagnose, and treat chronic pain. The NIH Back Pain Consortium (BACPAC) Research Program, a network of 14 funded entities, was launched as a part of the HEAL initiative to help address limitations surrounding the diagnosis and treatment of cLBP. This paper provides an overview of the BACPAC research program's goals and overall structure, and describes the harmonization efforts across the consortium, define its research agenda, and develop a collaborative project which utilizes the strengths of the network. The purpose of this paper is to serve as a blueprint for other consortia tasked with the advancement of pain related science., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Academy of Pain Medicine.)

Objective: Patients with chronic low back pain (CLBP) and comorbid depression or anxiety disorders are highly prevalent. Negative affect (NA) refers to a combination of negative thoughts, emotions, and behaviors. Patients with CLBP with high NA have greater pain, worse treatment outcomes, and greater prescription opioid misuse. We present the protocol for SYNNAPTIC (SYNergizing Negative Affect & Pain Treatment In Chronic pain)., Design: A randomized comparative-effectiveness study of antidepressants, fear-avoidance rehabilitation, or their combination in 300 patients with CLBP with high NA. In the antidepressant- or rehabilitation-only arms, SYNNAPTIC includes an adaptive design of re-randomization after 4 months for nonresponders., Setting: A multisite trial conducted in routine pain clinical treatment settings: pain clinics and physical and occupational therapy treatment centers., Methods: Inclusion criteria include CLBP with elevated depression and anxiety symptoms. Antidepressant and rehabilitation treatments follow validated and effective protocols for musculoskeletal pain in patients with high NA. Power and sample size are based on superior outcomes of combination therapy with these same treatments in a 71-subject 4-arm pilot randomized controlled trial., Conclusions: SYNNAPTIC addresses the lack of evidence-based protocols for the treatment of the vulnerable subgroup of patients with CLBP and high NA. We hypothesize that combination therapy of antidepressants plus fear-avoidance rehabilitation will be more effective than each treatment alone., Trial Registration: ClinicalTrials.gov ID: NCT04747314., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Academy of Pain Medicine.)

Objective: Clinical trials of cannabinoids for chronic pain have mixed and often inconclusive results. In contrast, many prospective observational studies show the analgesic effects of cannabinoids. This survey study aimed to examine the experiences/attitudes of individuals with chronic pain who are currently taking, have previously taken, or never taken cannabinoids for chronic pain to inform future research., Methods: This study is based on a cross-sectional, web-based survey of individuals with self-reported chronic pain. Participants were invited to participate through an email that was distributed to the listservs of patient advocacy groups and foundations that engage individuals with chronic pain., Results: Of the 969 respondents, 444 (46%) respondents reported currently taking, 213 (22%) previously taken, and 312 (32%) never taken cannabinoids for pain. Participants reported using cannabinoids to treat a wide variety of chronic pain conditions. Those currently taking cannabinoids (vs previously) more frequently reported: (1) large improvements from cannabinoids in all pain types, including particularly difficult-to-treat chronic overlapping pain conditions (eg, pelvic pain), (2) improvements in comorbid symptoms (eg, sleep), and (3) lower interference from side effects. Those currently taking cannabinoids reported more frequent and satisfactory communication with clinicians regarding cannabinoid use. Those never taken cannabinoids reported a lack of suggestion/approval of a clinician (40%), illegality (25%), and lack of FDA regulation (19%) as reasons for never trying cannabinoids., Conclusion: These findings underscore the importance of conducting high-quality clinical trials that include diverse pain populations and clinically relevant outcomes that if successful, could support FDA approval of cannabinoid products. Clinicians could then prescribe and monitor these treatments similarly to other chronic pain medications., Competing Interests: GW Pharmaceuticals (Cambridgeshire, UK) provided funds to support the conduct of the survey, including consulting fees too. The analyses and writing of this manuscript were supported by NIH (Bethesda, MD) grant K24NS126861. R.F., J.S.G., K.P.H., R.R.E., and A.D.W. received consulting fees from GW to design the survey. B.L.F. has obtained funding from Pfizer Inc. (GRAND Awards, including salary support) for investigator-initiated projects; Indivior for a clinical trial sponsored by Indivior. B.L.F. has in-kind donations of cannabis products from Aurora Cannabis Enterprises Inc. and study medication donations from Pfizer Inc. (varenicline for smoking cessation) and Bioprojet Pharma. He was also provided a coil for a Transcranial magnetic stimulation (TMS) study from Brainsway. B.L.F. has obtained industry funding from Canopy Growth Corporation (through research grants handled by the Centre for Addiction and Mental Health and the University of Toronto), Bioprojet Pharma, Alcohol Countermeasure Systems (ACS), Alkermes and Universal Ibogaine. He has participated in a session of a National Advisory Board Meeting (Emerging Trends BUP-XR) for Indivior Canada and has been consultant for Shinogi. He is supported by CAMH, Waypoint Centre for Mental Health Care, a clinician-scientist award from the department of Family and Community Medicine of the University of Toronto, and a Chair in Addiction Psychiatry from the department of Psychiatry of University of Toronto. The remaining authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Variability in pain-related outcomes can hamper assay sensitivity of chronic pain clinical trials. Expectations of outcome in such trials may account for some of this variability, and thereby impede development of novel pain treatments. Measurement of participants' expectations prior to initiating study treatment (active or placebo) is infrequent, variable, and often unvalidated. Efforts to optimize and standardize measurement, analysis, and management of expectations are needed. In this Focus Article, we provide an overview of research findings on the relationship between baseline expectations and pain-related outcomes in clinical trials of pharmacological and nonpharmacological pain treatments. We highlight the potential benefit of adjusting for participants' expectations in clinical trial analyses and draw on findings from patient interviews to discuss critical issues related to measurement of expectations. We conclude with suggestions regarding future studies focused on better understanding the utility of incorporating these measures into clinical trial analyses. PERSPECTIVE: This focus article provides an overview of the relationship between participants' baseline expectations and pain-related outcomes in the setting of clinical trials of chronic pain treatments. Systematic research focused on the measurement of expectations and the impact of adjusting for expectations in clinical trial analyses may improve assay sensitivity., (Copyright © 2023 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

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 (ie, "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 (ie, 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 prespecified 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., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Abstract: Chronic pain clinical trials have historically assessed benefit and risk outcomes separately. However, a growing body of research suggests that a composite metric that accounts for benefit and risk in relation to each other can provide valuable insights into the effects of different treatments. Researchers and regulators have developed a variety of benefit-risk composite metrics, although the extent to which these methods apply to randomized clinical trials (RCTs) of chronic pain has not been evaluated in the published literature. This article was motivated by an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials consensus meeting and is based on the expert opinion of those who attended. In addition, a review of the benefit-risk assessment tools used in published chronic pain RCTs or highlighted by key professional organizations (ie, Cochrane, European Medicines Agency, Outcome Measures in Rheumatology, and U.S. Food and Drug Administration) was completed. Overall, the review found that benefit-risk metrics are not commonly used in RCTs of chronic pain despite the availability of published methods. A primary recommendation is that composite metrics of benefit-risk should be combined at the level of the individual patient, when possible, in addition to the benefit-risk assessment at the treatment group level. Both levels of analysis (individual and group) can provide valuable insights into the relationship between benefits and risks associated with specific treatments across different patient subpopulations. The systematic assessment of benefit-risk in clinical trials has the potential to enhance the clinical meaningfulness of RCT results., (Copyright © 2021 International Association for the Study of Pain.)

Abstract: Randomized clinical trials have demonstrated the efficacy of opioid analgesics for the treatment of acute and chronic pain conditions, and for some patients, these medications may be the only effective treatment available. Unfortunately, opioid analgesics are also associated with major risks (eg, opioid use disorder) and adverse outcomes (eg, respiratory depression and falls). The risks and adverse outcomes associated with opioid analgesics have prompted efforts to reduce their use in the treatment of both acute and chronic pain. This article presents Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) consensus recommendations for the design of opioid-sparing clinical trials. The recommendations presented in this article are based on the following definition of an opioid-sparing intervention: any intervention that (1) prevents the initiation of treatment with opioid analgesics, (2) decreases the duration of such treatment, (3) reduces the total dosages of opioids that are prescribed for or used by patients, or (4) reduces opioid-related adverse outcomes (without increasing opioid dosages), all without causing an unacceptable increase in pain. These recommendations are based on the results of a background review, presentations and discussions at an IMMPACT consensus meeting, and iterative drafts of this article modified to accommodate input from the co-authors. We discuss opioid sparing definitions, study objectives, outcome measures, the assessment of opioid-related adverse events, incorporation of adequate pain control in trial design, interpretation of research findings, and future research priorities to inform opioid-sparing trial methods. The considerations and recommendations presented in this article are meant to help guide the design, conduct, analysis, and interpretation of future trials., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

Background: Fibromyalgia is a centralized multidimensional chronic pain syndrome, but its pathophysiology is not fully understood., Methods: We applied 3D magnetic resonance spectroscopic imaging (MRSI), covering multiple cortical and subcortical brain regions, to investigate the association between neuro-metabolite (e.g. combined glutamate and glutamine, Glx; myo-inositol, mIno; and combined (total) N-acetylaspartate and N-acetylaspartylglutamate, tNAA) levels and multidimensional clinical/behavioural variables (e.g. pain catastrophizing, clinical pain severity and evoked pain sensitivity) in women with fibromyalgia (N = 87)., Results: Pain catastrophizing scores were positively correlated with Glx and tNAA levels in insular cortex, and negatively correlated with mIno levels in posterior cingulate cortex (PCC). Clinical pain severity was positively correlated with Glx levels in insula and PCC, and with tNAA levels in anterior midcingulate cortex (aMCC), but negatively correlated with mIno levels in aMCC and thalamus. Evoked pain sensitivity was negatively correlated with levels of tNAA in insular cortex, MCC, PCC and thalamus., Conclusions: These findings support single voxel placement targeting nociceptive processing areas in prior 1 H-MRS studies, but also highlight other areas not as commonly targeted, such as PCC, as important for chronic pain pathophysiology. Identifying target brain regions linked to multidimensional symptoms of fibromyalgia (e.g. negative cognitive/affective response to pain, clinical pain, evoked pain sensitivity) may aid the development of neuromodulatory and individualized therapies. Furthermore, efficient multi-region sampling with 3D MRSI could reduce the burden of lengthy scan time for clinical research applications of molecular brain-based mechanisms supporting multidimensional aspects of fibromyalgia., Significance: This large N study linked brain metabolites and pain features in fibromyalgia patients, with a better spatial resolution and brain coverage, to understand a molecular mechanism underlying pain catastrophizing and other aspects of pain transmission. Metabolite levels in self-referential cognitive processing area as well as pain-processing regions were associated with pain outcomes. These results could help the understanding of its pathophysiology and treatment strategies for clinicians., (© 2021 European Pain Federation - EFIC®.)

Objective: To examine the benefits of an integrated psychosocial group treatment (IPGT) model for patients with chronic pain at risk of opioid misuse., Design: This study was a small-scale, single-blinded, two-group randomized controlled trial., Setting: Outpatient., Subjects: Adults with chronic pain of >3 months' duration who were currently prescribed opioid medication and were at risk of opioid misuse., Methods: Patients with chronic pain who were at risk of opioid misuse (n = 30) were randomly assigned to IPGT or treatment as usual. IPGT consists of six group sessions of psychoeducation, motivational interviewing, cognitive behavioral therapy, mindfulness, and peer support. Participants were assessed at baseline, first follow-up at 6 weeks, and a posttreatment follow-up at 9 weeks. Outcomes included feasibility, acceptability, and preliminary efficacy. Data were analyzed with descriptive and multivariate analyses., Results: All intervention components were delivered to 87% of the participants, and IPGT recipients reported a high level of satisfaction. Results of the multivariate analyses demonstrated nonsignificant improvements in pain severity (β = 0.22, 95% CI: -0.24 to 0.66, P = 0.35). However, we observed significant treatment × time interactions on pain interference (β = 3.32, 95% confidence interval [CI]: 0.01 to 6.65, P = 0.05) and pain catastrophizing (β = 2.74, 95% CI: 0.49 to 4.99, P = 0.02). Lastly, we detected no significant differences in opioid misuse (adjusted odds ratio = 0.69, 95% CI: -0.26 to 1.64, P = 0.16)., Conclusion: This study provides support for the IPGT intervention being acceptable and feasible for delivery in patients with chronic pain at risk of opioid misuse. Efficacy was achieved in pain interference and pain catastrophizing., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: In clinical practice, the bodily distribution of chronic pain is often used in conjunction with other signs and symptoms to support a diagnosis or treatment plan. For example, the diagnosis of fibromyalgia involves tallying the areas of pain that a patient reports using a drawn body map. It remains unclear whether patterns of pain distribution independently inform aspects of the pain experience and influence patient outcomes. The objective of the current study was to evaluate the clinical relevance of patterns of pain distribution using an algorithmic approach agnostic to diagnosis or patient-reported facets of the pain experience., Methods and Findings: A large cohort of patients (N = 21,658) completed pain body maps and a multi-dimensional pain assessment. Using hierarchical clustering of patients by body map selection alone, nine distinct subgroups emerged with different patterns of body region selection. Clinician review of cluster body maps recapitulated some clinically-relevant patterns of pain distribution, such as low back pain with radiation below the knee and widespread pain, as well as some unique patterns. Demographic and medical characteristics, pain intensity, pain impact, and neuropathic pain quality all varied significantly across cluster subgroups. Multivariate modeling demonstrated that cluster membership independently predicted pain intensity and neuropathic pain quality. In a subset of patients who completed 3-month follow-up questionnaires (N = 7,138), cluster membership independently predicted the likelihood of improvement in pain, physical function, and a positive overall impression of change related to multidisciplinary pain care., Conclusions: This study reports a novel method of grouping patients by pain distribution using an algorithmic approach. Pain distribution subgroup was significantly associated with differences in pain intensity, impact, and clinically relevant outcomes. In the future, algorithmic clustering by pain distribution may be an important facet in chronic pain biosignatures developed for the personalization of pain management., Competing Interests: The authors have declared that no competing interests exist.

Negative affect (NA) is a significant cause of disability for chronic pain patients. While little is known about the mechanism underlying pain-comorbid NA, previous studies have implicated neuroinflammation in the pathophysiology of both depression and chronic pain. Here, we tested the hypothesis that NA in pain patients is linked to elevations in the brain levels of the glial marker 18 kDa translocator protein (TSPO), and changes in functional connectivity. 25 cLBP patients (42.4 ± 13 years old; 13F, 12M) with chronic low back pain (cLBP) and 27 healthy control subjects (48.9 ± 13 years old; 14F, 13M) received an integrated (i.e., simultaneous) positron emission tomography (PET)/magnetic resonance imaging (MRI) brain scan with the second-generation TSPO ligand [ 11 C]PBR28. The relationship between [ 11 C]PBR28 signal and NA was assessed first with regression analyses against Beck Depression Inventory (BDI) scores in patients, and then by comparing cLBP patients with little-to-no, or mild-to-moderate depression against healthy controls. Further, the relationship between PET signal, BDI and frontolimbic functional connectivity was evaluated in patients with mediation models. PET signal was positively associated with BDI scores in patients, and significantly elevated in patients with mild-to-moderate (but not low) depression compared with controls, in anterior middle and pregenual anterior cingulate cortices (aMCC, pgACC). In the pgACC, PET signal was also associated with this region's functional connectivity to the dorsolateral PFC (pgACC-dlPFC), and mediated of the association between pgACC-dlPFC connectivity and BDI. These observations support a role for glial activation in pain-comorbid NA, identifying in neuroinflammation a potential therapeutic target for this condition.

Importance: Acute low back pain (LBP) is highly prevalent, with a presumed favorable prognosis; however, once chronic, LBP becomes a disabling and expensive condition. Acute to chronic LBP transition rates vary widely owing to absence of standardized operational definitions, and it is unknown whether a standardized prognostic tool (ie, Subgroups for Targeted Treatment Back tool [SBT]) can estimate this transition or whether early non-guideline concordant treatment is associated with the transition to chronic LBP., Objective: To assess the associations between the transition from acute to chronic LBP with SBT risk strata; demographic, clinical, and practice characteristics; and guideline nonconcordant processes of care., Design, Setting, and Participants: This inception cohort study was conducted alongside a multisite, pragmatic cluster randomized trial. Adult patients with acute LBP stratified by SBT risk were enrolled in 77 primary care practices in 4 regions across the United States between May 2016 and June 2018 and followed up for 6 months, with final follow-up completed by March 2019. Data analysis was conducted from January to March 2020., Exposures: SBT risk strata and early LBP guideline nonconcordant processes of care (eg, receipt of opioids, imaging, and subspecialty referral)., Main Outcomes and Measures: Transition from acute to chronic LBP at 6 months using the National Institutes of Health Task Force on Research Standards consensus definition of chronic LBP. Patient demographic characteristics, clinical factors, and LBP process of care were obtained via electronic medical records., Results: Overall, 5233 patients with acute LBP (3029 [58%] women; 4353 [83%] White individuals; mean [SD] age 50.6 [16.9] years; 1788 [34%] low risk; 2152 [41%] medium risk; and 1293 [25%] high risk) were included. Overall transition rate to chronic LBP at six months was 32% (1666 patients). In a multivariable model, SBT risk stratum was positively associated with transition to chronic LBP (eg, high-risk vs low-risk groups: adjusted odds ratio [aOR], 2.45; 95% CI, 2.00-2.98; P < .001). Patient and clinical characteristics associated with transition to chronic LBP included obesity (aOR, 1.52; 95% CI, 1.28-1.80; P < .001); smoking (aOR, 1.56; 95% CI, 1.29-1.89; P < .001); severe and very severe baseline disability (aOR, 1.82; 95% CI, 1.48-2.24; P < .001 and aOR, 2.08; 95% CI, 1.60-2.68; P < .001, respectively) and diagnosed depression/anxiety (aOR, 1.66; 95% CI, 1.28-2.15; P < .001). After controlling for all other variables, patients exposed to 1, 2, or 3 nonconcordant processes of care within the first 21 days were 1.39 (95% CI, 1.21-2.32), 1.88 (95% CI, 1.53-2.32), and 2.16 (95% CI, 1.10-4.25) times more likely to develop chronic LBP compared with those with no exposure (P < .001)., Conclusions and Relevance: In this cohort study, the transition rate to chronic LBP was substantial and increased correspondingly with SBT stratum and early exposure to guideline nonconcordant care.

Objective: High-quality chronic pain care emphasizes multimodal treatments that include medication and nonpharmacological treatments. But it is not clear which patients will participate in nonpharmacological treatments, such as physical therapy or mental health care, and previous research has shown conflicting evidence., Methods: We used the Patient Outcomes Repository for Treatment (PORT) registry, which combines patient-reported outcomes data with electronic medical records. In this retrospective observational study, we performed two separate multinomial regression analyses with feature selection to identify PORT variables that were predictive of 1) recommendation of a nonpharmacological treatment by the provider and 2) patient participation in nonpharmacological treatments. Two hundred thirty-six patients were recommended (REC) or not recommended (NO REC) a nonpharmacological treatment, and all REC patients were classified as participating (YES) or not participating (NO) in the recommendations., Results: Female gender and a diagnosis of Z79 "Opioid drug therapy" were significant positive and negative predictors of nonpharmacological treatment recommendations, respectively. Schedule II opioid use at initial presentation and recommendations for rehabilitation therapy were significant predictors of nonparticipation., Conclusions: Patients using opioids are less likely to be recommended nonpharmacological treatments as part of multimodal chronic pain care and are less likely to participate in nonpharmacological treatments once recommended. Males are also less likely to be recommended nonpharmacological treatments. Patients referred for rehabilitation therapies are less likely to comply with those recommendations. We have identified patients in vulnerable subgroups who may require additional resources and/or encouragement to comply with multimodal chronic pain treatment recommendations., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: It is nearly impossible to overestimate the burden of chronic pain, which is associated with enormous personal and socioeconomic costs. Chronic pain is the leading cause of disability in the world, is associated with multiple psychiatric comorbidities, and has been causally linked to the opioid crisis. Access to pain treatment has been called a fundamental human right by numerous organizations. The current COVID-19 pandemic has strained medical resources, creating a dilemma for physicians charged with the responsibility to limit spread of the contagion and to treat the patients they are entrusted to care for., Methods: To address these issues, an expert panel was convened that included pain management experts from the military, Veterans Health Administration, and academia. Endorsement from stakeholder societies was sought upon completion of the document within a one-week period., Results: In these guidelines, we provide a framework for pain practitioners and institutions to balance the often-conflicting goals of risk mitigation for health care providers, risk mitigation for patients, conservation of resources, and access to pain management services. Specific issues discussed include general and intervention-specific risk mitigation, patient flow issues and staffing plans, telemedicine options, triaging recommendations, strategies to reduce psychological sequelae in health care providers, and resource utilization., Conclusions: The COVID-19 public health crisis has strained health care systems, creating a conundrum for patients, pain medicine practitioners, hospital leaders, and regulatory officials. Although this document provides a framework for pain management services, systems-wide and individual decisions must take into account clinical considerations, regional health conditions, government and hospital directives, resource availability, and the welfare of health care providers., (The Author(s) 2020. Published by Oxford University Press on behalf of the American Academy of Pain Medicine. This work is written by a US Government employee and is in the public domain in the US.)

Interpreting randomized clinical trials (RCTs) is crucial to making decisions regarding the use of analgesic treatments in clinical practice. In this article, we report on an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) consensus meeting organized by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks, the purpose of which was to recommend approaches that facilitate interpretation of analgesic RCTs. We review issues to consider when drawing conclusions from RCTs, as well as common methods for reporting RCT results and the limitations of each method. These issues include the type of trial, study design, statistical analysis methods, magnitude of the estimated beneficial and harmful effects and associated precision, availability of alternative treatments and their benefit-risk profile, clinical importance of the change from baseline both within and between groups, presentation of the outcome data, and the limitations of the approaches used.

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., (Copyright © 2020. Published by Elsevier Inc.)

Chronic low back pain (cLBP) is a prevalent disorder. A growing body of evidence linking the pathology of the reward network to chronic pain suggests that pain sensitization may contribute to cLBP chronification via disruptions of mesocortical and mesolimbic circuits in the reward system. Resting-state (RS) functional magnetic resonance imaging (fMRI) data was acquired from 90 patients with cLBP and 74 matched pain-free controls (HCs) at baseline and after a manipulation for back pain intensification. The ventral tegmental area (VTA) was chosen as a seed region to perform RS functional connectivity (FC) analysis. Baseline rsFC of both the mesocortical (between the VTA and bilateral rostral anterior cingulate cortex (rACC)/and medial prefrontal cortex (mPFC)) and mesolimbic (between the VTA and bilateral hippocampus/parahippocampus) pathways was reduced in patients with cLBP (vs. HCs). In addition, patients exhibiting higher back pain intensity (compared to the relatively lower back pain intensity condition) also showed increases in both mesocortical and mesolimbic connectivity, implicating these pathways in pain downregulation in cLBP. Mediation analysis further isolated the mesolimbic (VTA-hippocampus/parahippocampus) dysconnectivity as a neural mechanism mediating the association between mechanical pain sensitivity (indexed by P40 pressure) and cLBP severity. In sum, the current study demonstrates deficient mesocorticolimbic connectivity in cLBP, with mesolimbic dysconnectivity potentially mediating the contribution of pain sensitization to pain chronification. These reward network dysfunctions and purportedly, dopaminergic dysregulations, may help us to identify key brain targets of neuromodulation in the treatment of cLBP., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Pain medication plays an important role in the treatment of acute and chronic pain conditions, but some drugs, opioids in particular, have been overprescribed or prescribed without adequate safeguards, leading to an alarming rise in medication-related overdose deaths. The NIH Helping to End Addiction Long-term (HEAL) Initiative is a trans-agency effort to provide scientific solutions to stem the opioid crisis. One component of the initiative is to support biomarker discovery and rigorous validation in collaboration with industry leaders to accelerate high-quality clinical research into neurotherapeutics and pain. The use of objective biomarkers and clinical trial end points throughout the drug discovery and development process is crucial to help define pathophysiological subsets of pain, evaluate target engagement of new drugs and predict the analgesic efficacy of new drugs. In 2018, the NIH-led Discovery and Validation of Biomarkers to Develop Non-Addictive Therapeutics for Pain workshop convened scientific leaders from academia, industry, government and patient advocacy groups to discuss progress, challenges, gaps and ideas to facilitate the development of biomarkers and end points for pain. The outcomes of this workshop are outlined in this Consensus Statement.

Objective: Embedded behavioral medicine services are a common component of multidisciplinary chronic pain treatment programs. However, few studies have studied whether these services are associated with improved treatment outcomes., Methods: Using a retrospective, matched, two-cohort study design, we examined patient-reported outcomes (PROs), including Patient-Reported Outcomes Measurement Information System pain, mental health, and physical function measures, collected at every clinic visit in every patient. Changes from baseline through 12 months were compared in those receiving embedded Behavioral Medicine in addition to usual care to a Standard Care group seen in the same pain practice and weighted via propensity scoring., Results: At baseline, Behavioral Medicine patients had worse scores on most pain, mental health, and physical health measures and were more likely to be female, a member of a racial minority, and have lower socioeconomic status. Regardless of having a worse clinical pain syndrome at baseline, at follow-up both Behavioral Medicine (N = 451) and Standard Care patients (N = 8,383) showed significant and comparable improvements in pain intensity, physical function, depression, and sleep disturbance. Behavioral Medicine patients showed significantly greater improvements in their global impressions of change than the Standard Care patients., Conclusions: Despite worse pain and physical and psychological functioning at baseline, Behavioral Medicine patients showed improvements comparable to patients not receiving these services. Further, Behavioral Medicine patients report higher global impressions of change, indicating that embedded mental health services appear to have the additive value of amplifying the benefits of multimodal pain care., (© 2019 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Increased opioid prescription to relieve pain among patients with chronic pain is associated with increased risk for misuse, potentially leading to substance use disorders and overdose death. We aimed to characterize the relative importance and identify the most significant of several potential risk factors for the severity of self-reported prescribed opioid misuse behaviors., Methods: A sample of 1,193 patients (mean age ± SD = 50.72 ± 14.97 years, 64.04% female) with various chronic pain conditions completed a multidimensional registry assessing four pain severity measures and 14 physical, mental, and social health status factors using the National Institutes of Health's Patient-Reported Outcomes Measurement Information System (PROMIS). A validated PROMIS measure of medication misuse was completed by 692 patients who endorsed currently taking opioid medication. Patients taking opioid medications were compared across all measures with those who do not take opioid medications. Subsequently, a data-driven regression analysis was used to determine which measures best explained variability in severity of misuse. We hypothesized that negative affect-related factors, namely anxiety, anger, and/or depression, would be key predictors of misuse severity due to their crucial role in chronic pain and substance use disorders., Results: Patients taking opioid medications had significantly greater impairment across most measures. Above and beyond demographic variables, the only and most significant predictors of prescribed opioid misuse severity were as follows: anxiety (β = 0.15, P = 0.01), anger (β = 0.13, P = 0.02), Pain Intensity-worst (β = 0.09, P = 0.02), and depression (β = 0.13, P = 0.04)., Conclusions: Findings suggest that anxiety, anger, and depression are key factors associated with prescribed opioid misuse tendencies in patients with chronic pain and that they are potential targets for therapeutic intervention., (© 2019 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Changes in central pain processing have been shown in patients with chronic low-back pain (cLBP). We used quantitative sensory testing methods to identify differences in pain sensitization between patients with cLBP (N = 167) and healthy controls (N = 33). Results indicated that, compared with healthy pain-free controls, cLBP patients showed increased sensitivity and greater painful aftersensations for mechanical pressure and pin-prick stimuli and lower tactile spatial acuity in the 2-point discrimination task (ps < 0.05). Then, we examined the role of pain catastrophizing as a mediator of the group differences in pain sensitization. We found that catastrophizing partially accounted for group differences in pressure required to produce moderate pain. Finally, we examined the relationship between pain sensitization, catastrophizing, and clinical pain among patients with cLBP. We found that catastrophizing and deep-tissue pressure pain were associated with greater pain intensity in the past month, week, and at the visit as well as low-back pain bothersomeness. Furthermore, deep-tissue pressure pain mediated the associations between catastrophizing and both pain in the past month and low-back pain severity. Taken together, these results indicate that not only do patients with cLBP demonstrate increased pain sensitization and decreased sensitivity to innocuous stimuli, but these changes are also linked with increased catastrophizing. Furthermore, both catastrophizing and sensitization are associated with increased clinical pain among cLBP patients.

Despite the high prevalence and socioeconomic impact of chronic low back pain (cLBP), treatments for cLBP are often unsatisfactory, and effectiveness varies widely across patients. Recent neuroimaging studies have demonstrated abnormal resting-state functional connectivity (rsFC) of the default mode, salience, central executive, and sensorimotor networks in chronic pain patients, but their role as predictors of treatment responsiveness has not yet been explored. In this study, we used machine learning approaches to test if pre-treatment rsFC can predict responses to both real and sham acupuncture treatments in cLBP patients. Fifty cLBP patients participated in 4 weeks of either real (N = 24, age = 39.0 ± 12.6, 16 females) or sham acupuncture (N = 26, age = 40.0 ± 13.7, 15 females) treatment in a single-blinded trial, and a resting-state fMRI scan prior to treatment was used in data analysis. Both real and sham acupuncture can produce significant pain reduction, with those receiving real treatment experiencing greater pain relief than those receiving sham treatment. We found that pre-treatment rsFC could predict symptom changes with up to 34% and 29% variances for real and sham treatment, respectively, and the rsFC characteristics that were significantly predictive for real and sham treatment differed. These results suggest a potential way to predict treatment responses and may facilitate the development of treatment plans that optimize time, cost, and available resources., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Opioid misuse in the context of chronic noncancer pain (CNCP) is a multifaceted and complex issue. As opioid misuse and corresponding rates of addiction and overdose deaths exceed epidemic proportions, there is an urgent need for research in this area. The objective of this review is to evaluate the literature addressing psychosocial interventions targeting CNCP and prescription opioid misuse., Design: A systematic search of PubMed, MEDLINE, PsychINFO, ClinicalTrials.gov was conducted to identify studies evaluating psychosocial interventions targeting CNCP and prescription opioid misuse. The review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines., Results: 56 peer-reviewed research articles from 1993 to July, 2016, which included studies of psychosocial interventions for CNCP and opioid use disorders. Studies that examined psychosocial interventions for CNCP, treatment modalities included: cognitive behavioral therapy (CBT), acceptance and commitment therapy, mindfulness-based cognitive therapy and mindfulness-based stress reduction, and chronic pain self-management programs. The psychosocial interventions for opioid misuse included: CBT and relapse prevention, motivational enhancement therapy and stages of change, contingency management, and self-help and peer support-based groups., Conclusions: The findings of this review offer clinical insight and reinforce the importance of psychosocial interventions in CNCP and opioid use disorders. However, little empirical data are available to guide practitioners in treating patients with CNCP who misuse opioid medications, and thus future research on integrated approaches, is needed.

Objective: Pain catastrophizing is a common feature of chronic pain, including fibromyalgia (FM), and is strongly associated with amplified pain severity and disability. While previous neuroimaging studies have focused on evoked pain response modulation by catastrophizing, the brain mechanisms supporting pain catastrophizing itself are unknown. We designed a functional magnetic resonance imaging (fMRI)-based pain catastrophizing task whereby patients with chronic pain engaged in catastrophizing-related cognitions. We undertook this study to test our hypothesis that catastrophizing about clinical pain would be associated with amplified activation in nodes of the default mode network (DMN), which encode self-referential cognition and show altered functioning in chronic pain., Methods: During fMRI, 31 FM patients reflected on how catastrophizing (CAT) statements (drawn from the Pain Catastrophizing Scale) impact their typical FM pain experience. Response to CAT statements was compared to response to matched neutral (NEU) statements., Results: During statement reflection, higher fMRI signal during CAT statements than during NEU statements was found in several DMN brain areas, including the ventral (posterior) and dorsal (anterior) posterior cingulate cortex (vPCC and dPCC, respectively). Patients' ratings of CAT statement applicability were correlated solely with activity in the vPCC, a main DMN hub supporting self-referential cognition (r = 0.38, P < 0.05). Clinical pain severity was correlated solely with activity in the dPCC, a PCC subregion associated with cognitive control and sensorimotor processing (r = 0.38, P < 0.05)., Conclusion: These findings provide evidence that the PCC encodes pain catastrophizing in FM and suggest distinct roles for different PCC subregions. Understanding the brain circuitry encoding pain catastrophizing in FM will prove to be important in identifying and evaluating the success of interventions targeting negative affect in chronic pain management., (© 2018, American College of Rheumatology.)

Background: Over the past 2 decades, the use of intravenous ketamine infusions as a treatment for chronic pain has increased dramatically, with wide variation in patient selection, dosing, and monitoring. This has led to a chorus of calls from various sources for the development of consensus guidelines., Methods: In November 2016, the charge for developing consensus guidelines was approved by the boards of directors of the American Society of Regional Anesthesia and Pain Medicine and, shortly thereafter, the American Academy of Pain Medicine. In late 2017, the completed document was sent to the American Society of Anesthesiologists' Committees on Pain Medicine and Standards and Practice Parameters, after which additional modifications were made. Panel members were selected by the committee chair and both boards of directors based on their expertise in evaluating clinical trials, past research experience, and clinical experience in developing protocols and treating patients with ketamine. Questions were developed and refined by the committee, and the groups responsible for addressing each question consisted of modules composed of 3 to 5 panel members in addition to the committee chair. Once a preliminary consensus was achieved, sections were sent to the entire panel, and further revisions were made. In addition to consensus guidelines, a comprehensive narrative review was performed, which formed part of the basis for guidelines., Results: Guidelines were prepared for the following areas: indications; contraindications; whether there was evidence for a dose-response relationship, or a minimum or therapeutic dose range; whether oral ketamine or another N-methyl-D-aspartate receptor antagonist was a reasonable treatment option as a follow-up to infusions; preinfusion testing requirements; settings and personnel necessary to administer and monitor treatment; the use of preemptive and rescue medications to address adverse effects; and what constitutes a positive treatment response. The group was able to reach consensus on all questions., Conclusions: Evidence supports the use of ketamine for chronic pain, but the level of evidence varies by condition and dose range. Most studies evaluating the efficacy of ketamine were small and uncontrolled and were either unblinded or ineffectively blinded. Adverse effects were few and the rate of serious adverse effects was similar to placebo in most studies, with higher dosages and more frequent infusions associated with greater risks. Larger studies, evaluating a wider variety of conditions, are needed to better quantify efficacy, improve patient selection, refine the therapeutic dose range, determine the effectiveness of nonintravenous ketamine alternatives, and develop a greater understanding of the long-term risks of repeated treatments.

Valid and reliable biomarkers can play an important role in clinical trials as indicators of biological or pathogenic processes or as a signal of treatment response. Currently, there are no biomarkers for pain qualified by the U.S. Food and Drug Administration or the European Medicines Agency for use in clinical trials. This article summarizes an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials meeting in which 3 potential biomarkers were discussed for use in the development of analgesic treatments: 1) sensory testing, 2) skin punch biopsy, and 3) brain imaging. The empirical evidence supporting the use of these tests is described within the context of the 4 categories of biomarkers: 1) diagnostic, 2) prognostic, 3) predictive, and 4) pharmacodynamic. Although sensory testing, skin punch biopsy, and brain imaging are promising tools for pain in clinical trials, additional evidence is needed to further support and standardize these tests for use as biomarkers in pain clinical trials., Perspective: The applicability of sensory testing, skin biopsy, and brain imaging as diagnostic, prognostic, predictive, and pharmacodynamic biomarkers for use in analgesic treatment trials is considered. Evidence in support of their use and outlining problems is presented, as well as a call for further standardization and demonstrations of validity and reliability., (Copyright © 2017 American Pain Society. All rights reserved.)

Objective: Opioids are frequently prescribed for chronic low back pain (CLBP), but there are broad individual differences in the benefits and risks of opioid therapy, including the development opioid-induced hyperalgesia. This study examined quantitative sensory testing (QST) data among a group of CLBP patients undergoing sustained oral opioid treatment. We investigated whether individual differences in psychological characteristics were related to opioid-induced changes in pain perception and pain modulation., Design: The six-month, open-label trial evaluated patients with low to high levels of negative affect (e.g., symptoms of distress, depression and anxiety); participants underwent QST at baseline (prior to initiating treatment) and during oral opioid treatment., Setting: A chronic pain management center., Patients: The 31 study participants had chronic discogenic back pain, with a pain intensity rating >3/10. Participants were divided into groups with high vs. low levels of Negative Affect (NA)., Results: In the previously-published manuscript describing the clinical outcomes of the trial, high NA patients achieved only about half of the analgesic effect observed in the low NA group (Wasan AD, Michna E, Edwards RR, et al. Psychiatric comorbidity is associated prospectively with diminished opioid analgesia and increased opioid misuse in patients with chronic low back pain. Anesthesiology 2015;123:861-72). The QST findings reported here suggested that tolerance to experimental (cold pressor) pain and conditioned pain modulation tended to decrease in the high NA group over the course of opioid treatment, while temporal summation of mechanical pain declined in the low NA group., Conclusions: These results reveal that while the low NA group seemed to exhibit a generally adaptive, analgesic pattern of changes during opioid management, the high NA group showed a pattern more consistent with opioid-induced hyperalgesic processes. A greater susceptibility to hyperalgesia-promoting changes in pain modulation among patients with high levels of distress may contribute to a lower degree of benefit from opioid treatment in high NA patients., (© 2016 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Unlabelled: 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., Perspective: 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., (Copyright © 2016 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Although pain reduction is commonly the primary outcome in chronic pain clinical trials, physical functioning is also important. A challenge in designing chronic pain trials to determine efficacy and effectiveness of therapies is obtaining appropriate information about the impact of an intervention on physical function. The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) and Outcome Measures in Rheumatology (OMERACT) convened a meeting to consider assessment of physical functioning and participation in research on chronic pain. The primary purpose of this article is to synthesize evidence on the scope of physical functioning to inform work on refining physical function outcome measurement. We address issues in assessing this broad construct and provide examples of frequently used measures of relevant concepts. Investigators can assess physical functioning using patient-reported outcome (PRO), performance-based, and objective measures of activity. This article aims to provide support for the use of these measures, covering broad aspects of functioning, including work participation, social participation, and caregiver burden, which researchers should consider when designing chronic pain clinical trials. Investigators should consider the inclusion of both PROs and performance-based measures as they provide different but also important complementary information. The development and use of reliable and valid PROs and performance-based measures of physical functioning may expedite development of treatments, and standardization of these measures has the potential to facilitate comparison across studies. We provide recommendations regarding important domains to stimulate research to develop tools that are more robust, address consistency and standardization, and engage patients early in tool development.

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: Over the past decade, there has been a substantial rise in the use of opioids for the treatment of chronic noncancer pain. Despite the potential benefits of opioid therapy, the rise in the use of opioids has been accompanied by escalating rates of prescription opioid misuse and addiction. There is now a growing body of evidence indicating that opioid craving (i.e., the subjective desire to consume opioids) is one of the strongest determinants of opioid misuse among patients with chronic pain prescribed opioids. Although research has elucidated some of the factors associated with opioid craving, the contribution of patients' levels of pain to opioid craving remains unclear., Objective: The main objective of this study was to examine the day-to-day association between pain and opioid craving., Methods: In this longitudinal cohort study, patients with chronic pain prescribed opioid therapy completed baseline measures and were then asked to provide daily reports of pain intensity and opioid craving for a period of 14 days., Results: Multilevel analyses indicated that day-to-day elevations in patients' levels of pain were associated with heightened opioid craving. That is, on more painful days, patients reported higher levels of craving. Within-person changes in pain intensity, however, explained less than 5% of the variance in patients' reports of craving., Conclusion: Findings from this study suggest that patients with chronic pain do not crave their opioid medications simply because they experience high levels of pain. The theoretical and clinical implications of our findings are discussed., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Opioids are frequently prescribed for chronic low back pain (CLBP), but there are little prospective data on which patient subgroups may benefit. Psychiatric comorbidity, such as high levels of depression and anxiety symptoms (termed comorbid negative affect [NA]), is a common presentation and may predict diminished opioid analgesia and/or increased opioid misuse., Methods: The authors conducted a 6½-month prospective cohort study of oral opioid therapy, with an active drug/placebo run-in period, in 81 CLBP patients with low, moderate, and high levels of NA. Treatment included an opioid titration phase with a prescribing physician blinded to NA group assignment and a 4-month continuation phase, during which subjects recorded daily pain levels using an electronic diary. The primary outcome was the percent improvement in average daily pain, summarized weekly., Results: There was an overall 25% dropout rate. Despite the high NA group being prescribed a higher average daily dose of morphine equivalents, linear mixed model analysis revealed that the 24 study completers in each of the high NA and low NA groups had an average 21 versus 39% improvement in pain, respectively (P < 0.01). The high NA group also had a significantly greater rate of opioid misuse (39 vs. 8%, P < 0.05) and significantly more and intense opioid side effects (P < 0.01)., Conclusions: These results indicate that the benefit and risk considerations in CLBP patients with high NA versus low NA are distinctly different. Thus, NA is an important phenotypic variable to characterize at baseline, before deciding whether to prescribe opioids for CLBP.

Unlabelled: Although high levels of negative affect and cognitions have been associated with greater pain sensitivity in chronic pain conditions, the neural mechanisms mediating the hyperalgesic effect of psychological factors in patients with pain disorders are largely unknown. In this cross-sectional study, we hypothesized that 1) catastrophizing modulates brain responses to pain anticipation and 2) anticipatory brain activity mediates the hyperalgesic effect of different levels of catastrophizing in fibromyalgia (FM) patients. Using functional magnetic resonance imaging, we scanned the brains of 31 FM patients exposed to visual cues anticipating the onset of moderately intense deep-tissue pain stimuli. Our results indicated the existence of a negative association between catastrophizing and pain-anticipatory brain activity, including in the right lateral prefrontal cortex. A bootstrapped mediation analysis revealed that pain-anticipatory activity in the lateral prefrontal cortex mediates the association between catastrophizing and pain sensitivity. These findings highlight the role of the lateral prefrontal cortex in the pathophysiology of FM-related hyperalgesia and suggest that deficits in the recruitment of pain-inhibitory brain circuitry during pain-anticipatory periods may play an important contributory role in the association between various degrees of widespread hyperalgesia in FM and levels of catastrophizing, a well-validated measure of negative cognitions and psychological distress., Perspective: This article highlights the presence of alterations in pain-anticipatory brain activity in FM. These findings provide the rationale for the development of psychological or neurofeedback-based techniques aimed at modifying patients' negative affect and cognitions toward pain., (Copyright © 2015 American Pain Society. Published by Elsevier Inc. All rights reserved.)

The primary purpose of this study was to examine the association between self-reports of medication side effects and pain-related activity interference in patients with chronic pain. The potential moderators of the association between reports of side effects and pain-related activity interference were also examined. A total of 111 patients with chronic musculoskeletal pain were asked to provide, once a month for a period of 6 months, self-reports of medication use and the presence of any perceived side effects (eg, nausea, dizziness, headaches) associated with their medications. At each of these time points, patients were also asked to provide self-reports of pain intensity, negative affect, and pain-related activity interference. Multilevel modeling analyses revealed that month-to-month increases in perceived medication side effects were associated with heightened pain-related activity interference (P < 0.05). Importantly, multilevel models revealed that perceived medication side effects were associated with heightened pain-related activity interference even after controlling for the influence of patient demographics, pain intensity, and negative affect. This study provides preliminary evidence that reports of medication side effects are associated with heightened pain-related activity interference in patients with chronic pain beyond the influence of other pain-relevant variables. The implications of our findings for clinical practice and the management of patients with chronic pain conditions are discussed.

Although substantial evidence has established that microglia and astrocytes play a key role in the establishment and maintenance of persistent pain in animal models, the role of glial cells in human pain disorders remains unknown. Here, using the novel technology of integrated positron emission tomography-magnetic resonance imaging and the recently developed radioligand (11)C-PBR28, we show increased brain levels of the translocator protein (TSPO), a marker of glial activation, in patients with chronic low back pain. As the Ala147Thr polymorphism in the TSPO gene affects binding affinity for (11)C-PBR28, nine patient-control pairs were identified from a larger sample of subjects screened and genotyped, and compared in a matched-pairs design, in which each patient was matched to a TSPO polymorphism-, age- and sex-matched control subject (seven Ala/Ala and two Ala/Thr, five males and four females in each group; median age difference: 1 year; age range: 29-63 for patients and 28-65 for controls). Standardized uptake values normalized to whole brain were significantly higher in patients than controls in multiple brain regions, including thalamus and the putative somatosensory representations of the lumbar spine and leg. The thalamic levels of TSPO were negatively correlated with clinical pain and circulating levels of the proinflammatory citokine interleukin-6, suggesting that TSPO expression exerts pain-protective/anti-inflammatory effects in humans, as predicted by animal studies. Given the putative role of activated glia in the establishment and or maintenance of persistent pain, the present findings offer clinical implications that may serve to guide future studies of the pathophysiology and management of a variety of persistent pain conditions., (© The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Diverting attention away from noxious stimulation (i.e., distraction) is a common pain-coping strategy. Its effects are variable across individuals, however, and the authors hypothesized that chronic pain patients who reported higher levels of pain catastrophizing would derive less pain-reducing benefit from distraction., Methods: Chronic pain patients (n=149) underwent psychometric and quantitative sensory testing, including assessment of the temporal summation of pain in the presence and absence of a distracting motor task., Results: A simple distraction task decreased temporal summation of pain overall, but, surprisingly, a greater distraction analgesia was observed in high catastrophizers. This enhanced distraction analgesia in high catastrophizers was not altered when controlling for current pain scores, depression, anxiety, or opioid use (analysis of covariance [ANCOVA]: F=8.7, P<0.005). Interestingly, the magnitude of distraction analgesia was inversely correlated with conditioned pain modulation (Pearson R=-0.23, P=0.005)., Conclusion: Distraction produced greater analgesia among chronic pain patients with higher catastrophizing, suggesting that catastrophizing's pain-amplifying effects may be due in part to greater attention to pain, and these patients may benefit from distraction-based pain management approaches. Furthermore, these data suggest that distraction analgesia and conditioned pain modulation may involve separate underlying mechanisms.

Background: Many cannabinoid medications are approved in North America or in phase III trials, such as dronabinol, nabilone, or nabiximols. Little is known about their subjective psychoactive effects when used for pain management. We hypothesized that when used for pain, dronabinol has psychoactive effects in a dose-response relationship, whose peak effects are comparable with smoking marijuana., Methods: This was a randomized controlled trial of single dose placebo, 10 or 20 mg dronabinol in 30 chronic noncancer pain patients taking opioids and not using marijuana. Participants completed the Addiction Research Center Inventory (ARCI) hourly for 8 hours during 3 monitored sessions. Comparison sample was the ARCI ratings in participants with no pain (N=20), monitored every 30 minutes after smoking a 1.99% THC (low) and a 3.51% (high strength) marijuana cigarette., Results: The 10 and 20 mg dronabinol doses had significantly elevated scores over time on 4/5 subscales versus placebo (P<0.05). Average daily morphine use, total pain relief (TOTPAR), age, sex, and baseline pain level were not significant covariates. ARCI peak effects at 2 hours were similar to peak effects of smoked marijuana at 30 minutes (P=0.80, 10 mg=low strength, 20 mg=high strength)., Conclusions: In pain patients, oral dronabinol has similar psychoactive effects to smoking marijuana. This risk must be considered in any decision to prescribe cannabinoid medications for pain.

Objective: To implement a collaborative care management program with buprenorphine in a primary care clinic., Design: Prospective observational study., Setting: A busy urban academic primary care clinic affiliated with a tertiary care hospital., Participants: Opioid-dependent patients or patients with chronic pain using opioids nonmedically were recruited for the study. A total of 45 participants enrolled., Interventions: Patients were treated with buprenorphine and managed by a supervising psychiatrist, pharmacist care manager, and health coaches. The care manager conducted buprenorphine inductions and all follow-up visits. Health coaches offered telephonic support. The psychiatrist supervised both the care manager and health coaches., Main Outcome Measures: Primary outcomes were treatment retention at 6 months, and change in the proportion of aberrant toxicology results and opioid craving scores from baseline to 6 months. After data collection, clinical outcomes were compared between opioid-dependent patients and patients with chronic pain using opioids nonmedically. Overall, 55.0 percent of participants (25/45) remained in treatment at 6 months. Primary care physicians (PCPs)' attitudes about opioid dependence treatment were surveyed at baseline and at 18 months., Results: Forty-three patients (95.6 percent) accepted treatment and 25 (55.0 percent) remained in treatment at 6 months. The proportion of aberrant urine toxicology results decreased significantly from baseline to 6 months (p < 0.01). Craving scores significantly decreased from baseline to 6 months (p < 0.01). Opioid-dependent patients, as opposed to patients with chronic pain using opioids nonmedically, were significantly more likely to complete 6 months of treatment (p < 0.05). PCPs' confidence in treating opioid dependence in primary care increased significantly from baseline to 18 months postimplementation (p < 0.01)., Conclusion: Collaborative care management for opioid dependence with buprenorphine may be feasible in a primary care clinic. More research is needed to understand the role of buprenorphine in managing patients with chronic pain using opioids nonmedically.

Unlabelled: Current approaches to classification of chronic pain conditions suffer from the absence of a systematically implemented and evidence-based taxonomy. Moreover, existing diagnostic approaches typically fail to incorporate available knowledge regarding the biopsychosocial mechanisms contributing to pain conditions. To address these gaps, the Analgesic, Anesthetic, and Addiction Clinical Trial Translations Innovations Opportunities and Networks (ACTTION) public-private partnership with the U.S. Food and Drug Administration and the American Pain Society (APS) have joined together to develop an evidence-based chronic pain classification system called the ACTTION-APS Pain Taxonomy. This paper describes the outcome of an ACTTION-APS consensus meeting, at which experts agreed on a structure for this new taxonomy of chronic pain conditions. Several major issues around which discussion revolved are presented and summarized, and the structure of the taxonomy is presented. ACTTION-APS Pain Taxonomy will include the following dimensions: 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 coming months, expert working groups will apply this taxonomy to clusters of chronic pain conditions, thereby developing a set of diagnostic criteria that have been consistently and systematically implemented across nearly all common chronic pain conditions. It is anticipated that the availability of this evidence-based and mechanistic approach to pain classification will be of substantial benefit to chronic pain research and treatment., Perspective: The ACTTION-APS Pain Taxonomy is an evidence-based chronic pain classification system designed to classify chronic pain along the following dimensions: 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., (Copyright © 2014 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Objectives: To examine the temporal stability of conditioned pain modulation (CPM), formerly termed diffuse noxious inhibitory controls, among a sample of patients with chronic pain. The study also examined the factors that might be responsible for the stability of CPM., Design, Subjects, and Methods: In this test-retest study, patients underwent a series of standardized psychophysical pain-testing procedures designed to assess CPM on two separate occasions (i.e., baseline and follow up). Patients also completed self-report measures of catastrophizing (Pain Catastrophizing Scale [PCS] and negative affect [NA])., Results: Overall, results provided evidence for the stability of CPM among patients with chronic pain. Results, however, revealed considerable sex differences in the stability of CPM. For women, results revealed a significant test-retest correlation between baseline and follow-up CPM scores. For men, however, the test-retest correlation between baseline and follow-up CPM scores was not significant. Results of a Fisher's Z-test revealed that the stability of CPM was significantly greater for women than for men. Follow-up analyses revealed that the difference between men and women in the stability of CPM could not be accounted for by any demographic (e.g., age) and/or psychological factors (PCS and NA)., Conclusions: Our findings suggest that CPM paradigms possess sufficient reliability to be incorporated into bedside clinical evaluation of patients with chronic pain, but only among women. The lack of CPM reproducibility/stability observed among men places limits on the potential use of CPM paradigms in clinical settings for the assessment of men's endogenous pain-inhibitory function., (Wiley Periodicals, Inc.)

Background: As a consequence of the substantial rise in the prescription of opioids for the treatment of chronic noncancer pain, greater attention has been paid to the factors that may be associated with an increased risk for prescription opioid misuse. Recently, a growing number of studies have shown that patients with high levels of catastrophizing are at increased risk for prescription opioid misuse., Objective: The primary objective of this study was to examine the variables that might underlie the association between catastrophizing and risk for prescription opioid misuse in patients with chronic pain., Methods: Patients with chronic musculoskeletal pain (n=115) were asked to complete the SOAPP-R, a validated self-report questionnaire designed to identify patients at risk for prescription opioid misuse. Patients were also asked to complete self-report measures of pain intensity, catastrophizing, anxiety, and depression., Results: Consistent with previous research, we found that catastrophizing was associated with an increased risk for prescription opioid misuse. Results also revealed that the association between catastrophizing and risk for opioid misuse was partially mediated by patients' levels of anxiety. Follow-up analyses, however, indicated that catastrophizing remained a significant 'unique' predictor of risk for opioid misuse even when controlling for patients' levels of pain severity, anxiety and depressive symptoms., Discussion: Discussion addresses the factors that might place patients with high levels of catastrophizing at increased risk for prescription opioid misuse. The implications of our findings for the management of patients considered for opioid therapy are also discussed., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

A fundamental characteristic of neural circuits is the capacity for plasticity in response to experience. Neural plasticity is associated with the development of chronic pain disorders. In this study, we investigated 1) brain resting state functional connectivity (FC) differences between patients with chronic low back pain (cLBP) and matched healthy controls (HC); 2) FC differences within the cLBP patients as they experienced different levels of endogenous low back pain evoked by exercise maneuvers, and 3) morphometric differences between cLBP patients and matched HC. We found the dynamic character of FC in the primary somatosensory cortex (S1) in cLBP patients, i.e., S1 FC decreased when the patients experienced low intensity LBP as compared with matched healthy controls, and FC at S1 increased when cLBP patients experienced high intensity LBP as compared with the low intensity condition. In addition, we also found increased cortical thickness in the bilateral S1 somatotopically associated with the lower back in cLBP patients as compared to healthy controls. Our results provide evidence of structural plasticity co-localized with areas exhibiting FC changes in S1 in cLBP patients.

Background: Patients prescribed opioids for chronic pain may suffer from inadequate postoperative pain control. Ketamine is an adjuvant demonstrating analgesic and opioid-sparing effects. We hypothesize that an intravenous ketamine infusion in addition to opioid-based patient-controlled analgesia (PCA) improves postoperative pain relief in this patient population., Methods: We evaluated 64 patients with chronic pain taking opioids undergoing nononcologic surgery. Patients were randomized to receive either postoperative hydromorphone PCA and continuous ketamine (0.2 mg/kg/hour), or hydromorphone PCA and saline. Patients provided numeric rating scale (NRS) pain scores for "worst," "average," and "least" pain following surgery. The primary outcome measure was change in patients' postoperative NRS scores compared with baseline NRS. Secondary and tertiary outcomes included postoperative day one 24-hour opioid use and the amount of opioid used 24 hours prior to hospital discharge., Results: Fifty-nine patients were included in the analysis. Baseline patient characteristics were similar with the exception of age. Patients using ketamine had decreased "average" pain scores (percent change between postoperative and preoperative NRS) after surgery (13.5% decrease in the ketamine group vs 15.5% increase in NRS in the placebo group, P = 0.0057). There were no differences in "worst" or "least" pain scores or postoperative opioid use. Side effects between groups were similar., Conclusions: Our study demonstrates that a postoperative ketamine infusion at 0.2 mg/kg/hour in addition to opioids results in a statistically significant reduction of "average" pain scores in patients undergoing surgery who take opioids for chronic pain. However, "least" and "worst" pain scores and the amount of opioid used postoperatively did not differ between groups. Thus, the use of a postoperative ketamine infusion at 0.2 mg/kg/hour provides limited benefit in improving pain management for this challenging population., (Wiley Periodicals, Inc.)

A large number of studies have provided evidence for the efficacy of psychological and other non-pharmacological interventions in the treatment of chronic pain. While these methods are increasingly used to treat pain, remarkably few studies focused on the exploration of their neural correlates. The aim of this article was to review the findings from neuroimaging studies that evaluated the neural response to distraction-based techniques, cognitive behavioral therapy (CBT), clinical hypnosis, mental imagery, physical therapy/exercise, biofeedback, and mirror therapy. To date, the results from studies that used neuroimaging to evaluate these methods have not been conclusive and the experimental methods have been suboptimal for assessing clinical pain. Still, several different psychological and non-pharmacological treatment modalities were associated with increased pain-related activations of executive cognitive brain regions, such as the ventral- and dorsolateral prefrontal cortex. There was also evidence for decreased pain-related activations in afferent pain regions and limbic structures. If future studies will address the technical and methodological challenges of today's experiments, neuroimaging might have the potential of segregating the neural mechanisms of different treatment interventions and elucidate predictive and mediating factors for successful treatment outcomes. Evaluations of treatment-related brain changes (functional and structural) might also allow for sub-grouping of patients and help to develop individualized treatments., (Copyright © 2012. Published by Elsevier Ireland Ltd.)

Objective: Previous vagus nerve stimulation (VNS) studies have demonstrated antinociceptive effects, and recent noninvasive approaches, termed transcutaneous-vagus nerve stimulation (t-VNS), have utilized stimulation of the auricular branch of the vagus nerve in the ear. The dorsal medullary vagal system operates in tune with respiration, and we propose that supplying vagal afferent stimulation gated to the exhalation phase of respiration can optimize t-VNS., Design: Counterbalanced, crossover study., Patients: Patients with chronic pelvic pain (CPP) due to endometriosis in a specialty pain clinic. INTERVENTIONS/OUTCOMES: We evaluated evoked pain analgesia for respiratory-gated auricular vagal afferent nerve stimulation (RAVANS) compared with nonvagal auricular stimulation (NVAS). RAVANS and NVAS were evaluated in separate sessions spaced at least 1 week apart. Outcome measures included deep-tissue pain intensity, temporal summation of pain, and anxiety ratings, which were assessed at baseline, during active stimulation, immediately following stimulation, and 15 minutes after stimulus cessation., Results: RAVANS demonstrated a trend for reduced evoked pain intensity and temporal summation of mechanical pain, and significantly reduced anxiety in N = 15 CPP patients, compared with NVAS, with moderate to large effect sizes (η(2) > 0.2)., Conclusion: Chronic pain disorders such as CPP are in great need of effective, nonpharmacological options for treatment. RAVANS produced promising antinociceptive effects for quantitative sensory testing (QST) outcomes reflective of the noted hyperalgesia and central sensitization in this patient population. Future studies should evaluate longer-term application of RAVANS to examine its effects on both QST outcomes and clinical pain., (Wiley Periodicals, Inc.)

A number of pharmacologic treatments examined in recent randomized clinical trials (RCTs) have failed to show statistically significant superiority to placebo in conditions in which their efficacy had previously been demonstrated. Assuming the validity of previous evidence of efficacy and the comparability of the patients and outcome measures in these studies, such results may be a consequence of limitations in the ability of these RCTs to demonstrate the benefits of efficacious analgesic treatments vs placebo ("assay sensitivity"). Efforts to improve the assay sensitivity of analgesic trials could reduce the rate of falsely negative trials of efficacious medications and improve the efficiency of analgesic drug development. Therefore, an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials consensus meeting was convened in which the assay sensitivity of chronic pain trials was reviewed and discussed. On the basis of this meeting and subsequent discussions, the authors recommend consideration of a number of patient, study design, study site, and outcome measurement factors that have the potential to affect the assay sensitivity of RCTs of chronic pain treatments. Increased attention to and research on methodological aspects of clinical trials and their relationships with assay sensitivity have the potential to provide the foundation for an evidence-based approach to the design of analgesic clinical trials and expedite the identification of analgesic treatments with improved efficacy and safety., (Copyright © 2012 International Association for the Study of Pain. All rights reserved.)

Unlabelled: Little is known about whether patients with chronic pain treated with opioids experience craving for their medications, whether contextual cues may influence craving, or if there is a relationship between craving and medication compliance. We hypothesized that craving for prescription opioids would be significantly correlated with the urge for more medication, preoccupation with the next dose, and current mood symptoms. We studied craving in 62 patients with chronic pain who were at low or high risk for opioid misuse, while they were enrolled in an RCT to improve prescription opioid medication compliance. Using electronic diaries, patients completed ratings of craving at monthly clinic visits and daily during a 14-day take-home period. Both groups consistently endorsed craving, whose levels were highly correlated (P < .001) with urge, preoccupation, and mood. The intervention to improve opioid compliance in the high-risk group was significantly associated with a rate of decrease in craving over time in comparison to a high-risk control group (P < .05). These findings indicate that craving is a potentially important psychological construct in pain patients prescribed opioids, regardless of their level of risk to misuse opioids. Targeting craving may be an important intervention to decrease misuse and improve prescription opioid compliance., Perspective: Patients with noncancer pain can crave their prescription opioids, regardless of their risk for opioid misuse. We found craving to be highly correlated with the urge to take more medication, fluctuations in mood, and preoccupation with the next dose, and to diminish with a behavioral intervention to improve opioid compliance., (Copyright © 2012 American Pain Society. Published by Elsevier Inc. All rights reserved.)