# Publications by Year: 2020

## 2020

Importance  Chronic low back pain has high societal and personal impact but remains challenging to treat. Electroacupuncture has demonstrated superior analgesia compared with placebo in animal studies but has not been extensively studied in human chronic pain conditions.

Objective  To evaluate the treatment effect of real electroacupuncture vs placebo in pain and disability among adults with chronic low back pain and to explore psychophysical, affective, and demographic factors associated with response to electroacupuncture vs placebo in treating chronic low back pain.

Design, Setting, and Participants  This double-blind randomized clinical trial was conducted between August 2, 2016, and December 18, 2018, at a single center in Stanford, California. Primary outcomes were collected at approximately 2 weeks before and after intervention. Participants included English-speaking adults with at least 6 months of chronic low back pain, pain intensity of at least 4 on a scale of 0 to 10, and no radiculopathy. Data analyses for this intent-to-treat study were conducted from June 2019 to June 2020.

Interventions  Twelve sessions of real or placebo (sham) electroacupuncture administered twice a week over 6 weeks.

Main Outcomes and Measures  The main outcome was change in pain severity from baseline to 2 weeks after completion of treatment, measured by the National Institutes of Health PROMIS pain intensity scale. A secondary outcome was change in the Roland Morris Disability Questionnaire (RMDQ). Baseline factors potentially associated with these outcomes included psychophysical testing (ie, thermal temporal summation, conditioned pain modulation, pressure pain threshold), participant’s self-report (ie, widespread pain, coping strategies, expectations, self-efficacy, and pain catastrophizing), and demographic characteristics (eg, age, sex, and race).

Results  A total of 121 adults were recruited to the study, among whom 59 participants (mean [SD] age, 46.8 [11.9] years; 36 [61.0%] women) were randomized to real electroacupuncture and 62 participants (mean [SD] age, 45.6 [12.8] years; 33 [53.2%] women) were randomized to sham electroacupuncture. At baseline, the mean (SD) PROMIS T-score was 50.49 (3.36) in the real electroacupuncture group and 51.71 (4.70) in the sham acupuncture group, and the mean (SD) RMDQ score was 10.16 (4.76) in the real electroacupuncture group and 10.03 (5.45) in the sham acupuncture group. After adjusting for baseline pain scores, there was no statistically significant difference between groups in change in T-scores 2 weeks after completion of treatment (real electroacupuncture: −4.33; 95% CI, −6.36 to −2.30; sham acupuncture: −2.90; 95% CI, −4.85 to −0.95; difference: −2.09; 95% CI, −4.27 to 0.09; P = .06). After adjusting for baseline RMDQ, there was a significantly greater reduction in RMDQ in the real electroacupuncture group (−2.77; 95% CI, −4.11 to −1.43) compared with the sham electroacupuncture group (−0.67; 95% CI, −1.88 to 0.55; difference: −2.11; 95% CI, −3.75 to −0.47; P = .01). Within the real electroacupuncture group, effective coping at baseline was associated with greater RMDQ reduction (r = −0.32; 95% CI, −0.54 to −0.05; P = .02), and White race was associated with worse outcomes in PROMIS score (β = 3.791; 95% CI, 0.616 to 6.965; P = .02) and RMDQ (β = 2.878; 95% CI, 0.506 to 5.250; P = .02).

Conclusions and Relevance  This randomized clinical trial found no statistically significant difference in change in PROMIS pain score in real electroacupuncture vs sham electroacupuncture. There was a statistically significant treatment effect for the secondary outcome of RMDQ compared with sham electroacupuncture. Effective coping skills and non-White race were associated with response to electroacupuncture.

Nicol AL, Adams MCB, Gordon DB, et al. AAAPT Diagnostic Criteria for Acute Low Back Pain with and Without Lower Extremity Pain. Pain Med. 2020;21(11):2661-2675.
OBJECTIVE: Low back pain is one of the most common reasons for which people visit their doctor. Between 12% and 15% of the US population seek care for spine pain each year, with associated costs exceeding \$200 billion. Up to 80% of adults will experience acute low back pain at some point in their lives. This staggering prevalence supports the need for increased research to support tailored clinical care of low back pain. This work proposes a multidimensional conceptual taxonomy. METHODS: A multidisciplinary task force of the ACTTION-APS-AAPM Pain Taxonomy (AAAPT) with clinical and research expertise performed a focused review and analysis, applying the AAAPT five-dimensional framework to acute low back pain. RESULTS: Application of the AAAPT framework yielded the following: 1) Core Criteria: location, timing, and severity of acute low back pain were defined; 2) Common Features: character and expected trajectories were established in relevant subgroups, and common pain assessment tools were identified; 3) Modulating Factors: biological, psychological, and social factors that modulate interindividual variability were delineated; 4) Impact/Functional Consequences: domains of impact were outlined and defined; 5) Neurobiological Mechanisms: putative mechanisms were specified including nerve injury, inflammation, peripheral and central sensitization, and affective and social processing of acute low back pain. CONCLUSIONS: The goal of applying the AAAPT taxonomy to acute low back pain is to improve its assessment through a defined evidence and consensus-driven structure. The criteria proposed will enable more rigorous meta-analyses and promote more generalizable studies of interindividual variation in acute low back pain and its potential underlying mechanisms. Wilson AC, Stone AL, Cordts KMP, et al. Baseline Characteristics of a Dyadic Cohort of Mothers With Chronic Pain and Their Children. Clin. J. Pain. 2020;36(10):782-792. OBJECTIVES: A growing body of research has demonstrated a robust link between parental chronic pain and child pain and psychological function. Although the association between parent and child pain is strong, there are limited data to understand environmental and behavioral processes that account for the association and how this develops over time. This longitudinal cohort study was designed to understand the potential mechanisms that confer risk or resilience for chronic pain among child offspring of mothers with chronic pain. METHODS: The current paper presents baseline data on the cohort to describe the pain and psychosocial characteristics of mothers with chronic pain and their 8- to 12-year-old children. A total of 400 mothers with chronic pain and their children were enrolled into the longitudinal study and completed measures of pain, physical, and psychosocial functioning. RESULTS: Mothers reported a range of pain and pain-related disability and were grouped into 4 pain grades (PGs) representing different pain and disability levels. Mothers in these groups differed on rates of widespread pain and opioid use. Maternal PGs also differed by physical function, fatigue, sleep disturbance, and psychological function. Most children in this sample reported pain and psychosocial symptoms in the nonclinical range, and child variables did not differ by maternal PG. Maternal disability and function were concurrently associated with child psychosocial function. DISCUSSION: While maternal PGs map broadly onto several dimensions of maternal functioning, they were not significantly related to child pain or function. Results may help identify potential protective factors in the intergenerational transmission of risk for chronic pain. OBJECTIVES: Post-traumatic stress disorder (PTSD) commonly co-occurs with chronic pain. Although PTSD symptoms are associated with negative health outcomes in patients with chronic pain, PTSD is typically under-detected and under-treated in outpatient pain settings. There is a need for rapid, brief screening tools to identify those at greatest risk for severe PTSD symptoms. To achieve that goal, our aim was to use item response theory (IRT) to identify the most informative PTSD symptoms characterizing severe PTSD in patients with chronic pain. METHODS: Fifty-six patients (71% female, 61% White) with mixed etiology chronic pain completed the PTSD Checklist-Civilian Version (PCL-C) as part of their appointment with a pain psychologist at a tertiary outpatient pain clinic. We used an IRT approach to evaluate each item s discriminant (a) and severity (b) parameters. RESULTS: Findings revealed that “feeling upset at reminders” (a = 3.67, b = 2.44) and “avoid thinking or talking about it” (a = 3.61, b = 2.17) as being highly discriminant for severe PTSD. CONCLUSIONS: We identified 2 candidate items for a brief PTSD screener as they were associated with severe PTSD symptoms. These 2 items may provide clinical utility in outpatient pain treatment settings to identify those suffering from severe PTSD, enabling physicians to refer them to trauma-specific evaluation or therapy. Future research is needed to further validate and confirm these candidate PTSD items in a larger clinic sample. LAY SUMMARY: The current study used the IRT approach to identify candidate items for a brief screener for severe PTSD. We examined 17 items of the PCL-C, and identified 2 items that were highly discriminant for severe PTSD. The 2 items were “feeling upset at reminders” and “avoid thinking or talking about it.” These 2 items may provide clinical utility, since they may enable physicians to screen and make a referral for further assessment or treatment for PTSD. BACKGROUND: Independent of pain intensity, pain-specific distress is highly predictive of pain treatment needs, including the need for prescription opioids. Given the inherently distressing nature of chronic pain, there is a need to equip individuals with pain education and self-regulatory skills that are shown to improve adaptation and improve their response to medical treatments. Brief, targeted behavioral medicine interventions may efficiently address the key individual factors, improve self-regulation in the context of pain, and reduce the need for opioid therapy. This highlights the critical need for targeted, cost-effective interventions that efficiently address the key psychological factors that can amplify the need for opioids and increased risk for misuse. In this trial, the primary goal is to test the comparative efficacy of a single-session skills-based pain management class to a health education active control group among patients with chronic pain who are taking opioids. METHODS/DESIGN: Our study is a randomized, double-blind clinical trial testing the superiority of our 2-h, single-session skills-based pain management class against a 2-h health education class. We will enroll 136 adult patients with mixed-etiology chronic pain who are taking opioid prescription medication and randomize 1:1 to one of the two treatment arms. We hypothesize superiority for the skills-based pain class for pain control, self-regulation of pain-specific distress, and reduced opioid use measured by daily morphine equivalent. Team researchers masked to treatment assignment will assess outcomes up to 12 months post treatment. DISCUSSION: This study aims to test the utility of a single-session, 2-h skills-based pain management class to improve self-regulation of pain and reduce opioid use. Findings from our project have the potential to shift current research and clinical paradigms by testing a brief and scalable intervention that could reduce the need for opioids and prevent misuse effectively, efficiently, and economically. Further, elucidation of the mechanisms of opioid use can facilitate refinement of more targeted future treatments. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03950791. Registered on 10 May 2019. Cumulative evidence supports the association between perceived childhood neglect and adulthood psychological and physical health. To date, pathways mediating this association remain largely unknown, though other evidence suggests that negative patterns of appraisal, including injustice perception related to pain, may be shaped by prior adverse social experiences. Consequently, the current study examined perceived injustice about chronic pain as a possible factor connecting childhood neglect and pain-related outcomes, given its relevance for both adaptation to chronic pain and to prior adverse life experiences. Patients (n = 742) visiting a tertiary pain clinic completed a survey administered via the Collaborative Health Outcomes Information Registry. Path modeling analyses were used to examine perceived injustice as a mediator of the relationships between childhood neglect and affective distress and physical function, after controlling for pain intensity and pain catastrophizing. Patients endorsing childhood neglect reported higher levels of perceived injustice and worse affective distress and physical function. Further, inclusion of perceived injustice as a mediator fully accounted for the relationship between neglect and current levels of physical function, and accounted for a significant proportion of the relationship between neglect and current levels of affective distress. These preliminary findings suggest that perceived injustice appears to be a more proximal factor by which prior experiences of neglect may adversely affect adaptation to chronic pain. Given the single-item assessment of childhood neglect and cross-sectional nature of the current findings, further research may focus on replicating these findings in longitudinal studies with validated measures and examining other adverse social experiences (e.g., abuse, social disparities) that may contribute to injustice perception and poor pain-related outcomes. AIMS: The Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network initiated a second observational cohort study-the Symptom Patterns Study (SPS)-to further investigate the underlying pathophysiology of Urologic Chronic Pelvic Pain Syndrome (UCPPS) and to discover factors associated with longitudinal symptom changes and responses to treatments. METHODS: This multisite cohort study of males and females with UCPPS features a run-in period of four weekly web-based symptom assessments before a baseline visit, followed by quarterly assessments up to 36 months. Controls were also recruited and assessed at baseline and 6 months. Extensive clinical data assessing urological symptoms, nonurological pain, chronic overlapping pain syndromes, and psychosocial factors were collected. Diverse biospecimens for biomarker and microbiome studies, quantitative sensory testing (QST) data under multiple stimuli, and structural and functional neuroimaging scans were obtained under a standardized protocol. RESULTS: Recruitment was initiated (July 2015) and completed (February 2019) at six discovery sites. A total of 620 males and females with UCPPS and 73 Controls were enrolled, including 83 UCPPS participants who re-enrolled from the first MAPP Network cohort study (2009-2012). Baseline neuroimaging scans, QST measures, and biospecimens were obtained on 578 UCPPS participants. The longitudinal follow-up of the cohort is ongoing. CONCLUSIONS: This comprehensive characterization of a large UCPPS cohort with extended follow-up greatly expands upon earlier MAPP Network studies and provides unprecedented opportunities to increase our understanding of UCPPS pathophysiology, factors associated with symptom change, clinically relevant patient phenotypes, and novel targets for future interventions. 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. Falasinnu T, Drenkard C, Bao G, Mackey S, Lim S. The problem of pain in lupus: an explication of the role of biopsychosocial mechanisms. J. Rheumatol. 2020. OBJECTIVE: To define biopsychosocial mechanisms of pain that go above and beyond disease activity and organ damage in systemic lupus erythematosus (SLE). METHODS: We conducted a cross-sectional analysis of patient-reported data in a population-based registry of 766 people with SLE. Predictors of pain intensity and interference were examined using hierarchical linear regression. We built two main hierarchical regression models: pain intensity regressed on disease activity and organ damage; and pain interference regressed on disease activity and organ damage. For each model, we sought to establish the relationship between pain outcomes and the primary exposures using sequential steps comprising the inclusion of each construct in six stages: demographic, socioeconomic, physical, psychological, behavioral and social factors. We also conducted sensivity analyses eliminating all overt aspects of pain in the disease activity measure and reestimated the models. RESULTS: Disease activity and organ damage explained 32-33% of the variance in pain intensity and interference. Sociodemographic factors accounted for an additional 4-9% of variance in pain outcomes, while psychosocial/behavioral factors accounted for the final 4% of variance. In the sensitivity analyses, we found that disease activity and organ damage explained 25% of the variance in pain outcomes. CONCLUSION: Disease activity only explained 33% of the variance of pain outcomes. However, there was an attenuation in these associations after accounting for psychosocial/behavioral factors, highlighting their roles in modifying the relationship between disease activity and pain. These findings suggest that multilevel interventions may be needed to tackle the negative impact of pain in SLE. 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 \$\pm\$SD = 50.72 \$\pm\\$ 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.