# PUBLICATIONS

## 2019

Importance: Acute postoperative pain is associated with the development of persistent postsurgical pain, but it is unclear which aspect is most estimable. Objective: To identify patient clusters based on acute pain trajectories, preoperative psychosocial characteristics associated with the high-risk cluster, and the best acute pain predictor of remote outcomes. Design, Setting, and Participants: A secondary analysis of the Stanford Accelerated Recovery Trial randomized, double-blind clinical trial was conducted at a single-center, tertiary, referral teaching hospital. A total of 422 participants scheduled for thoracotomy, video-assisted thoracoscopic surgery, total hip replacement, total knee replacement, mastectomy, breast lumpectomy, hand surgery, carpal tunnel surgery, knee arthroscopy, shoulder arthroplasty, or shoulder arthroscopy were enrolled between May 25, 2010, and July 25, 2014. Data analysis was performed from January 1 to August 1, 2018. Interventions: Patients were randomized to receive gabapentin (1200 mg, preoperatively, and 600 mg, 3 times a day postoperatively) or active placebo (lorazepam, 0.5 mg preoperatively, inactive placebo postoperatively) for 72 hours. Main Outcomes and Measures: A modified Brief Pain Inventory prospectively captured 3 surgical site pain outcomes: average pain and worst pain intensity over the past 24 hours, and current pain intensity. Within each category, acute pain trajectories (first 10 postoperative pain scores) were compared using a k-means clustering algorithm. Fifteen descriptors of acute pain were compared as predictors of remote postoperative pain resolution, opioid cessation, and full recovery. Results: Of the 422 patients enrolled, 371 patients (\$łeq\$10% missing pain scores) were included in the analysis. Of these, 146 (39.4%) were men; mean (SD) age was 56.67 (11.70) years. Two clusters were identified within each trajectory category. The high pain cluster of the average pain trajectory significantly predicted prolonged pain (hazard ratio [HR], 0.63; 95% CI, 0.50-0.80; P \textless .001) and delayed opioid cessation (HR, 0.52; 95% CI, 0.41-0.67; P \textless .001) but was not a predictor of time to recovery in Cox proportional hazards regression (HR, 0.89; 95% CI, 0.69-1.14; P = .89). Preoperative risk factors for categorization to the high average pain cluster included female sex (adjusted relative risk [ARR], 1.36; 95% CI, 1.08-1.70; P = .008), elevated preoperative pain (ARR, 1.11; 95% CI, 1.07-1.15; P \textless .001), a history of alcohol or drug abuse treatment (ARR, 1.90; 95% CI, 1.42-2.53; P \textless .001), and receiving active placebo (ARR, 1.27; 95% CI, 1.03-1.56; P = .03). Worst pain reported on postoperative day 10 was the best predictor of time to pain resolution (HR, 0.83; 95% CI, 0.78-0.87; P \textless .001), opioid cessation (HR, 0.84; 95% CI, 0.80-0.89; P \textless .001), and complete surgical recovery (HR, 0.91; 95% CI, 0.86-0.96; P \textless .001). Conclusions and Relevance: This study has shown a possible uniform predictor of remote postoperative pain, opioid use, and recovery that can be easily assessed. Future work is needed to replicate these findings. Trial Registration: ClinicalTrials.gov Identifier: NCT01067144.
Islam H, Law CSW, Weber KA, Mackey SC, Glover GH. Dynamic per slice shimming for simultaneous brain and spinal cord fMRI. Magn. Reson. Med. 2019;81(2):825-838.
PURPOSE: Simultaneous brain and spinal cord functional MRI is emerging as a new tool to study the central nervous system but is challenging. Poor B0 homogeneity and small size of the spinal cord are principal obstacles to this nascent technology. Here we extend a dynamic shimming approach, first posed by Finsterbusch, by shimming per slice for both the brain and spinal cord. METHODS: We shim dynamically by a simple and fast optimization of linear field gradients and frequency offset separately for each slice in order to minimize off-resonance for both the brain and spinal cord. Simultaneous acquisition of brain and spinal cord fMRI is achieved with high spatial resolution in the spinal cord by means of an echo-planar RF pulse for reduced FOV. Brain slice acquisition is full FOV. RESULTS: T2*-weighted images of brain and spinal cord are acquired with high clarity and minimal observable image artifacts. Fist-clenching fMRI experiments reveal task-consistent activation in motor cortices, cerebellum, and C6-T1 spinal segments. CONCLUSIONS: High quality functional results are obtained for a sensory-motor task. Consistent activation in both the brain and spinal cord is observed at individual levels, not only at group level. Because reduced FOV excitation is applicable to any spinal cord section, future continuation of these methods holds great potential.
Hoang NS, Hwang W, Katz DA, Mackey SC, Hofmann L. Electronic Patient-Reported Outcomes: Semi-Automated Data Collection in the Interventional Radiology Clinic. J. Am. Coll. Radiol. 2019;16(4 Pt A):472-477.
INTRODUCTION: Patient-reported outcomes are important for clinical research and will likely be used in the near future as a metric for physician reimbursement. This study aims to evaluate the implementation of an electronic data collection system for deep vein thrombosis and lymphedema quality-of-life (QOL) questionnaires in a tertiary care interventional radiology practice. METHODS: A single provider s clinic patients were automatically e-mailed validated questionnaires 1 week before their appointments. If not completed via e-mail, the questionnaire was administered on an electronic tablet in clinic by a research coordinator. Patients were also sent postprocedure questionnaires. RESULTS: In all, 106 patients visited the clinic for a pre-intervention venous consultation. Of them, 96% (n = 102 of 106) completed the pre-intervention questionnaire: 48% (n = 47 of 98) via e-mail and 52% (n = 51 of 98) via tablet. Of the patients who had procedures and were sent questionnaires, 49% (n = 26 of 53) were seen in person. Of the postprocedure in-person clinic patients, 76% (n = 20 of 26) completed the questionnaire via e-mail, and the remainder with the tablet in clinic. Twenty-seven of the 53 (51%) patients did not return for follow-up and instead were sent an electronic questionnaire as their only source of follow-up, of which 74% (n = 20 of 27) complied. CONCLUSION: After an initial introduction to electronic QOL reporting, patients were more likely to complete the questionnaires remotely for their follow-up appointment. A semi-automated electronic QOL system allows physicians to collect patient outcome data even in the absence of a clinic visit.
Heirich MS, Sinjary LS, Ziadni MS, et al. Use of Immersive Learning and Simulation Techniques to Teach and Research Opioid Prescribing Practices. Pain Med. 2019;20(3):456-463.
INTRODUCTION: Unsafe opioid prescribing practices to treat acute and chronic pain continue to contribute to the opioid overdose crisis in the United States, a growing public health emergency that harms patients and their communities. Poor opioid prescribing practices stem in part from a lack of education and skills training surrounding pain and opioid management. METHODS: As part of the Clinical Pain Medicine Fellowship at Stanford University, physicians were given the opportunity to participate in a pilot program to practice opioid management in a live, simulated interaction. Twenty-seven physician trainees participated in the simulation with a live, standardized patient actor. Before beginning the simulation, participants were given a detailed patient history that included the patient s risk for opioid abuse. They were also provided with relevant risk evaluation and mitigation (REM) tools. All simulation interactions were video-recorded and coded by two independent reviewers. A detailed coding scheme was developed before video analysis, and an inter-rater reliability score showed substantial agreement between reviewers. RESULTS: Contrary to expectations, many of the observed performances by trainees contained aspects of unsafe opioid prescribing, given the patient history. Many trainees did not discuss their patient s aberrant behaviors related to opioids or the patient s risk for opioid abuse. Marked disparities were also observed between the trainees active patient interactions and their written progress notes. DISCUSSION: This simulation addresses a pressing need to further educate, train, and provide point-of-care tools for providers prescribing opioids. We present our experience and preliminary findings.
Karshikoff B, Tadros MA, Mackey S, Zouikr I. Neuroimmune modulation of pain across the developmental spectrum. Curr Opin Behav Sci. 2019;28:85-92.
Today s treatment for chronic pain is inadequate, and novel targets need to be identified. This requires a better understanding of the mechanisms involved in pain sensitization and chronification. In this review, we discuss how peripheral inflammation, as occurs during an infection, modulates the central pain system. In rodents, neonatal inflammation leads to increased pain sensitivity in adulthood by priming immune components both peripherally and centrally. The excitability of neurons in the spinal cord is also altered by neonatal inflammation and may add to pain sensitization later in life. In adult humans, inflammation modulates pain sensitivity as well, partly by affecting the activity in brain areas that process and regulate pain signals. Low-grade inflammation is common in clinical populations both peripherally and centrally, and priming of the immune system has also been suggested in some pain populations. The nociceptive and immune systems are primed by infections and inflammation. The early life programming of nociceptive responses following exposure to infections or inflammation will define individual differences in adult pain perception. Immune-to-brain mechanisms and neuroimmune pathway need further investigation as they may serve both as predictors and therapeutic targets in chronic pain.
Background: Temporal summation (TS) refers to the increased perception of pain with repetitive noxious stimuli. While thermal TS is generally considered a behavioral correlate of spinal windup, noxious heat pulses also trigger additional sensory processes which were modeled in this study. Methods: Nineteen healthy volunteers (9 females, mean age 29.2, SD 10.5) underwent two identical TS experiments, spaced a week apart. The TS paradigm consisted of 10 identical heat pulses with individualized temperatures at the thenar eminence (0.5Hz). We extracted 3 features from continuous TS response curves: Lag, time to first feel pain; Slope, the rate of pain increase between the first and most painful heat pulse; and Delta, the maximum drop in pain after peak pain is reached. We then examined the within-individual stability of these features, followed by the Pearson s correlations among these features and between the features and negative affect. Results: All 3 features were stable over 1 week. Lag and Delta were negatively correlated (r = -0.5, p = 0.042). Slope did not correlate with Lag or Delta, but strongly correlated with a traditional TS measure, first pulse pain and peak pain difference (r = 0.91, p \textless 0.0001). Negative affects such as trait and state anxiety were negatively correlated with baseline (r = -0.49, p = 0.031) and peak stimulating temperature (r = -0.48, p = 0.039), respectively, suggesting an association between anxiety and greater pain sensitivity. Conclusion: We were able to decouple spinal windup from other perceptual processes generated by phasic thermal TS paradigms and demonstrate temporal stability of these curve features. These curve features may help better characterize the complex sensory response to noxious heat pulses and serve as biomarkers to profile patients with chronic pain.
Persistent postsurgical pain is defined as pain localized to the area of surgery of a duration of \$\geq\$2 months and is, unfortunately, a common complication after breast cancer surgery. Although there is insufficient evidence to support any preventative strategy, prior literature suggests the possible efficacy of intravenous lidocaine and perioperative pregabalin in preventing persistent pain after surgery. To determine feasibility of conducting a larger definitive trial, we conducted a multicenter 2 \$\times\$ 2 factorial, randomized, placebo-controlled pilot trial of 100 female patients undergoing breast cancer surgery. Patients were randomized to receive an intraoperative lidocaine infusion (1.5 mg/kg bolus followed by 2 mg/kg/h) or placebo and perioperative pregabalin (300 mg preoperatively, 75 mg twice daily for 9 days) or placebo. All feasibility criteria were surpassed; recruitment of 100 patients was accomplished within 42 weeks, with a follow-up rate of 100% and study drug compliance of \$\geq\$80%. At 3 months, 53% of patients reported persistent neuropathic pain. Although there was no interaction between lidocaine and pregabalin, lidocaine decreased the development of persistent neuropathic pain (43.1% vs 63.3%; relative risk = .68; 95% confidence interval = .47-1.0). Pregabalin did not reduce persistent pain (60% vs 46%; relative risk = 1.3; 95% confidence interval = .90-1.90) and neither pregabalin nor lidocaine impacted acute postoperative pain, opioid consumption, pain interference, or quality of life. Our pilot trial successfully demonstrated feasibility and provided promising data for conducting further trials of intraoperative lidocaine infusions during breast cancer surgeries. Clinical trial number: NCT02240199 PERSPECTIVE: This article reports the findings of a pilot randomized, controlled trial evaluating the effects of perioperative pregabalin and intraoperative lidocaine infusions in patients undergoing breast cancer surgery. This trial demonstrated the feasibility of conducting a larger trial and provided promising data that these interventions may decrease the development of persistent pain.
Tobacco smoking is associated with adverse health effects, and its relationship to pain is complex. The longitudinal effect of smoking on patients attending a tertiary pain management center is not well established. Using the Collaborative Health Outcomes Information Registry of patients attending the Stanford Pain Management Center from 2013 to 2017, we conducted a propensity-weighted analysis to determine independent effects of smoking on patients with chronic pain. We adjusted for covariates including age, sex, body mass index, depression and anxiety history, ethnicity, alcohol use, marital status, disability, and education. We compared smokers and nonsmokers on pain intensity, physical function, sleep, and psychological and mood variables using self-reported NIH PROMIS outcomes. We also conducted a linear mixed-model analysis to determine effect of smoking over time. A total of 12,368 patients completed the CHOIR questionnaire of which 8584 patients had complete data for propensity analysis. Smokers at time of pain consultation reported significantly worse pain intensities, pain interference, pain behaviors, physical functioning, fatigue, sleep-related impairment, sleep disturbance, anger, emotional support, depression, and anxiety symptoms than nonsmokers (all P \textless 0.001). In mixed-model analysis, smokers tended to have worse pain interference, fatigue, sleep-related impairment, anger, emotional support, and depression over time compared with nonsmokers. Patients with chronic pain who smoke have worse pain, functional, sleep, and psychological and mood outcomes compared with nonsmokers. Smoking also has prognostic importance for poor recovery and improvement over time. Further research is needed on tailored therapies to assist people with chronic pain who smoke and to determine an optimal strategy to facilitate smoking cessation.
ABSTRACTBackground: Electronic data collection is increasingly available as a means to collect pain-related clinical trial data; however, effectiveness and costs relative to traditional data collection are uncertain.Aims: The aim of this study was to evaluate data quality, protocol adherence, satisfaction, and resource requirements of electronic data collection (i.e., Internet-based electronic submission) compared to traditional data collection methods (i.e., paper-based diaries and telephone interviews) in a perioperative factorial randomized controlled trial.Methods: This study was an open-label two-arm parallel randomized controlled trial. Women (18?75 years) undergoing breast cancer surgery were allocated to either electronic or traditional data collection and completed pain-related questionnaires at baseline, postoperative period, and 3-month follow-up (NCT02240199).Results: We acquired outcome data at all time points from 78 randomized patients, 38 in the electronic group and 40 in the traditional group. The number of data queries (e.g., erroneously entered data) per patient was higher in the electronic data group (4.92 [SD = 4.67] vs. 1.88 [SD = 1.51]; P \textless 0.001). No between-group differences were observed for compliance with medications, data completeness, loss to follow-up, or patient or research assistant satisfaction. More research assistant time per patient was spent collecting data in the traditional group (42.6 min [SD = 12.8] vs. 9.92 min [SD = 7.6]; P \textless 0.001); however, costs per patient were higher in the electronic group (\$176.85 [SD = 2.90] vs. \$16.33 [SD = 4.90]; P \textless 0.001).Conclusion: Electronic data collection is feasible for perioperative pain clinical trials. Additional trials, including different surgical populations, are needed to confirm our findings and optimize use of electronic data capture methods.