Exploratory study of VVZ-149, a novel analgesic molecule, in the affective component of acute postoperative pain after laparoscopic colorectal surgery.

STUDY OBJECTIVE: VVZ-149 is a small molecule that inhibits the glycine transporter type 2 and the serotonin receptor 5-hydroxytryptamine 2A. In the present study, we investigated the efficacy and safety of VVZ-149 as a single-use injectable analgesic for treating moderate to severe postoperative pain after colorectal surgery. DESIGN: Randomized, parallel group, double-blind Phase 2 clinical trial (NCT02489526). SETTING: 3 academic institutions in the United States. PATIENTS: 60 patients undergoing laparoscopic colorectal surgery. INTERVENTIONS: A continuous 8-h intravenous infusion of VVZ-149 Injections (n = 40) or placebo (n = 20) administered after emergence from anesthesia. MEASUREMENTS: The outcome measures included pain intensity (PI), opioid consumption via patient-controlled analgesia (PCA), and rescue dosing provided "as needed". Early rescue dosing with opioids postoperatively was associated with preoperative negative affect (anxiety, depression, and pain catastrophizing), enabling it to be used as an indirect measure of the affective component of pain. Efficacy outcomes were compared between treatment groups based on preoperative negative affect and early rescue dosing of opioids. MAIN RESULTS: Postoperative PI was non-significantly lower in patients receiving VVZ-149 compared to those receiving placebo. The VVZ-149 group had a 34.2% reduction in opioid consumption for 24 h post-dose, along with fewer PCA demands. Somnolence and headache was higher in the intervention group. For patients characterized by high levels of preoperative negative affect, the VVZ-149 group experienced a significant pain reduction and 40% less opioid use compared to the placebo group. CONCLUSIONS: VVZ-149 resulted in a non-significant reduction of postoperative pain during the first 8 h after surgery. Post hoc analysis indicates that VVZ-149 may benefit patients with negative affect who otherwise have higher postoperative opioid use. REGISTRATION NUMBER: www.clinicaltrials.gov, ID: NCT02489526.

Randomized trial of transversus abdominis plane block with liposomal bupivacaine after cesarean delivery with or without intrathecal morphine.

STUDY OBJECTIVE: To investigate efficacy and safety of liposomal bupivacaine (LB) transversus abdominis plane (TAP) block with or without intrathecal morphine (ITM) compared with ITM alone for postsurgical analgesia after cesarean delivery (CD). DESIGN: Multicenter, open-label, randomized trial (NCT03853694). SETTING: Operating room. PATIENTS: Women with term pregnancy of 37 to 42 weeks scheduled for elective CD under spinal anesthesia. INTERVENTION: Patients were randomized 1:1:1 to LB 266 mg TAP block alone (LB group), ITM 50 µg followed by LB 266 mg TAP block (LB + ITM group), or ITM 150 µg alone (ITM group). All groups received the same postsurgical multimodal analgesic regimen. MEASUREMENTS: The LB and LB + ITM groups were compared with the ITM group for all efficacy outcomes. Postsurgical opioid consumption in morphine milligram equivalents (MMEs) through 72 h was compared by assessing noninferiority before testing superiority. Postsurgical pruritus severity was assessed on an 11-point numerical rating scale. MAIN RESULTS: Between March 4, 2019, and January 10, 2020, 153 patients (LB, n = 52; LB + ITM, n = 48; ITM, n = 53) were enrolled. Baseline characteristics were comparable across groups. The LB group had statistically noninferior postsurgical opioid consumption through 72 h compared with the ITM group (least squares mean [LSM], 19.2 vs 16.4 MMEs; LSM treatment ratio, 1.17 [95% confidence interval (CI), 0.74-1.86]; noninferiority P < 0.0034) as did the LB + ITM group (LSM, 14.6 vs 16.4 MMEs; LSM treatment ratio, 0.89 [95% CI, 0.55-1.44]; noninferiority P < 0.0001). The LB and LB + ITM groups had significantly reduced pruritus severity scores through 12, 24, 48, and 72 h compared with the ITM group (P ≤ 0.0121). Adverse events occurred in 58%, 85%, and 81% of the LB, LB + ITM, and ITM groups, respectively. CONCLUSIONS: LB TAP block with or without ITM resulted in statistically noninferior postsurgical opioid consumption through 72 h, reduced pruritus, and favorable safety compared with ITM in women undergoing CD.

Role of VVZ-149, a Novel Analgesic Molecule, in the Affective Component of Pain: Results from an Exploratory Proof-of-Concept Study of Postoperative Pain following Laparoscopic and Robotic-Laparoscopic Gastrectomy.

OBJECTIVE: VVZ-149 is a small molecule that both inhibits the glycine transporter type 2 and the serotonin receptor 5 hydroxytryptamine 2 A. In a randomized, parallel-group, and double-blind trial (NCT02844725), we investigated the analgesic efficacy and safety of VVZ-149 Injections, which is under clinical development as a single-use injectable product for treating moderate to severe postoperative pain. METHODS: Sixty patients undergoing laparoscopic and robotic-laparoscopic gastrectomy were randomly assigned to receive a 10-hour intravenous infusion of VVZ-149 Injections or placebo, initiated approximately 1 hour before completion of surgical suturing. Major outcomes included pain intensity and opioid consumption via patient-controlled analgesia and rescue analgesia provided "as needed." The treatment efficacy of VVZ-149 was further examined in a subpopulation requiring early rescue medication, previously associated with the presence of high levels of preoperative negative affect in a prior Phase 2 study (NCT02489526). RESULTS: Pain intensity was lower in the VVZ-149 (n = 30) than the placebo group (n = 29), reaching statistical significance at 4 hours post-emergence (P < .05), with a 29.5% reduction in opioid consumption for 24 hours and fewer demands for patient-controlled analgesia. In the rescued subgroup, VVZ-149 further reduced pain intensity (P < .05) with 32.6% less opioid consumption for 24 hours compared to placebo patients. CONCLUSIONS: VVZ-149 demonstrated effective analgesia with reduced postoperative pain and opioid requirements. Consistent with the results from the previous Phase 2 study, patients with early rescue requirement had greater benefit from VVZ-149, supporting the hypothesis that VVZ-149 may alleviate the affective component of pain and mitigate excessive use of opioids postoperatively.

Transversus Abdominis Plane Block With Liposomal Bupivacaine for Pain After Cesarean Delivery in a Multicenter, Randomized, Double-Blind, Controlled Trial.

BACKGROUND: In women undergoing cesarean delivery under spinal anesthesia with intrathecal morphine, transversus abdominis plane (TAP) block with bupivacaine hydrochloride (HCl) may not improve postsurgical analgesia. This lack of benefit could be related to the short duration of action of bupivacaine HCl. A retrospective study reported that TAP block with long-acting liposomal bupivacaine (LB) reduced opioid consumption and improved analgesia following cesarean delivery. Therefore, we performed a prospective multicenter, randomized, double-blind trial examining efficacy and safety of TAP block with LB plus bupivacaine HCl versus bupivacaine HCl alone. METHODS: Women (n = 186) with term pregnancies undergoing elective cesarean delivery under spinal anesthesia were randomized (1:1) to TAP block with LB 266 mg plus bupivacaine HCl 50 mg or bupivacaine HCl 50 mg alone. Efficacy was evaluated in a protocol-compliant analysis (PCA) set that was defined a priori. The primary end point was total postsurgical opioid consumption (oral morphine equivalent dosing [MED]) through 72 hours. Pain intensity was measured using a visual analog scale. Adverse events (AEs) after treatment were recorded through day 14. RESULTS: Total opioid consumption through 72 hours was reduced with LB plus bupivacaine HCl versus bupivacaine HCl alone (least squares mean [LSM] [standard error (SE)] MED, 15.5 mg [6.67 mg] vs 32.0 mg [6.25 mg]). This corresponded to an LSM treatment difference of -16.5 mg (95% confidence interval [CI], -30.8 to -2.2 mg; P = .012). The area under the curve of imputed pain intensity scores through 72 hours supported noninferiority of LB plus bupivacaine HCl versus bupivacaine HCl alone (LSM [SE], 147.9 [21.13] vs 178.5 [19.78]; LSM treatment difference, -30.6; 95% CI, -75.9 to 14.7), with a prespecified noninferiority margin of 36 (P = .002). In an analysis of all treated patients, including those not meeting criteria for inclusion in the PCA, there was no difference in postsurgical opioid consumption between groups. In the LB plus bupivacaine HCl group, 63.6% of patients experienced an AE after treatment versus 56.2% in the bupivacaine HCl-alone group. Serious AEs after treatment were rare (≈3% in both groups). CONCLUSIONS: TAP block using LB plus bupivacaine HCl as part of a multimodal analgesia protocol incorporating intrathecal morphine resulted in reduced opioid consumption after cesarean delivery in the PCA set. Results suggest that with correct TAP block placement and adherence to a multimodal postsurgical analgesic regimen, there is an opioid-reducing benefit of adding LB to bupivacaine TAP blocks after cesarean delivery (ClinicalTrials.gov identifier: NCT03176459).

Brachial Plexus Block with Liposomal Bupivacaine for Shoulder Surgery Improves Analgesia and Reduces Opioid Consumption: Results from a Multicenter, Randomized, Double-Blind, Controlled Trial.

OBJECTIVE: The utility of single-injection and continuous peripheral nerve blocks is limited by short duration of analgesia and catheter-related complications, respectively. This double-blind, multicenter trial evaluated the efficacy, safety, and pharmacokinetics of single-injection, ultrasound-guided brachial plexus block (BPB) with liposomal bupivacaine (LB) added to a standardized pain management protocol for shoulder surgery. METHODS: Adults undergoing total shoulder arthroplasty or rotator cuff repair were randomized to receive LB 133 mg, LB 266 mg (pharmacokinetic and safety analyses only), or placebo, added to a standardized analgesia protocol. The primary end point was area under the curve (AUC) of visual analog scale pain intensity scores through 48 hours postsurgery. Secondary end points were total opioid consumption, percentage of opioid-free patients, and time to first opioid rescue through 48 hours. Pharmacokinetic samples were collected through 120 hours and on days 7 and 10. Adverse events were documented. RESULTS: One hundred fifty-five patients received treatment (LB 133 mg, N = 69; LB 266 mg, N = 15; placebo, N = 71). BPB with LB 133 mg was associated with significantly improved AUC of pain scores (least squares mean [SE] = 136.4 [12.09] vs 254.1 [11.77], P < 0.0001), opioid consumption (least squares mean [SE] = 12.0 [2.27] vs 54.3 [10.05] mg, P < 0.0001), median time to opioid rescue (4.2 vs 0.6 h, P < 0.0001), and percentage of opioid-free patients (treatment difference = 0.166, 95% confidence interval = 0.032-0.200, P = 0.008) through 48 hours vs placebo. Adverse event incidence was comparable between groups. CONCLUSIONS: Single-injection BPB with LB 133 mg provided analgesia through 48 hours postsurgery with reduced opioid use compared with placebo after shoulder surgery.

Multi-site Pain Is Associated with Long-term Patient-Reported Outcomes in Older Adults with Persistent Back Pain.

OBJECTIVE: To estimate the prevalence of co-occurring pain sites among older adults with persistent back pain and associations of multisite pain with longitudinal outcomes. DESIGN: Secondary analysis of a cohort study. SETTING: Three integrated health systems in the United States. SUBJECTS: Eight hundred ninety-nine older adults with persistent back pain. METHODS: Participants reported pain in the following sites: stomach, arms/legs/joints, headaches, neck, pelvis/groin, and widespread pain. Over 18 months, we measured back-related disability (Roland Morris, scored 0-24), pain intensity (11-point numerical rating scale), health-related quality of life (EuroQol-5D [EQ-5D], utility from 0-1), and falls in the past three weeks. We used mixed-effects models to test the association of number and type of pain sites with each outcome. RESULTS: Nearly all (N = 839, 93%) respondents reported at least one additional pain site. There were 216 (24%) with one additional site and 623 (69%) with multiple additional sites. The most prevalent comorbid pain site was the arms/legs/joints (N = 801, 89.1%). Adjusted mixed-effects models showed that for every additional pain site, RMDQ worsened by 0.65 points (95% confidence interval [CI] = 0.43 to 0.86), back pain intensity increased by 0.14 points (95% CI = 0.07 to 0.22), EQ-5D worsened by 0.012 points (95% CI = -0.018 to -0.006), and the odds of falling increased by 27% (odds ratio = 1.27, 95% CI = 1.12 to 1.43). Some specific pain sites (extremity pain, widespread pain, and pelvis/groin pain) were associated with greater long-term disability. CONCLUSIONS: Multisite pain is common among older adults with persistent back pain. Number of pain sites was associated with all outcomes; individual pain sites were less consistently associated with outcomes.

Systemic effects of epidural steroid injections for spinal stenosis.

This analysis of the lumbar epidural steroid injections for spinal stenosis multicenter randomized controlled trial data identifies the degree of and risk factors for cortisol suppression after epidural steroid injections in older adults with spinal stenosis. Four hundred patients aged 50 years and older with back or leg pain and central lumbar spinal stenosis completed baseline demographic and psychosocial measures. Morning serum cortisol levels were measured at baseline and 3 weeks after initial injection. Patients were randomized to receive epidural injections of either local anesthetic with corticosteroid (n = 200) or local anesthetic only (n = 200). The specific corticosteroid was chosen at the treating physician's discretion (methylprednisolone, betamethasone, triamcinolone, or dexamethasone). Thirty-two patients (20.3%) treated with corticosteroid experienced cortisol reduction at 3 weeks of >50% compared with 10 patients (6.7%) treated with lidocaine only (adjusted treatment effect = 3.5, 95% confidence interval: 1.6-7.9, P = 0.002). The effect on 3-week cortisol changes did not differ by demographic or patient-level characteristics. Those treated with methylprednisolone or triamcinolone had an average 3-week cortisol reduction of 41.0% (P = 0.005) and 41.6% (P < 0.001) from baseline, respectively, whereas patients treated with betamethasone or dexamethasone were not significantly different than comparable patients in the lidocaine arm. The higher rates of cortisol suppression at 3 weeks in those receiving epidural corticosteroid injections, particularly with longer-acting insoluble corticosteroid formulations, are consistent with sustained systemic absorption of corticosteroid.

Long-term outcomes of a large, prospective observational cohort of older adults with back pain.

BACKGROUND CONTEXT: Although back pain is common among older adults, there is relatively little research on the course of back pain in this age group. PURPOSE: Our primary goals were to report 2-year outcomes of older adults initiating primary care for back pain and to examine the relative importance of patient factors versus medical interventions in predicting 2-year disability and pain. STUDY DESIGN/SETTING: This study used a predictive model using data from a prospective, observational cohort from a primary care setting. PATIENT SAMPLE: The study included patients aged ≥65 years at the time of new primary care visits for back pain. OUTCOME MEASURES: Self-reported 2-year disability (Roland-Morris Disability Questionnaire [RDQ]) and back pain (0-10 numerical rating scale [NRS]). METHODS: We developed our models using a machine learning least absolute shrinkage and selection operator approach. We evaluated the predictive value of baseline characteristics and the incremental value of interventions that occurred between 0 and 90 days, and the change in patient disability and pain from 0 to 90 days. Limitations included confounding by indication and unmeasured confounding. RESULTS: Of 4,665 patients (89%) with follow-up, both RDQ (from mean 9.6 [95% confidence interval {CI} 9.4-9.7] to mean 8.3 [95% CI 8.0-8.5]) and back pain NRS (from mean 5.0 [95% CI 4.9-5.1] to mean 3.5 [95% CI 3.4-3.6]) scores improved slightly. Only 16% (15%-18%) reported no back pain-related disability or back pain at 2 years after initial visits. Regression model parameters explained 40% of the variation (R2) in 2-year RDQ scores, and the addition of 0- to 3-month change in RDQ score and pain improved prediction (R2=51%). The most consistent predictors of 2-year RDQ scores and back pain NRS scores were 0- to 90-day change in each respective outcome and patient confidence in improvement. Patients experienced 50% and 43% improvement in back pain and disability, respectively, 2 years after their initial visit. However, fewer than 20% of patients had complete resolution of their back pain and disability at that time. CONCLUSIONS: Baseline patient factors were more important than early interventions in explaining disability and pain after 2 years.

Using Natural Language Processing of Free-Text Radiology Reports to Identify Type 1 Modic Endplate Changes.

Electronic medical record (EMR) systems provide easy access to radiology reports and offer great potential to support quality improvement efforts and clinical research. Harnessing the full potential of the EMR requires scalable approaches such as natural language processing (NLP) to convert text into variables used for evaluation or analysis. Our goal was to determine the feasibility of using NLP to identify patients with Type 1 Modic endplate changes using clinical reports of magnetic resonance (MR) imaging examinations of the spine. Identifying patients with Type 1 Modic change who may be eligible for clinical trials is important as these findings may be important targets for intervention. Four annotators identified all reports that contained Type 1 Modic change, using N = 458 randomly selected lumbar spine MR reports. We then implemented a rule-based NLP algorithm in Java using regular expressions. The prevalence of Type 1 Modic change in the annotated dataset was 10%. Results were recall (sensitivity) 35/50 = 0.70 (95% confidence interval (C.I.) 0.52-0.82), specificity 404/408 = 0.99 (0.97-1.0), precision (positive predictive value) 35/39 = 0.90 (0.75-0.97), negative predictive value 404/419 = 0.96 (0.94-0.98), and F1-score 0.79 (0.43-1.0). Our evaluation shows the efficacy of rule-based NLP approach for identifying patients with Type 1 Modic change if the emphasis is on identifying only relevant cases with low concern regarding false negatives. As expected, our results show that specificity is higher than recall. This is due to the inherent difficulty of eliciting all possible keywords given the enormous variability of lumbar spine reporting, which decreases recall, while availability of good negation algorithms improves specificity.

Associations of Race and Ethnicity With Patient-Reported Outcomes and Health Care Utilization Among Older Adults Initiating a New Episode of Care for Back Pain.

STUDY DESIGN: Secondary analysis of the Back Pain Outcomes using Longitudinal Data (BOLD) cohort study. OBJECTIVE: To characterize associations of self-reported race/ethnicity with back pain (BP) patient-reported outcomes (PROs) and health care utilization among older adults with a new episode of care for BP. SUMMARY OF BACKGROUND DATA: No prior longitudinal studies have characterized associations between multiple race/ethnicity groups, and BP-related PROs and health care utilization in the United States. METHODS: This study included 5117 participants ≥65 years from three US health care systems. The primary BP-related PROs were BP intensity and back-related functional limitations over 24 months. Health care utilization measures included common diagnostic tests and treatments related to BP (spine imaging, spine-related relative value units [RVUs], and total RVUs) over 24 months. Analyses were adjusted for multiple potential confounders including sociodemographics, clinical characteristics, and study site. RESULTS: Baseline BP ratings were significantly higher for blacks vs. whites (5.8 vs. 5.0; P < 0.001). Participants in all race/ethnicity groups showed statistically significant, but modest improvements in BP over 24 months. Blacks and Hispanics did not have statistically significant improvement in BP-related functional limitations over time, unlike whites, Asians, and non-Hispanics; however, the magnitude of differences in improvement between groups was small. Blacks had less spine-related health care utilization over 24 months than whites (spine-related RVU ratio of means 0.66, 95% confidence interval [CI] 0.51-0.86). Hispanics had less spine-related health care utilization than non-Hispanics (spine-related RVU ratio of means 0.60; 95% CI 0.40-0.90). CONCLUSION: Blacks and Hispanics had slightly less improvement in BP-related functional limitations over time, and less spine-related health care utilization, as compared to whites and non-Hispanics, respectively. Residual confounding may explain some of the association between race/ethnicity and health outcomes. Further studies are needed to understand the factors underlying these differences and which differences reflect disparities. LEVEL OF EVIDENCE: 3.

Long-Term Effects of Repeated Injections of Local Anesthetic With or Without Corticosteroid for Lumbar Spinal Stenosis: A Randomized Trial.

OBJECTIVE: To determine the overall long-term effectiveness of treatment with epidural corticosteroid injections for lumbar central spinal stenosis and the effect of repeat injections, including crossover injections, on outcomes through 12 months. DESIGN: Multicenter, double-blind, randomized controlled trial comparing epidural injections of corticosteroid plus lidocaine versus lidocaine alone. SETTING: Sixteen clinical sites. PARTICIPANTS: Participants with imaging-confirmed lumbar central spinal stenosis (N=400). INTERVENTIONS: Participants were randomized to receive either epidural injections with corticosteroid plus lidocaine or lidocaine alone with the option of blinded crossover after 6 weeks to receive the alternate treatment. Participants could receive 1 to 2 injections from 0 to 6 weeks and up to 2 injections from 6 to 12 weeks. After 12 weeks, participants received usual care. MAIN OUTCOME MEASURES: Primary outcomes were the Roland-Morris Disability Questionnaire (RDQ) (range, 0-24, where higher scores indicate greater disability) and leg pain intensity (range, 0 [no pain] to 10 [pain as bad as you can imagine]). Secondary outcomes included opioid use, spine surgery, and crossover rates. RESULTS: At 12 months, both treatment groups maintained initial observed improvements, with no significant differences between groups on the RDQ (adjusted mean difference, -0.4; 95% confidence interval [CI], -1.6 to 0.9; P=.55), leg pain (adjusted mean difference, 0.1; 95% CI, -0.5 to 0.7; P=.75), opioid use (corticosteroid plus lidocaine: 41.4% vs lidocaine alone: 36.3%; P=.41), or spine surgery (corticosteroid plus lidocaine: 16.8% vs lidocaine alone: 11.8%; P=.22). Fewer participants randomized to corticosteroid plus lidocaine (30%, n=60) versus lidocaine alone (45%, n=90) crossed over after 6 weeks (P=.003). Among participants who crossed over at 6 weeks, the 6- to 12-week RDQ change did not differ between the 2 randomized treatment groups (adjusted mean difference, -1.0; 95% CI, -2.6 to 0.7; P=.24). In both groups, participants crossing over at 6 weeks had worse 12-month trajectories compared with participants who did not choose to crossover. CONCLUSIONS: For lumbar spinal stenosis symptoms, epidural injections of corticosteroid plus lidocaine offered no benefits from 6 weeks to 12 months beyond that of injections of lidocaine alone in terms of self-reported pain and function or reduction in use of opioids and spine surgery. In patients with improved pain and function 6 weeks after initial injection, these outcomes were maintained at 12 months. However, the trajectories of pain and function outcomes after 3 weeks did not differ by injectate type. Repeated injections of either type offered no additional long-term benefit if injections in the first 6 weeks did not improve pain.

Associations Between Relative Value Units and Patient-Reported Back Pain and Disability.

Objective: To describe associations between health care utilization measures and patient-reported outcomes (PROs). Method: Primary data were collected from patients ≥65 years with low back pain visits from 2011 to 2013. Six PROs of pain and functionality were collected 12 and 24 months after the index visits and total and spine-specific relative value units (RVUs) from electronic health records were tabulated over 1 year. We calculated correlation coefficients between RVUs and 12- and 24-month PROs and conducted linear regressions with each 12- and 24-month PRO as the outcome variables and RVUs as predictors of interest. Results: We observed very weak correlations between worse PROs at 12 and 24 months and greater 12-month utilization. In regression analyses, we observed slight associations between greater utilization and worse 12- and 24-month PROs. Discussion: We found that 12-month health care utilization is not strongly associated with PROs at 12 or 24 months.

Randomised, double-blind, parallel group, placebo-controlled study to evaluate the analgesic efficacy and safety of VVZ-149 injections for postoperative pain following laparoscopic colorectal surgery.

INTRODUCTION: In spite of advances in understanding and technology, postoperative pain remains poorly treated for a significant number of patients. In colorectal surgery, the need for developing novel analgesics is especially important. Patients after bowel surgery are assessed for rapid return of bowel function and opioids worsen ileus, nausea and constipation. We describe a prospective, double-blind, parallel group, placebo-controlled randomised controlled trial testing the hypothesis that a novel analgesic drug, VVZ -149, is safe and effective in improving pain compared with providing opioid analgesia alone among adults undergoing laparoscopic colorectal surgery. METHODS AND ANALYSIS: Based on sample size calculations for primary outcome, we plan to enrol 120 participants. Adult patients without significant medical comorbidities or ongoing opioid use and who are undergoing laparoscopic colorectal surgery will be enrolled. Participants are randomly assigned to receive either VVZ-149 with intravenous (IV) hydromorphone patient-controlled analgesia (PCA) or the control intervention (IV PCA alone) in the postoperative period. The primary outcome is the Sum of Pain Intensity Difference over 8 hours (SPID-8 postdose). Participants receive VVZ-149 for 8 hours postoperatively to the primary study end point, after which they continue to be assessed for up to 24 hours. We measure opioid consumption, record pain intensity and pain relief, and evaluate the number of rescue doses and requests for opioid. To assess safety, we record sedation, nausea and vomiting, respiratory depression, laboratory tests and ECG readings after study drug administration. We evaluate for possible confounders of analgesic response, such as anxiety, depression and catastrophising behaviours. The study will also collect blood sample data and evaluate for pharmacokinetic and pharmacodynamic relationships. ETHICS AND DISSEMINATION: Ethical approval of the study protocol has been obtained from Institutional Review Boards at the participating institutions. Trial results will be disseminated through scientific conference presentations and by publication in scientific journals. TRIAL REGISTRATION NUMBER: NCT02489526; pre-results.

Predictors of Persistent Disability and Back Pain in Older Adults with a New Episode of Care for Back Pain.

Objective: To identify predictors of persistent disability and back pain in older adults. Design: Prospective cohort study. Setting: Back pain outcomes using longitudinal data registry. Subjects: Five thousand two hundred twenty adults age 65 years and older with a new primary care visit for back pain. Methods: Baseline measurements included: demographics, health, and back pain characteristics. We abstracted imaging findings from 348 radiology reports. The primary outcomes were the Roland-Morris Disability Questionnaire (RMDQ) and back pain intensity. We defined persistent disability as RMDQ of 4/24 or higher at both six and 12 months and persistent back pain as pain 3/10 or higher at both six and 12 months. Results: There were 2,498 of 4,143 (60.3%) participants with persistent disability, and 2,099 of 4,144 (50.7%) had persistent back pain. Adjusted analyses showed the following characteristics most strongly predictive of persistent disability and persistent back pain: sex, race, worse baseline clinical characteristics of back pain, leg pain, back-related disability and duration of symptoms, smoking, anxiety symptoms, depressive symptoms, a history of falls, greater number of comorbidities, knee osteoarthritis, wide-spread pain syndromes, and an index diagnosis of lumbar spinal stenosis. Within the imaging data subset, central spinal stenosis was not associated with disability or pain. Conclusion: We found that many predictors in older adults were similar to those for younger populations.

Effect of Comorbid Knee and Hip Osteoarthritis on Longitudinal Clinical and Health Care Use Outcomes in Older Adults With New Visits for Back Pain.

OBJECTIVE: To examine if a comorbid diagnosis of knee or hip osteoarthritis (OA) in older adults with new back pain visits is associated with long-term patient-reported outcomes and back-related health care use. DESIGN: Prospective cohort study. SETTING: Three integrated health systems forming the Back pain Outcomes using Longitudinal Data cohort. PARTICIPANTS: Participants (N=5155) were older adults (≥65y) with a new visit for back pain and a complete electronic health record data. INTERVENTIONS: Not applicable; we obtained OA diagnoses using diagnostic codes in the electronic health record 12 months prior to the new back pain visit. MAIN OUTCOME MEASURES: The Roland-Morris Disability Questionnaire (RDQ) and the EuroQol-5D (EQ-5D) were key patient-reported outcomes. Health care use, measured by relative-value units (RVUs), was summed for the 12 months after the initial visit. We used linear mixed-effects models to model patient-reported outcomes. We also used generalized linear models to test the association between comorbid knee or hip OA and total back-related RVUs. RESULTS: Of the 5155 participants, 368 (7.1%) had a comorbid knee OA diagnosis, and 94 (1.8%) had a hip OA diagnosis. Of the participants, 4711 (91.4%) had neither knee nor hip OA. In adjusted models, the 12-month RDQ score was 1.23 points higher (95% confidence interval [CI], 0.72-1.74) for patients with knee OA and 1.26 points higher (95% CI, 0.24-2.27) for those with hip OA than those without knee or hip OA, respectively. A lower EQ-5D score was found among participants with knee OA (.02 lower; 95% CI, -.04 to -.01) and hip OA diagnoses (.03 lower; 95% CI, -.05 to -.01) compared with those without knee or hip OA, respectively. Comorbid knee or hip OA was not significantly associated with total 12-month back-related resource use. CONCLUSIONS: Comorbid knee or hip OA in older adults with a new back pain visit was associated with modestly worse long-term disability and health-related quality of life.

Psychiatric Comorbidity Is Associated Prospectively with Diminished Opioid Analgesia and Increased Opioid Misuse in Patients with Chronic Low Back Pain.

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.

Can patient characteristics predict benefit from epidural corticosteroid injections for lumbar spinal stenosis symptoms?

BACKGROUND CONTEXT: Epidural corticosteroid injections are commonly used to treat back and leg pain associated with lumbar spinal stenosis. However, little is known about which patient characteristics may predict favorable responses. PURPOSE: The aim was to identify patient characteristics associated with benefits from epidural injections of corticosteroid with lidocaine versus epidural injections of lidocaine only for lumbar spinal stenosis symptoms. STUDY DESIGN/SETTING: This was a secondary analysis of Lumbar Epidural steroid injections for Spinal Stenosis randomized controlled trial data from 16 US clinical sites. PATIENT SAMPLE: Patients aged older than or equal to 50 years with moderate-to-severe leg pain and lumbar central spinal stenosis randomized to epidural injections of corticosteroids with lidocaine (n=200) or lidocaine only (n=200) were included. OUTCOME MEASURES: Primary outcomes were the Roland-Morris Disability Questionnaire (RMDQ) and 0 to 10 leg pain intensity ratings. Secondary outcomes included the Brief Pain Inventory Interference Scale and the Swiss Spinal Stenosis Questionnaire. METHODS: At baseline, clinicians rated severity of patient spinal stenosis, and patients completed predictor and outcome measures. Patients completed outcome measures again 3 and 6 (primary end point) weeks after randomization/initial injection. Analysis of covariance was used with treatment by covariate interactions to identify baseline predictors of greater benefit from corticosteroid+lidocaine versus lidocaine alone. We also identified nonspecific (independent of treatment) predictors of outcomes. RESULTS: Among 21 candidate predictors and six outcomes, only one baseline variable predicted greater benefit from corticosteroid+lidocaine versus lidocaine only at 3 or 6 weeks. Compared with patients who rated their health-related quality of life as high on the EQ-5D Index, patients who rated it as poor had greater improvement with corticosteroid than with lidocaine only in leg pain at 6 (but not 3) weeks (interaction coefficient=2.94; 95% confidence interval [CI]=0.11-5.76; p=.04) and in RMDQ disability scores at 3 (but not 6) weeks (interaction coefficient=4.77, 95% CI= -0.04 to 9.59; p = .05). Several baseline patient characteristics predicted outcomes regardless of treatment assignment. CONCLUSIONS: Among 21 baseline patient characteristics examined, none, including clinician-rated spinal stenosis severity, were consistent predictors of benefit from epidural injections of lidocaine+corticosteroid versus lidocaine only.

Short-term improvements in disability mediate patient satisfaction after epidural corticosteroid injections for symptomatic lumbar spinal stenosis.

STUDY DESIGN: Secondary analysis of data from a double-blind randomized controlled trial. OBJECTIVE: To identify mediators of the effect of lumbar epidural injections of corticosteroid plus lidocaine on patient satisfaction at 6 weeks postinjection in patients with lumbar spinal stenosis. We hypothesized that short-term (≤3 wk) change in leg pain would be a significant mediator of satisfaction. SUMMARY OF BACKGROUND DATA: No prior studies have identified mediators of effects of epidural injections on patient satisfaction with treatment of lumbar spinal stenosis. METHODS: We used mediation analysis methods to examine selected intermediate variables (adverse events and change in leg pain, back pain, disability, depression, and fatigue at 3 wk) as potential mediators of the effect of lumbar epidural injections of corticosteroid plus lidocaine on patient satisfaction with treatment. We used the overall satisfaction item from the Swiss Spinal Stenosis Questionnaire as our primary outcome to measure patient satisfaction with the injection procedure at 6 weeks. RESULTS: Among 400 patients randomized to receive epidural injections with corticosteroid plus lidocaine or with lidocaine alone, 369 had complete data for the satisfaction outcome and potential mediators and served as the analysis sample. Contrary to our expectations, 3-week change in leg pain intensity did not have significant mediation effects on patient satisfaction. Three-week change in disability as measured by the Roland-Morris Disability Questionnaire was a significant mediator of the effects of lumbar epidural corticosteroid injections on patient satisfaction at 6 weeks, explaining 48% to 60% of the treatment effect on satisfaction. Changes in pain intensity in the leg and back together explained very little of the treatment effect on satisfaction beyond the information contributed by disability change alone. We did not find other intermediate variables to be mediators of patient satisfaction. CONCLUSION: These findings support the current approach of examining disability as a primary patient-reported outcome in comparative effectiveness studies of lumbar spinal stenosis. LEVEL OF EVIDENCE: 2.