Links between brain neuroimaging and blood inflammatory markers in urological chronic pelvic pain syndrome.

Urological chronic pelvic pain syndrome (UCPPS) is a debilitating painful condition with unclear etiology. Prior researchers have indicated that compared to healthy controls, patients with UCPPS demonstrated altered brain activity. Researchers have also shown that in UCPPS, several blood inflammatory markers relate to clinical variables of pain, fatigue, and pain widespreadness. However, how altered brain function in patients with UCPPS relates to blood inflammation remains unknown. To extend and connect prior findings of altered brain function and inflammatory factors in UCPPS, we conducted a secondary analysis of data from a cohort of UCPPS patients (N = 29) and healthy controls (N = 31) who provided both neuroimaging and blood data (National Institute of Health MAPP Research Network publicly available dataset). In our present study, we aimed to evaluate relationships between a priori-defined brain neuroimaging markers and inflammatory factors of interest and their relationships to pain-psychological variables. We hypothesized that two brain alterations of interest (i.e., PCC - left hippocampus functional connectivity and PCC - bilateral amygdala functional connectivity) would be correlated with four cytokine markers of interest: interleukin (IL) - 6, tumor necrosis factor-alpha (TNF-a), IL-8, and granulocyte-macrophage colony-stimulating factor (GM-CSF). In the UCPPS cohort, we identified a significant PCC - left hippocampus functional connectivity relationship with IL-6 (p = 0.0044). Additionally, in the UCPPS cohort, we identified a PCC - amygdala functional connectivity relationship with GM-CSF which did not meet our model's threshold for statistical significance (p = 0.0665). While these data are preliminary and cross-sectional, our findings suggest connections between brain function and levels of low-grade systemic inflammation in UCPPS. Thus, while further study is needed, our data indicate the potential for advancing the understanding of how brain functional circuits may relate to clinical symptoms and systemic inflammation.

Preoperative Versus Perioperative Risk Factors for Delayed Pain and Opioid Cessation After Total Joint Arthroplasty: A Prospective Cohort Study.

INTRODUCTION: The evolution of pre- versus postoperative risk factors remains unknown in the development of persistent postoperative pain and opioid use. We identified preoperative versus comprehensive perioperative models of delayed pain and opioid cessation after total joint arthroplasty including time-varying postoperative changes in emotional distress. We hypothesized that time-varying longitudinal measures of postoperative psychological distress, as well as pre- and postoperative use of opioids would be the most significant risk factors for both outcomes. METHODS: A prospective cohort of 188 patients undergoing total hip or knee arthroplasty at Stanford Hospital completed baseline pain, opioid use, and emotional distress assessments. After surgery, a modified Brief Pain Inventory was assessed daily for 3 months, weekly thereafter up to 6 months, and monthly thereafter up to 1 year. Emotional distress and pain catastrophizing were assessed weekly to 6 months, then monthly thereafter. Stepwise multivariate time-varying Cox regression modeled preoperative variables alone, followed by all perioperative variables (before and after surgery) with time to postoperative opioid and pain cessation. RESULTS: The median time to opioid and pain cessation was 54 and 152 days, respectively. Preoperative total daily oral morphine equivalent use (hazard ratio-HR 0.97; 95% confidence interval-CI 0.96-0.98) was significantly associated with delayed postoperative opioid cessation in the perioperative model. In contrast, time-varying postoperative factors: elevated PROMIS (Patient-Reported Outcomes Measurement Information System) depression scores (HR 0.92; 95% CI 0.87-0.98), and higher Pain Catastrophizing Scale scores (HR 0.85; 95% CI 0.75-0.97) were independently associated with delayed postoperative pain resolution in the perioperative model. CONCLUSIONS: These findings highlight preoperative opioid use as a key determinant of delayed postoperative opioid cessation, while postoperative elevations in depressive symptoms and pain catastrophizing are associated with persistent pain after total joint arthroplasty providing the rationale for continued risk stratification before and after surgery to identify patients at highest risk for these distinct outcomes. Interventions targeting these perioperative risk factors may prevent prolonged postoperative pain and opioid use.

Altered resting-state functional connectivity within corticostriatal and subcortical-striatal circuits in chronic pain.

Brain corticostriatal circuits are important for understanding chronic pain and highly relevant to motivation and cognitive processes. It has been demonstrated that in patients with chronic back pain, altered nucleus accumbens (NAcc)-medial prefrontal cortex (MPFC) circuit fMRI-based activity is predictive of patient outcome. We evaluated the NAcc-MPFC circuit in patients with another chronic pain condition, fibromyalgia, to extend these important findings. First, we compared fMRI-based NAcc-MPFC resting-state functional connectivity in patients with fibromyalgia (N = 32) vs. healthy controls (N = 37). Compared to controls, the NAcc-MPFC circuit's connectivity was significantly reduced in fibromyalgia. In addition, within the fibromyalgia group, NAcc-MPFC connectivity was significantly correlated with trait anxiety. Our expanded connectivity analysis of the NAcc to subcortical brain regions showed reduced connectivity of the right NAcc with mesolimbic circuit regions (putamen, thalamus, and ventral pallidum) in fibromyalgia. Lastly, in an exploratory analysis comparing our fibromyalgia and healthy control cohorts to a separate publicly available dataset from patients with chronic back pain, we identified reduced NAcc-MPFC connectivity across both the patient groups with unique alterations in NAcc-mesolimbic connectivity. Together, expanding upon prior observed alterations in brain corticostriatal circuits, our results provide novel evidence of altered corticostriatal and mesolimbic circuits in chronic pain.

Spinal Cord Resting State Activity in Individuals With Fibromyalgia Who Take Opioids.

Chronic pain coincides with myriad functional alterations throughout the brain and spinal cord. While spinal cord mechanisms of chronic pain have been extensively characterized in animal models and in vitro, to date, research in patients with chronic pain has focused only very minimally on the spinal cord. Previously, spinal cord functional magnetic resonance imaging (fMRI) identified regional alterations in spinal cord activity in patients (who were not taking opioids) with fibromyalgia, a chronic pain condition. Here, in patients with fibromyalgia who take opioids (N = 15), we compared spinal cord resting-state fMRI data vs. patients with fibromyalgia not taking opioids (N = 15) and healthy controls (N = 14). We hypothesized that the opioid (vs. non-opioid) patient group would show greater regional alterations in spinal cord activity (i.e., the amplitude of low frequency fluctuations or ALFF, a measure of regional spinal cord activity). However, we found that regional spinal cord activity in the opioid group was more similar to healthy controls, while regional spinal cord activity in the non-opioid group showed more pronounced differences (i.e., ventral increases and dorsal decreases in regional ALFF) vs. healthy controls. Across patient groups, self-reported fatigue correlated with regional differences in spinal cord activity. Additionally, spinal cord functional connectivity and graph metrics did not differ among groups. Our findings suggest that, contrary to our main hypothesis, patients with fibromyalgia who take opioids do not have greater alterations in regional spinal cord activity. Thus, regional spinal cord activity may be less imbalanced in patients taking opioids compared to patients not taking opioids.

Effectiveness of a multidisciplinary rehabilitation program in real-world patients with chronic back pain: A pilot cohort data analysis.

BACKGROUND: Randomized clinical trials (RCT) suggest a multidisciplinary approach to pain rehabilitation is superior to other active treatments in improving pain intensity, function, disability, and pain interference for patients with chronic pain, with small effect size (ds= 0.20-0.36) but its effectiveness remains unknown in real-world practice. OBJECTIVE: The current study examined the effectiveness of a multidisciplinary program to a cognitive and behavioral therapy (pain-CBT) in real-world patients with chronic back pain. METHODS: Twenty-eight patients (M𝑎𝑔𝑒= 57.6, 82.1% Female) completed a multidisciplinary program that included pain psychology and physical therapy. Eighteen patients (M𝑎𝑔𝑒= 58.9, 77.8% Female) completed a CBT-alone program. Using a learning healthcare system, the Pain Catastrophizing Scale, 0-10 Numerical Pain Rating Scale, and Patient-Reported Outcomes Measurement Information System® measures were administered before and after the programs. RESULTS: We found significant improvement in mobility and pain behavior only after a multidisciplinary program (p's < 0.031; d= 0.69 and 0.55). We also found significant improvement in pain interference, fatigue, depression, anxiety, social role satisfaction, and pain catastrophizing after pain-CBT or multidisciplinary programs (p's < 0.037; ds = 0.29-0.73). Pain ratings were not significantly changed by either program (p's > 0.207). CONCLUSIONS: The effect of a multidisciplinary rehabilitation program observed in RCT would be generalizable to real-world practice.

A Brief Screening Tool for Opioid Use Disorder: EMPOWER Study Expert Consensus Protocol.

Growing concerns about the safety of long-term opioid therapy and its uncertain efficacy for non-cancer pain have led to relatively rapid opioid deprescribing in chronic pain patients who have been taking opioid for years. To date, empirically supported processes for safe and effective opioid tapering are lacking. Opioid tapering programs have shown high rates of dropouts and increases in patient distress and suicidal ideation. Therefore, safe strategies for opioid deprescribing that are more likely to succeed are urgently needed. In response to this demand, the EMPOWER study has been launched to examine the effectiveness of behavioral medicine strategies within the context of patient-centered opioid tapering in outpatient settings (https://empower.stanford.edu/). The EMPOWER protocol requires an efficient process for ensuring that collaborative opioid tapering would be offered to the most appropriate patients while identifying patients who should be offered alternate treatment pathways. As a first step, clinicians need a screening tool to identify patients with Opioid Use Disorder (OUD) and to assess for OUD severity. Because such a tool is not available, the study team composed of eight chronic pain and/or addiction experts has extended a validated screening instrument to develop a brief and novel consensus screening tool to identify OUD and assess for OUD severity for treatment stratification. Our screening tool has the potential to assist busy outpatient clinicians to assess OUD among patients receiving long-term opioid therapy for chronic pain.

Efficacy of motivational-interviewing and guided opioid tapering support for patients undergoing orthopedic surgery (MI-Opioid Taper): A prospective, assessor-blind, randomized controlled pilot trial.

BACKGROUND: Postoperative opioid use can lead to chronic use and misuse. Few studies have examined effective approaches to taper postoperative opioid use while maintaining adequate analgesia. METHODS: This randomized, assessor-blinded, pilot trial of postoperative motivational interviewing and guided opioid tapering support (MI-Opioid Taper) added to usual care (UC) enrolled patients undergoing total hip or knee arthroplasty at a single U.S. academic medical center. MI-Opioid Taper involved weekly (to seven weeks) and monthly (to one year) phone calls until patient-reported opioid cessation. Opioid tapering involved 25% weekly dose reductions. The primary feasibility outcome was study completion in the group to which participants were randomized. The primary efficacy outcome, time to baseline opioid use, was the first of five consecutive days of return to baseline preoperative dose. Intention-to-treat analysis with Cox proportional hazards regression was adjusted for operation. ClinicalTrials.gov registration: NCT02070003. FINDINGS: From November 26, 2014, to April 27, 2018, 209 patients were screened, and 104 patients were assigned to receive MI-Opioid Taper (49 patients) or UC only (55 patients). Study completion after randomization was similar between groups (96.4%, 53 patients receiving UC, 91.8%, 45 patients receiving MI-Opioid Taper). Patients receiving MI-Opioid Taper had a 62% increase in the rate of return to baseline opioid use after surgery (HR 1.62; 95%CI 1.06-2.46; p = 0•03). No trial-related adverse events occurred. INTERPRETATION: In patients undergoing total joint arthroplasty, MI-Opioid Taper is feasible and future research is needed to establish the efficacy of MI-Opioid Taper to promote postoperative opioid cessation. FUNDING: National Institute on Drug Abuse.

Preoperative Factors Associated with Remote Postoperative Pain Resolution and Opioid Cessation in a Mixed Surgical Cohort: Post Hoc Analysis of a Perioperative Gabapentin Trial.

BACKGROUND: Preoperative patient-specific risk factors may elucidate the mechanisms leading to the persistence of pain and opioid use after surgery. This study aimed to determine whether similar or discordant preoperative factors were associated with the duration of postoperative pain and opioid use. METHODS: In this post hoc analysis of a randomized, double-blind, placebo-controlled trial of perioperative gabapentin vs active placebo, 410 patients aged 18-75 years, undergoing diverse operations underwent preoperative assessments of pain, opioid use, substance use, and psychosocial variables. After surgery, a modified Brief Pain Inventory was administered over the phone daily up to 3 months, weekly up to 6 months, and monthly up to 2 years after surgery. Pain and opioid cessation were defined as the first of 5 consecutive days of 0 out of 10 pain or no opioid use, respectively. RESULTS: Overall, 36.1%, 19.8%, and 9.5% of patients continued to report pain, and 9.5%, 2.4%, and 1.7% reported continued opioid use at 3, 6, and 12 months after surgery. Preoperative pain at the future surgical site (every 1-point increase in the Numeric Pain Rating Scale; HR 0.93; 95% CI 0.87-1.00; P=0.034), trait anxiety (every 10-point increase in the Trait Anxiety Inventory; HR 0.79; 95% CI 0.68-0.92; P=0.002), and a history of delayed recovery after injury (HR 0.62; 95% CI 0.40-0.96; P=0.034) were associated with delayed pain cessation. Preoperative opioid use (HR 0.60; 95% CI 0.39-0.92; P=0.020), elevated depressive symptoms (every 5-point increase in the Beck Depression Inventory-II score; HR 0.88; 95% CI 0.80-0.98; P=0.017), and preoperative pain outside of the surgical site (HR 0.94; 95% CI 0.89-1.00; P=0.046) were associated with delayed opioid cessation, while perioperative gabapentin promoted opioid cessation (HR 1.37; 95% CI 1.06-1.77; P=0.016). CONCLUSION: Separate risk factors for prolonged post-surgical pain and opioid use indicate that preoperative risk stratification for each outcome may identify patients needing personalized care to augment universal protocols for perioperative pain management and conservative opioid prescribing to improve long-term outcomes.

Apparent Effects of Opioid Use on Neural Responses to Reward in Chronic Pain.

Neural responses to incentives are altered in chronic pain and by opioid use. To understand how opioid use modulates the neural response to reward/value in chronic pain, we compared brain functional magnetic resonance imaging (fMRI) responses to a monetary incentive delay (MID) task in patients with fibromyalgia taking opioids (N = 17), patients with fibromyalgia not taking opioids (N = 17), and healthy controls (N = 15). Both groups of patients with fibromyalgia taking and not taking opioids had similar levels of pain, psychological measures, and clinical symptoms. Neural responses in the nucleus accumbens to anticipated reward and non-loss outcomes did not differ from healthy controls in either fibromyalgia group. However, neural responses in the medial prefrontal cortex differed, such that patients with fibromyalgia not taking opioids demonstrated significantly altered responses to anticipated rewards and non-loss outcomes compared to healthy controls, but patients with fibromyalgia taking opioids did not. Despite limitations including the use of additional non-opioid medications by fibromyalgia patients taking opioids, these preliminary findings suggest relatively "normalized" neural responses to monetary incentives in chronic pain patients who take opioids versus those who do not.

Effects of smoking on patients with chronic pain: a propensity-weighted analysis on the Collaborative Health Outcomes Information Registry.

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 < 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.

Factors Associated With Acute Pain Estimation, Postoperative Pain Resolution, Opioid Cessation, and Recovery: Secondary Analysis of a Randomized Clinical Trial.

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 (≤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 < .001) and delayed opioid cessation (HR, 0.52; 95% CI, 0.41-0.67; P < .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 < .001), a history of alcohol or drug abuse treatment (ARR, 1.90; 95% CI, 1.42-2.53; P < .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 < .001), opioid cessation (HR, 0.84; 95% CI, 0.80-0.89; P < .001), and complete surgical recovery (HR, 0.91; 95% CI, 0.86-0.96; P < .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.

Altered Cervical Spinal Cord Resting-State Activity in Fibromyalgia.

OBJECTIVE: Altered afferent input and central neural modulation are thought to contribute to fibromyalgia symptoms, and these processes converge within the spinal cord. We undertook this study to investigate the hypothesis that, using resting-state functional magnetic resonance imaging (rs-fMRI) of the cervical spinal cord, we would observe altered frequency-dependent activity in fibromyalgia. METHODS: Cervical spinal cord rs-fMRI was conducted in fibromyalgia patients (n = 16) and healthy controls (n = 17). We analyzed the amplitude of low-frequency fluctuations (ALFF), a measure of low-frequency oscillatory power, for frequencies of 0.01-0.198 Hz and frequency sub-bands to determine regional and frequency-specific alterations in fibromyalgia. Functional connectivity and graph metrics were also analyzed. RESULTS: As compared to healthy controls (n = 14), greater ventral and lesser dorsal mean ALFF of the cervical spinal cord was observed in fibromyalgia patients ( n = 15) (uncorrected P < 0.05) for frequencies of 0.01-0.198 Hz and all sub-bands. Additionally, lesser mean ALFF within the right dorsal quadrant (corrected P < 0.05) for frequencies of 0.01-0.198 Hz and sub-band frequencies of 0.073-0.198 Hz was observed in fibromyalgia. Regional mean ALFF was not correlated with pain; however, regional lesser mean ALFF was correlated with fatigue in patients (r = 0.763, P = 0.001). Functional connectivity and graph metrics were similar between groups. CONCLUSION: Our results indicate unbalanced activity between the ventral and dorsal cervical spinal cord in fibromyalgia. Increased ventral neural processes and decreased dorsal neural processes may reflect the presence of central sensitization and contribute to fatigue and other bodily symptoms in fibromyalgia.

Succinylcholine Use and Dantrolene Availability for Malignant Hyperthermia Treatment: Database Analyses and Systematic Review.

BACKGROUND: Although dantrolene effectively treats malignant hyperthermia (MH), discrepant recommendations exist concerning dantrolene availability. Whereas Malignant Hyperthermia Association of the United States guidelines state dantrolene must be available within 10 min of the decision to treat MH wherever volatile anesthetics or succinylcholine are administered, a Society for Ambulatory Anesthesia protocol permits Class B ambulatory facilities to stock succinylcholine for airway rescue without dantrolene. The authors investigated (1) succinylcholine use rates, including for airway rescue, in anesthetizing/sedating locations; (2) whether succinylcholine without volatile anesthetics triggers MH warranting dantrolene; and (3) the relationship between dantrolene administration and MH morbidity/mortality. METHODS: The authors performed focused analyses of the Multicenter Perioperative Outcomes Group (2005 through 2016), North American MH Registry (2013 through 2016), and Anesthesia Closed Claims Project (1970 through 2014) databases, as well as a systematic literature review (1987 through 2017). The authors used difficult mask ventilation (grades III and IV) as a surrogate for airway rescue. MH experts judged dantrolene treatment. For MH morbidity/mortality analyses, the authors included U.S. and Canadian cases that were fulminant or scored 20 or higher on the clinical grading scale and in which volatile anesthetics or succinylcholine were given. RESULTS: Among 6,368,356 queried outcomes cases, 246,904 (3.9%) received succinylcholine without volatile agents. Succinylcholine was used in 46% (n = 710) of grade IV mask ventilation cases (median dose, 100 mg, 1.2 mg/kg). Succinylcholine without volatile anesthetics triggered 24 MH cases, 13 requiring dantrolene. Among 310 anesthetic-triggered MH cases, morbidity was 20 to 37%. Treatment delay increased complications every 10 min, reaching 100% with a 50-min delay. Overall mortality was 1 to 10%; 15 U.S. patients died, including 4 after anesthetics in freestanding facilities. CONCLUSIONS: Providers use succinylcholine commonly, including during difficult mask ventilation. Succinylcholine administered without volatile anesthetics may trigger MH events requiring dantrolene. Delayed dantrolene treatment increases the likelihood of MH complications. The data reported herein support stocking dantrolene wherever succinylcholine or volatile anesthetics may be used.

Altered prefrontal correlates of monetary anticipation and outcome in chronic pain.

Chronic pain may alter both affect- and value-related behaviors, which represents a potentially treatable aspect of chronic pain experience. Current understanding of how chronic pain influences the function of brain reward systems, however, is limited. Using a monetary incentive delay task and functional magnetic resonance imaging (fMRI), we measured neural correlates of reward anticipation and outcomes in female participants with the chronic pain condition of fibromyalgia (N = 17) and age-matched, pain-free, female controls (N = 15). We hypothesized that patients would demonstrate lower positive arousal, as well as altered reward anticipation and outcome activity within corticostriatal circuits implicated in reward processing. Patients demonstrated lower arousal ratings as compared with controls, but no group differences were observed for valence, positive arousal, or negative arousal ratings. Group fMRI analyses were conducted to determine predetermined region of interest, nucleus accumbens (NAcc) and medial prefrontal cortex (mPFC), responses to potential gains, potential losses, reward outcomes, and punishment outcomes. Compared with controls, patients demonstrated similar, although slightly reduced, NAcc activity during gain anticipation. Conversely, patients demonstrated dramatically reduced mPFC activity during gain anticipation-possibly related to lower estimated reward probabilities. Further, patients demonstrated normal mPFC activity to reward outcomes, but dramatically heightened mPFC activity to no-loss (nonpunishment) outcomes. In parallel to NAcc and mPFC responses, patients demonstrated slightly reduced activity during reward anticipation in other brain regions, which included the ventral tegmental area, anterior cingulate cortex, and anterior insular cortex. Together, these results implicate altered corticostriatal processing of monetary rewards in chronic pain.

Predictors of Daily Pain Medication Use in Individuals with Recurrent Back Pain.

PURPOSE: A key component to chronic pain management regimens is the use of analgesic medications. Psychological factors, such as mood states, may also affect the use of pain medications for individuals with chronic pain, but few observational studies have examined how these factors may predict pain medication use at the daily level. METHODS: Daily assessments from 104 individuals with back pain were used to examine fluctuations in daily pain intensity, mood, sleep quality, and physical activity as predictors of the likelihood of pain medication (opioid and non-opioid) use and levels of medication use on the same day. RESULTS: Pain intensity and mood ratings significantly predicted whether participants used pain medication on the same day, while only pain intensity predicted whether participants used more medication than usual. Further, current opioid users were more likely to increase the amount of their medication use on days of higher pain. DISCUSSION: This article identifies fluctuations in daily pain intensity and mood as salient predictors of daily pain medication use in individuals with recurrent back pain. The current study is among the first to highlight both pain and mood states as predictors of daily pain medication use in individuals with back pain, though future studies may expand on these findings through the use of higher-resolution daily medication use variables.

Effect of Perioperative Gabapentin on Postoperative Pain Resolution and Opioid Cessation in a Mixed Surgical Cohort: A Randomized Clinical Trial.

Importance: Guidelines recommend using gabapentin to decrease postoperative pain and opioid use, but significant variation exists in clinical practice. Objective: To determine the effect of perioperative gabapentin on remote postoperative time to pain resolution and opioid cessation. Design, Setting, and Participants: A randomized, double-blind, placebo-controlled trial of perioperative gabapentin was conducted at a single-center, tertiary referral teaching hospital. A total of 1805 patients aged 18 to 75 years scheduled for surgery (thoracotomy, video-assisted thoracoscopic surgery, total hip replacement, total knee replacement, mastectomy, breast lumpectomy, hand surgery, carpal tunnel surgery, knee arthroscopy, shoulder arthroplasty, and shoulder arthroscopy) were screened. Participants were enrolled from May 25, 2010, to July 25, 2014, and followed up for 2 years postoperatively. Intention-to-treat analysis was used in evaluation of the findings. Interventions: Gabapentin, 1200 mg, preoperatively and 600 mg, 3 times a day postoperatively or active placebo (lorazepam, 0.5 mg) preoperatively followed by inactive placebo postoperatively for 72 hours. Main Outcomes and Measures: Primary outcome was time to pain resolution (5 consecutive reports of 0 of 10 possible levels of average pain at the surgical site on the numeric rating scale of pain). Secondary outcomes were time to opioid cessation (5 consecutive reports of no opioid use) and the proportion of participants with continued pain or opioid use at 6 months and 1 year. Results: Of 1805 patients screened for enrollment, 1383 were excluded, including 926 who did not meet inclusion criteria and 273 who declined to participate. Overall, 8% of patients randomized were lost to follow-up. A total of 202 patients were randomized to active placebo and 208 patients were randomized to gabapentin in the intention-to-treat analysis (mean [SD] age, 56.7 [11.7] years; 256 (62.4%) women and 154 (37.6%) men). Baseline characteristics of the groups were similar. Perioperative gabapentin did not affect time to pain cessation (hazard ratio [HR], 1.04; 95% CI, 0.82-1.33; P = .73) in the intention-to-treat analysis. However, participants receiving gabapentin had a 24% increase in the rate of opioid cessation after surgery (HR, 1.24; 95% CI, 1.00-1.54; P = .05). No significant differences were noted in the number of adverse events as well as the rate of medication discontinuation due to sedation or dizziness (placebo, 42 of 202 [20.8%]; gabapentin, 52 of 208 [25.0%]). Conclusions and Relevance: Perioperative administration of gabapentin had no effect on postoperative pain resolution, but it had a modest effect on promoting opioid cessation after surgery. The routine use of perioperative gabapentin may be warranted to promote opioid cessation and prevent chronic opioid use. Optimal dosing and timing of perioperative gabapentin in the context of specific operations to decrease opioid use should be addressed in further research. Trial Registration: clinicaltrials.gov Identifier: NCT01067144.

Brain signature and functional impact of centralized pain: a multidisciplinary approach to the study of chronic pelvic pain (MAPP) network study.

Chronic pain is often measured with a severity score that overlooks its spatial distribution across the body. This widespread pain is believed to be a marker of centralization, a central nervous system process that decouples pain perception from nociceptive input. Here, we investigated whether centralization is manifested at the level of the brain using data from 1079 participants in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network (MAPP) study. Participants with a clinical diagnosis of urological chronic pelvic pain syndrome (UCPPS) were compared to pain-free controls and patients with fibromyalgia, the prototypical centralized pain disorder. Participants completed questionnaires capturing pain severity, function, and a body map of pain. A subset (UCPPS N = 110; fibromyalgia N = 23; healthy control N = 49) underwent functional and structural magnetic resonance imaging. Patients with UCPPS reported pain ranging from localized (pelvic) to widespread (throughout the body). Patients with widespread UCPPS displayed increased brain gray matter volume and functional connectivity involving sensorimotor and insular cortices (P < 0.05 corrected). These changes translated across disease diagnoses as identical outcomes were present in patients with fibromyalgia but not pain-free controls. Widespread pain was also associated with reduced physical and mental function independent of pain severity. Brain pathology in patients with centralized pain is related to pain distribution throughout the body. These patients may benefit from interventions targeting the central nervous system.

Factors associated with prescription opioid misuse in a cross-sectional cohort of patients with chronic non-cancer pain.

OBJECTIVE: To examine demographic features, psychosocial characteristics, pain-specific behavioral factors, substance abuse history, sleep, and indicators of overall physical function as predictors of opioid misuse in patients presenting for new patient evaluation at a tertiary pain clinic. METHODS: Overall, 625 patients with chronic non-cancer pain prospectively completed the Collaborative Health Outcomes Information Registry, assessing pain catastrophizing, National Institutes of Health Patient-Reported Outcomes Measurement Information System standardized measures (pain intensity, pain behavior, pain interference, physical function, sleep disturbance, sleep-related impairment, anger, depression, anxiety, and fatigue), and substance use history. Additional information regarding current opioid prescriptions and opioid misuse was examined through retrospective chart review. RESULTS: In all, 41 (6.6%) patients presented with some indication of prescription opioid misuse. In the final multivariable logistic regression model, those with a history of illicit drug use (odds ratio [OR] 5.45, 95% confidence interval [CI] 2.48-11.98, p<0.0001) and a current opioid prescription (OR 4.06, 95% CI 1.62-10.18, p=0.003) were at elevated risk for opioid misuse. Conversely, every 1-h increase in average hours of nightly sleep decreased the risk of opioid misuse by 20% (OR 0.80, 95% CI 0.66-0.97, p=0.02). CONCLUSION: These findings indicate the importance of considering substance use history, current opioid prescriptions, and sleep in universal screening of patients with chronic non-cancer pain for opioid misuse. Future work should target longitudinal studies to verify the causal relationships between these variables and subsequent opioid misuse.

Unique Microstructural Changes in the Brain Associated with Urological Chronic Pelvic Pain Syndrome (UCPPS) Revealed by Diffusion Tensor MRI, Super-Resolution Track Density Imaging, and Statistical Parameter Mapping: A MAPP Network Neuroimaging Study.

Studies have suggested chronic pain syndromes are associated with neural reorganization in specific regions associated with perception, processing, and integration of pain. Urological chronic pelvic pain syndrome (UCPPS) represents a collection of pain syndromes characterized by pelvic pain, namely Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) and Interstitial Cystitis/Painful Bladder Syndrome (IC/PBS), that are both poorly understood in their pathophysiology, and treated ineffectively. We hypothesized patients with UCPPS may have microstructural differences in the brain compared with healthy control subjects (HCs), as well as patients with irritable bowel syndrome (IBS), a common gastrointestinal pain disorder. In the current study we performed population-based voxel-wise DTI and super-resolution track density imaging (TDI) in a large, two-center sample of phenotyped patients from the multicenter cohort with UCPPS (N = 45), IBS (N = 39), and HCs (N = 56) as part of the MAPP Research Network. Compared with HCs, UCPPS patients had lower fractional anisotropy (FA), lower generalized anisotropy (GA), lower track density, and higher mean diffusivity (MD) in brain regions commonly associated with perception and integration of pain information. Results also showed significant differences in specific anatomical regions in UCPPS patients when compared with IBS patients, consistent with microstructural alterations specific to UCPPS. While IBS patients showed clear sex related differences in FA, MD, GA, and track density consistent with previous reports, few such differences were observed in UCPPS patients. Heat maps illustrating the correlation between specific regions of interest and various pain and urinary symptom scores showed clustering of significant associations along the cortico-basal ganglia-thalamic-cortical loop associated with pain integration, modulation, and perception. Together, results suggest patients with UCPPS have extensive microstructural differences within the brain, many specific to syndrome UCPPS versus IBS, that appear to be localized to regions associated with perception and integration of sensory information and pain modulation, and seem to be a consequence of longstanding pain.