Stephen Bruehl’s research while affiliated with Vanderbilt University and other places

Objectives This review and meta-analysis evaluated the impact of diagnostic criteria and clinical phenotypes on quantitative sensory testing (QST) outcomes in patients with complex regional pain syndrome (CRPS). Methods Eight databases were searched based on a previously published protocol. Forty studies comparing QST outcomes between CRPS-I versus II, warm versus cold CRPS, upper versus lower limb CRPS, males versus females, or using Budapest versus older IASP criteria were included. Results Studies investigating QST differences between CRPS-I versus II (n = 4), between males versus females (n = 2), and between upper and lower limb CRPS (n = 2) showed no significant differences. Four studies compared QST outcomes in warm versus cold CRPS, showing heat hyperalgesia in warm CRPS, with thermal and mechanical sensory loss in cold CRPS. Although CRPS diagnosed using the Budapest criteria (24 studies) versus 1994 IASP criteria (13 studies) showed similar sensory profiles, there was significant heterogeneity and low quality of evidence in the latter. Conclusion Based on the findings of this review, classifying CRPS according to presence or absence of nerve lesion into CRPS-I and II, location (upper or lower limb) or according to sex might not be clinically relevant as all appear to have comparable sensory profiles that might suggest similar underlying mechanisms. In contrast, warm versus cold phenotypes exhibited clear differences in their associated QST sensory profiles. To the extent that differences in underlying mechanisms might lead to differential treatment responsiveness, it appears unlikely that CRPS-I vs. II, CRPS location, or patient sex would prove useful in guiding clinical management.

Anesthetists and anesthesiologists are frequently in the unique position of administering high-volume resuscitation in the setting of hemorrhage, hypovolemia, or vasodilatory shock. The ability to rapidly infuse intravenous (IV) fluid solutions differs vastly for different types and sizes of IV access. In patients that may require rapid large volume resuscitation, it is critical to understand the capacity of existing IV devices. Selecting the most appropriate IV access for patients can be paramount in preventing hypotension, end organ dysfunction, and even death. This article objectively reviews and compares the flow rates of commonly used central and peripheral intravenous devices to demonstrate the influence of catheter length and radius.

Objectives Accurately assessing the probability of significant respiratory depression following opioid administration can potentially enhance perioperative risk assessment and pain management. We developed and validated a risk prediction tool to estimate the probability of significant respiratory depression (indexed by naloxone administration) in patients undergoing noncardiac surgery. Design Retrospective cohort study. Setting Single academic centre. Participants We studied n=63 084 patients (mean age 47.1±18.2 years; 50% men) who underwent emergency or elective non-cardiac surgery between 1 January 2007 and 30 October 2017. Interventions A derivation subsample reflecting two-thirds of available patients (n=42 082) was randomly selected for model development, and associations were identified between predictor variables and naloxone administration occurring within 5 days following surgery. The resulting probability model for predicting naloxone administration was then cross-validated in a separate validation cohort reflecting the remaining one-third of patients (n=21 002). Results The rate of naloxone administration was identical in the derivation (n=2720 (6.5%)) and validation (n=1360 (6.5%)) cohorts. The risk prediction model identified female sex (OR: 3.01; 95% CI: 2.73 to 3.32), high-risk surgical procedures (OR: 4.16; 95% CI: 3.78 to 4.58), history of drug abuse (OR: 1.81; 95% CI: 1.52 to 2.16) and any opioids being administered on a scheduled rather than as-needed basis (OR: 8.31; 95% CI: 7.26 to 9.51) as risk factors for naloxone administration. Advanced age (OR: 0.971; 95% CI: 0.968 to 0.973), opioids administered via patient-controlled analgesia pump (OR: 0.55; 95% CI: 0.49 to 0.62) and any scheduled non-opioids (OR: 0.63; 95% CI: 0.58 to 0.69) were associated with decreased risk of naloxone administration. An overall risk prediction model incorporating the common clinically available variables above displayed excellent discriminative ability in both the derivation and validation cohorts (c-index=0.820 and 0.814, respectively). Conclusion Our cross-validated clinical predictive model accurately estimates the risk of serious opioid-related respiratory depression requiring naloxone administration in postoperative patients.

There have been some modest recent advancements in the research of Complex Regional Pain Syndrome, yet the amount and quality of the work in this complicated multifactorial disease remains low (with some notable exceptions; e.g., the recent work on the dorsal root ganglion stimulation). The semi-systematic (though in some cases narrative) approach to review is necessary so that we might treat our patients while waiting for "better research." This semi-systematic review was conducted by experts in the field, (deliberately) some of whom are promising young researchers supplemented by the experience of "elder statesman" researchers, who all mention the system they have used to examine the literature. What we found is generally low- to medium-quality research with small numbers of subjects; however, there are some recent exceptions to this. The primary reason for this paucity of research is the fact that this is a rare disease, and it is very difficult to acquire a sufficient sample size for statistical significance using traditional statistical approaches. Several larger trials have failed, probably due to using the broad general diagnostic criteria (the "Budapest" criteria) in a multifactorial/multi-mechanism disease. Responsive subsets can often be identified in these larger trials, but not sufficient to achieve statistically significant results in the general diagnostic grouping. This being the case the authors have necessarily included data from less compelling protocols, including trials such as case series and even in some instances case reports/empirical information. In the humanitarian spirit of treating our often desperate patients with this rare syndrome, without great evidence, we must take what data we can find (as in this work) and tailor a treatment regime for each patient.

Objective Complex regional pain syndrome (CRPS) is usually triggered by trauma or a surgical procedure, and it typically becomes an established one after an intense inflammatory process with chronic pain and edema as the main symptoms. Available treatments for CRPS have low efficacy. This study aimed to evaluate the clinical and immunoregulatory effects of omega-3 polyunsaturated fatty acid (PUFA) supplementation on paw edema and anti- and pro-inflammatory cytokines and macrophage phenotypes in the chronic post-ischemia pain (CPIP) preclinical model of CRPS-Type I.Methods Female Swiss mice were supplemented with omega-3, corn oil, or saline and then submitted to the CPIP model of ischemia/reperfusion (I/R) injury. Supplementation was carried out for 30 days prior to and up to 2 or 15 days after the induction of CPIP, according to experimental protocols. The supplementation protocol included 1,500 mg/kg of omega-3 or corn oil through an intragastric route (gavage). Paw edema, interleukin- (IL-) 4, IL-10, transforming growth factor-β1 (TGF-β1), monocyte chemotactic protein-1 (MCP-1), and tumor necrosis factor (TNF) were then measured in the paw skin and muscle by enzyme-linked immunosorbent assay (ELISA), and macrophage phenotypes (M1 and M2) assessed in the paw muscle by Western blotting.ResultsThe CPIP model induced an increase in paw thickness up to 72 h post-I/R. Mice supplemented with omega-3 compared to the saline group displayed reduced edema but neither altered skin IL-4 or skin and muscle TGF-β1, TNF, and MCP-1 concentrations, nor did they exhibit significantly altered muscle macrophage phenotype on the 2nd-day post-CPIP. However, omega-3 supplementation reversed the I/R-related reduction in IL-4 in the paw muscle compared to groups supplemented with saline and corn oil. Furthermore, omega-3 promoted the reduction of IL-10 levels in the paw skin, compared to animals with lesions supplemented with saline, until the 2nd-day post-CPIP. On the 15th day post-CPIP, IL-10 was significantly increased in the muscle of animals supplemented with omega-3 compared to the saline group.Conclusion The results suggest that omega-3 PUFA supplementation has anti-inflammatory effects in the CPIP model of CRPS-Type I, significantly reducing paw edema and regulating concentrations of anti-inflammatory cytokines, including IL-4 and IL-10.

Background: Accurately assessing the probability of significant respiratory depression following opioid administration can potentially enhance perioperative risk assessment and pain management. We developed and validated a risk prediction tool to estimate the probability of significant respiratory depression (indexed by naloxone administration) in patients undergoing noncardiac surgery. Methods: We studied n=63,084 patients (mean age 47.1±18.2 years; 50% male) who underwent emergency or elective noncardiac surgery between January 1st, 2007 and October 30th, 2017 at Vanderbilt University Medical Center. A derivation subsample reflecting two-thirds of available patients (n=42,082) was randomly selected for model development, and associations were identified between predictor variables and naloxone administration occurring within 5 days following surgery. The resulting probability model for predicting naloxone administration was then cross-validated in a separate validation cohort reflecting the remaining one-third of patients (n=21,002). Results: The rate of naloxone administration was identical in the derivation (n = 2,720 [6.5%]) and validation (n = 1,360 [6.5%]) cohorts. The risk prediction model identified female sex (Odds Ratio [OR]: 3.01; 95% confidence interval [CI]: 2.73-3.32), high-risk surgical procedures (OR: 4.16; 95% CI: 3.78-4.58), history of drug abuse (OR: 1.81; 95% CI: 1.52-2.16), and any opioids being administered on a scheduled rather than as-needed basis (OR: 8.31; 95% CI: 7.26-9.51) as risk factors for naloxone administration. Advanced age (OR: 0.40; 95% CI: 0.36-0.43), opioids administered via patient-controlled analgesia pump (OR: 0.55; 95% CI:0.49-0.62), and any scheduled non-opioids (OR: 0.63; 95% CI: 0.58-0.69) were associated with decreased risk of naloxone administration. An overall risk-prediction model incorporating the common clinically-available variables above displayed excellent discriminative ability both the derivation and validation cohorts (c-index = 0.820 and 0.814, respectively). Conclusion: Our cross-validated clinical predictive model accurately estimates the risk of serious opioid-related respiratory depression requiring naloxone administration in postoperative patients. In the precision medicine context, it may prove useful in facilitating selection of opioid-sparing pain management strategies for high-risk surgical patients.

Factors contributing to development of Complex Regional Pain Syndrome (CRPS) are not fully understood. This study examined possible epigenetic mechanisms that may contribute to CRPS following traumatic injury. DNA methylation profiles were compared between individuals developing CRPS (n=9) and those developing non-CRPS neuropathic pain (n=38) after undergoing amputation following military trauma. Linear Models for Microarray (LIMMA) analyses revealed 48 differentially methylated cytosine-phosphate-guanine dinucleotide (CpG) sites between groups (unadjusted p's<.005), with the top gene COL11A1 meeting Bonferroni-adjusted p<0.05. The second largest differential methylation was observed for the HLA-DRB6 gene, an immune-related gene linked previously to CRPS in a small gene expression study. For all but seven of the significant CpG sites, the CRPS group was hypomethylated. Numerous functional Gene Ontology-Biological Process categories were significantly enriched [FDR (q value)<.15], including multiple immune-related categories (e.g., activation of immune response, immune system development, regulation of immune system processes, antigen processing and presentation). Differentially methylated genes were more highly connected in human protein-protein networks than expected by chance (p<.05), supporting the biological relevance of the findings. Results were validated in an independent sample linking a DNA biobank with electronic health records (n=126 CRPS phenotype, n=19,768 non-CRPS chronic pain phenotype). Analyses using PrediXcan methodology indicated differences in the genetically-determined component of gene expression in 7 of 48 genes identified in methylation analyses (p's<.02). Results suggest immune- and inflammatory-related factors might confer risk for developing CRPS following traumatic injury. Validation findings demonstrate the potential of using electronic health records linked to DNA for genomic studies of CRPS.

Objective: Evidence supports high rates of co-occurrence of posttraumatic stress disorder (PTSD) and chronic pain disorders involving central sensitization (CS). The nature of this relationship, however, remains relatively unexplored. In this study, we aimed to (1) assess how both trauma exposure and current PTSD symptoms are related to clinical manifestations of CS, and (2) test whether PTSD symptoms explain the relationship between trauma exposure and CS. Because experiential avoidance has been shown to impact the relationship between trauma and health outcomes, we (3) explored experiential avoidance as a possible mediator or moderator of the trauma-CS relationship. Methods: A sample of 202 adult patients (79% female) with chronic pain completed validated self-report measures of trauma exposure, current PTSD symptoms, experiential avoidance, and three manifestations of CS: widespread pain, greater pain severity, and polysomatic symptom reporting. We used path analysis and multivariate regression to assess our study aims. Results: Both trauma exposure and PTSD symptoms were significantly associated with all three clinical indicators of CS. PTSD symptoms partially explained the relationship between trauma exposure and widespread pain, pain intensity, and polysomatic symptoms. Experiential avoidance did not mediate or moderate the trauma-CS relationship. Conclusion: Our findings suggest that trauma exposure is linked to elevated clinical markers of CS, but a critical factor in this relationship is the mediating effect of current PTSD symptoms.

Background: Acute vaso-occlusive pain episodes in sickle cell disease (SCD) are associated with increased rates of hospitalization and early mortality. Despite the observation that women have higher rates of acute vaso-occlusive pain episodes than men, sex-specific risk factors for acute vaso-occlusive pain have not been identified. We tested the hypothesis that acute vaso-occlusive pain is temporally associated with the onset of menstruation in women with SCD. Methods: Initially, using a cross-sectional study design, we administered questionnaires, including validated measures of SCD pain frequency and severity within the last 30 days, as well as menstrual symptoms in a discovery group (n = 103). We then confirmed our findings by administering the same questionnaires online in a replication group (n = 118). A validated questionnaire was used to define dysmenorrhea. Results: In the initial discovery group, 28% (29 of 103) reported acute vaso-occlusive pain episodes temporally associated with menstruation, and 72% (74 of 103) did not. Of the 29 reporting acute vaso-occlusive pain associated with menstruation, 90% (26) and 10% (3) did and did not meet criteria for dysmenorrhea, respectively. In the replication group, 36% (43 of 118) reported acute vaso-occlusive pain temporally associated with menstruation. Of the 43 reporting acute vaso-occlusive pain associated with menstruation, 60% (26) and 40% (17) did and did not meet criteria for dysmenorrhea, respectively. Conclusions: In both the discovery and replication groups, we demonstrate that acute vaso-occlusive pain is temporally associated with the onset of menstruation that women with SCD can distinguish from dysmenorrhea.

Peripheral neuropathic pain is among the most prevalent types of neuropathic pain. No comprehensive peripheral neuropathic pain classification system that incorporates contemporary clinical, diagnostic, biological, and psychological information exists. To address this need, this article covers the taxonomy for 4 focal or segmental peripheral neuropathic pain disorders, as part of the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership and the American Pain Society (APS) collaborative to develop a standardized, evidence-based taxonomy initiative: the ACTTION-APS Pain Taxonomy (AAPT). The disorders—postherpetic neuralgia, persistent posttraumatic neuropathic pain, complex regional pain disorder, and trigeminal neuralgia—were selected because of their clinical and clinical research relevance. The multidimensional features of the taxonomy are suitable for clinical trials and can also facilitate hypothesis-driven case-control and cohort epidemiologic studies. Perspective The AAPT peripheral neuropathic pain taxonomy subdivides the peripheral neuropathic pain disorders into those that are generalized and symmetric and those that are focal or segmental and asymmetric. In this article, we cover the focal and segmental disorders: postherpetic neuralgia, persistent posttraumatic neuropathic pain, complex regional pain disorder, and trigeminal neuralgia. The taxonomy is evidence-based and multidimensional, with the following dimensions: 1) core diagnostic criteria; 2) common features; 3) common medical and psychiatric comorbidities; 4) neurobiological, psychosocial, and functional consequences; and 5) putative neurobiological and psychosocial mechanisms, risk factors, and protective factors.