Self-report Pain Scale Reliability in Veterans and Service Members With Traumatic Brain Injuries Undergoing Inpatient Rehabilitation.

INTRODUCTION: Pain in trauma patients with traumatic brain injury (TBI) may heighten cognitive-behavioral impairment and impede rehabilitation efforts. Multiple self-report pain assessment tools have been shown reliable in cognitively intact adults and children but are understudied in the cognitively impaired, particularly in persons with TBI. The objective of this study was to assess the utility and reliability of four pain assessment instruments among TBI patients during inpatient rehabilitation and the influence of cognitive impairment. METHODS: Participants self-completed four pain intensity measures, the Verbal Descriptor Scale, Faces Pain Scale (Faces), Numerical Rating Scale (NRS), and Color-Enhanced Visual Analog Scale (CAS), during five study visits over a 2-week period. Data were collected on time to completion and most preferred pain measure. To assess scale reliability, participants re-rated their current pain. To assess scale responsiveness, standard mean response was measured across time and a worst past pain experience was rated. Cognitive impairment was assessed with the Memory, Orientation, and Amnesia Test. RESULTS: The NRS was the most preferred measure by participants at every time point in the study. Mean pain measure completion time for all measures was under 11 seconds and did not significantly change during the study period. All scales showed very high test-retest reliability, with very strong correlations. Standard mean response from day 0 to 14 ranged from 0.387 to 0.532 across the scales. When stratified by cognitive impairment, the mean scores were consistently nominally higher for impaired participants, reaching statistical significance only for the CAS and Faces at baseline. In the cognitive impaired group, reliability for the Faces showed some weakening, as did the VAS to a milder degree. CONCLUSIONS: All four pain measures demonstrated good utility, very high test-retest reliability, and satisfactory responsiveness. Greater cognitive impairment was associated with elevated pain ratings, especially in the Faces and CAS. The NRS was the most preferred by patients, regardless of cognitive impairment level.

Pediatric Ventilator-Associated Events: Analysis of the Pediatric Ventilator-Associated Infection Data.

OBJECTIVES: To compare the prevalence of infection applying the proposed pediatric ventilator-associated events criteria versus clinician-diagnosed ventilator-associated infection to subjects in the pediatric ventilator-associated infection study. DESIGN: Analysis of prospectively collected data from the pediatric ventilator-associated infection study. SETTING: PICUs of 47 hospitals in the United States, Canada, and Australia. PATIENTS: Two-hundred twenty-nine children ventilated for greater than 48 hours who had respiratory secretion cultures performed to evaluate for suspected ventilator-associated infection. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Applying the proposed pediatric ventilator-associated event criteria, 15 of 229 subjects in the ventilator-associated infection study qualified as "ventilator-associated condition" and five of 229 (2%) met criteria for "infection-related ventilator-associated complication." This was compared with 89 of 229 (39%) diagnosed as clinical ventilator-associated infection (Kappa = 0.068). Ten of 15 subjects identified as ventilator-associated condition did not meet criteria for infection-related ventilator-associated complication primarily because they did not receive 4 days of antibiotics. Ventilator-associated condition subjects were similar demographically to nonventilator-associated condition subjects and had similar mortality (13% vs 10%), PICU-free days (6.9 ± 7.7; interquartile range, 0-14 vs 9.8 ± 9.6; interquartile range, 0-19; p = 0.25), but fewer ventilator-free days (6.6 ± 9.3; interquartile range, 1-15 vs 12.4 ± 10.7; interquartile range, 0-22; p = 0.04). The clinical ventilator-associated infection diagnosis in the ventilator-associated infection study was associated with fewer PICU-free days but no difference in mortality or ventilator-free days. CONCLUSIONS: The ventilator-associated event criteria appear to be insensitive to the clinical diagnosis of ventilator-associated infection. Differentiation between ventilator-associated condition and infection-related ventilator-associated complication was primarily determined by the clinician decision to treat with antibiotics rather than clinical signs and symptoms. The utility of the proposed pediatric ventilator-associated event criteria as a surrogate for ventilator-associated infection criteria is unclear.

Pain and chronic mild traumatic brain injury in the US military population: a Chronic Effects of Neurotrauma Consortium study.

PRIMARY OBJECTIVES: To describe the association between mild traumatic brain injury (mTBI) and pain intensity and pain interference outcomes while accounting for potential confounders and mediators including environmental factors and comorbidities in a cohort of US Veterans of the Iraq and Afghanistan wars. RESEARCH DESIGN: Cross-sectional snapshot of baseline data from a prospective, longitudinal study. METHODS: Effects of mTBI on pain intensity and pain interference were compared between participants with or without mTBI exposure. Data were analysed using covariate-adjusted regression analyses as well as structural equation modelling (SEM) methods to assess the robustness of findings across different modelling assumptions. As results of the two approaches were consistent with respect to the overall association between mTBI exposure and pain, the results focus primarily on the SEM findings. RESULTS: The mTBI exposed group reported significantly greater indices of post-traumatic stress disorder (PTSD), depression, anxiety and sleep disturbance. After accounting for other factors, mTBI exposure was significantly, but indirectly associated with the pain interference and pain intensity outcomes. CONCLUSIONS: mTBI is strongly associated with pain intensity and pain interference in this sample. However, the effect appears to be mediated by other common mTBI comorbidities: PTSD, depression, anxiety and sleep disturbance.

A one-pot multicomponent approach to a new series of morphine derivatives and their biological evaluation.

A novel and facile domino reaction has been developed to synthesize a variety of new derivatives from hydromorphone, amines and paraformaldehyde in good yields in a catalyst-free fashion with high atom efficiency. The products show a mixed MOR/DOR biological characteristic which makes them valuable for further study as opioid analgesics.

Pediatric Ventilator-Associated Infections: The Ventilator-Associated INfection Study.

OBJECTIVE: Suspected ventilator-associated infection is the most common reason for antibiotics in the PICU. We sought to characterize the clinical variables associated with continuing antibiotics after initial evaluation for suspected ventilator-associated infection and to determine whether clinical variables or antibiotic treatment influenced outcomes. DESIGN: Prospective, observational cohort study conducted in 47 PICUs in the United States, Canada, and Australia. Two hundred twenty-nine pediatric patients ventilated more than 48 hours undergoing respiratory secretion cultures were enrolled as "suspected ventilator-associated infection" in a prospective cohort study, those receiving antibiotics of less than or equal to 3 days were categorized as "evaluation only," and greater than 3 days as "treated." Demographics, diagnoses, comorbidities, culture results, and clinical data were compared between evaluation only and treated subjects and between subjects with positive versus negative cultures. SETTING: PICUs in 47 hospitals in the United States, Canada, and Australia. SUBJECTS: All patients undergoing respiratory secretion cultures during the 6 study periods. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Treated subjects differed from evaluation-only subjects only in frequency of positive cultures (79% vs 36%; p < 0.0001). Subjects with positive cultures were more likely to have chronic lung disease, tracheostomy, and shorter PICU stay, but there were no differences in ventilator days or mortality. Outcomes were similar in subjects with positive or negative cultures irrespective of antibiotic treatment. Immunocompromise and higher Pediatric Logistic Organ Dysfunction scores were the only variables associated with mortality in the overall population, but treated subjects with endotracheal tubes had significantly lower mortality. CONCLUSIONS: Positive respiratory cultures were the primary determinant of continued antibiotic treatment in children with suspected ventilator-associated infection. Positive cultures were not associated with worse outcomes irrespective of antibiotic treatment although the lower mortality in treated subjects with endotracheal tubes is notable. The necessity of continuing antibiotics for a positive respiratory culture in suspected ventilator-associated infection requires further study.

Discovery of novel antinociceptive α-conotoxin analogues from the direct in vivo screening of a synthetic mixture-based combinatorial library.

Marine cone snail venoms consist of large, naturally occurring combinatorial libraries of disulfide-constrained peptide neurotoxins known as conotoxins, which have profound potential in the development of analgesics. In this study, we report a synthetic combinatorial strategy that probes the hypervariable regions of conotoxin frameworks to discover novel analgesic agents by utilizing high diversity mixture-based positional-scanning synthetic combinatorial libraries (PS-SCLs). We hypothesized that the direct in vivo testing of these mixture-based combinatorial library samples during the discovery phase would facilitate the identification of novel individual compounds with desirable antinociceptive profiles while simultaneously eliminating many compounds with poor activity or liabilities of locomotion and respiration. A PS-SCL was designed based on the α-conotoxin RgIA-ΔR n-loop region and consisted of 10,648 compounds systematically arranged into 66 mixture samples. Mixtures were directly screened in vivo using the mouse 55 °C warm-water tail-withdrawal assay, which allowed deconvolution of amino acid residues at each position that confer antinociceptive activity. A second generation library of 36 individual α-conotoxin analogues was synthesized using systematic combinations of amino acids identified from PS-SCL deconvolution and further screened for antinociceptive activity. Six individual analogues exhibited comparable antinociceptive activity to that of the recognized analgesic α-conotoxin RgIA-ΔR, and were selected for further examination of antinociceptive, respiratory, and locomotor effects. Three lead compounds were identified that produced dose-dependent antinociception without significant respiratory depression or decreased locomotor activity. Our results represent a unique approach for rapidly developing novel lead α-conotoxin analogues as low-liability analgesics with promising therapeutic potential.

Inhibition of Gßγ-subunit signaling potentiates morphine-induced antinociception but not respiratory depression, constipation, locomotion, and reward.

Inhibition of Gßγ-subunit signaling to phospholipase C ß3 has been shown to potentiate morphine-mediated antinociception while attenuating the development of tolerance and dependence in mice. The objective of this study was to determine the effect of Gßγ-subunit inhibition on antinociception and other pharmacological effects, such as respiratory depression, constipation, and hyperlocomotion, mediated by the µ-opioid receptor. The Gßγ-subunit inhibitor, gallein, was administered to C57BL/6J mice by intraperitoneal injection before morphine, and data were compared with mice treated with vehicle, morphine, or gallein alone. Morphine-induced antinociception was measured using the 55°C warm-water tail-withdrawal test. Pretreatment with gallein produced a dose-dependent potentiation of morphine-mediated antinociception, producing up to a 10-fold leftward shift in the morphine dose-response curve and extending the duration of antinociception induced by a single dose of morphine. Gallein pretreatment also prevented acute antinociceptive tolerance induced by morphine. In contrast, the dose-dependent respiratory depression and hyperlocomotion induced by morphine were not potentiated by gallein pretreatment. Similarly, gallein pretreatment did not potentiate morphine-conditioned place preference responses or morphine-induced constipation, as measured as a reduction in excreta. These results suggest that selectively inhibiting Gßγ-mediated signaling may selectively increase µ-opioid receptor-mediated antinociception without matching increases in adverse physiological effects.

A preliminary study of psychiatric, familial, and medical characteristics of high-utilizing sickle cell disease patients.

OBJECTIVES: To identify demographic, medical, and psychosocial characteristics that distinguished sickle cell disease (SCD) patients who were frequent utilizers of urgent or emergent care resources from low-utilizing patients. METHODS: Patients at a large urban comprehensive SCD treatment center were recruited from clinic or during urgent care visits. Participants who were high utilizers, defined as having >4 acute or emergency care visits in the prior 12 months, were compared with patients with more typical utilization patterns on lifetime complications of SCD, family background, psychiatric history, occupational function, coping, depressive symptoms, and personality. RESULTS: High utilizers were nearly a decade younger on average; despite this they had a similar lifetime history of SCD complications. High-utilizing patients' parents seemed to have greater educational achievement overall. High utilizers reported a nearly 3-fold greater prevalence of psychiatric illness in family members than low utilizers. On other measures, including coping strategies, social support, and personality, the 2 groups were comparable. DISCUSSION: The study strengthens emerging evidence that disease severity, familial factors related to greater parental education, and psychiatric illness are important factors in high care utilization in patients with SCD.

Chronic neuropathic pain in mice reduces µ-opioid receptor-mediated G-protein activity in the thalamus.

Neuropathic pain is a debilitating condition that is often difficult to treat using conventional pharmacological interventions and the exact mechanisms involved in the establishment and maintenance of this type of chronic pain have yet to be fully elucidated. The present studies examined the effect of chronic nerve injury on µ-opioid receptors and receptor-mediated G-protein activity within the supraspinal brain regions involved in pain processing of mice. Chronic constriction injury (CCI) reduced paw withdrawal latency, which was maximal at 10 days post-injury. [d-Ala2,(N-Me)Phe4,Gly5-OH] enkephalin (DAMGO)-stimulated [(35)S]GTPγS binding was then conducted at this time point in membranes prepared from the rostral ACC (rACC), thalamus and periaqueductal grey (PAG) of CCI and sham-operated mice. Results showed reduced DAMGO-stimulated [(35)S]GTPγS binding in the thalamus and PAG of CCI mice, with no change in the rACC. In thalamus, this reduction was due to decreased maximal stimulation by DAMGO, with no difference in EC(50) values. In PAG, however, DAMGO E(max) values did not significantly differ between groups, possibly due to the small magnitude of the main effect. [(3)H]Naloxone binding in membranes of the thalamus showed no significant differences in B(max) values between CCI and sham-operated mice, indicating that the difference in G-protein activation did not result from differences in µ-opioid receptor levels. These results suggest that CCI induced a region-specific adaptation of µ-opioid receptor-mediated G-protein activity, with apparent desensitization of the µ-opioid receptor in the thalamus and PAG and could have implications for treatment of neuropathic pain.

Chronic constriction injury reduces cannabinoid receptor 1 activity in the rostral anterior cingulate cortex of mice.

The present studies examined the effect of chronic neuropathic pain on cannabinoid receptor density and receptor-mediated G-protein activity within supraspinal brain areas involved in pain processing and modulation in mice. Chronic constriction injury (CCI) produced a significant decrease in WIN 55,212-2-stimulated [(35)S]GTPgammaS binding in membranes prepared from the rostral anterior cingulate cortex (rACC) of CCI mice when compared to sham-operated controls. Saturation binding with [(3)H]SR 141716A in membranes of the rACC showed no significant differences in binding between CCI and sham mice. Analysis of levels of the endocannabinoids anandamide (AEA) or 2-arachidonoylglycerol (2-AG) in the rACC following CCI showed no significant differences between CCI and sham mice. These data suggest that CCI produced desensitization of the cannabinoid 1 receptor in the rACC in the absence of an overall decrease in cannabinoid 1 receptor density or change in levels of AEA or 2-AG. These data are the first to show alterations in cannabinoid receptor function in the rostral anterior cingulate cortex in response to a model of neuropathic pain.

Involvement of the intralaminar parafascicular nucleus in muscarinic-induced antinociception in rats.

The thalamic contribution to cholinergic-induced antinociception was examined by microinjecting the acetylcholine (ACh) agonist carbachol into the intralaminar nucleus parafascicularis (nPf) of rats. Pain behaviors organized at spinal (spinal motor reflexes), medullary (vocalizations during shock), and forebrain (vocalization afterdischarges, VADs) levels of the neuraxis were elicited by noxious tailshock. Carbachol (0.5, 1, and 2 microg/side) administered into nPf produced dose-dependent elevations of vocalization thresholds, but failed to elevate spinal motor reflex threshold. Injections of carbachol into adjacent sites dorsal or ventral to nPf failed to alter vocalization thresholds. Elevations in vocalization thresholds produced by intra-nPf carbachol were reversed in a dose-dependent manner by local administration of the muscarinic receptor antagonist atropine (30 and 60 microg/side). These results provide the first direct evidence supporting the involvement of the intralaminar thalamus in muscarinic-induced antinociception. Results are discussed in terms of the contribution of nPf to the processing of the affective dimension of pain.